Clinical trial NCT04425629
Conditions: COVID-19
Keywords: Coronavirus disease 2019 (COVID-19) Severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) coronavirus
Sponsor: Regeneron Pharmaceuticals
Start date: 2020-06-16; Completion date: 2022-06-09
Enrollment: 10078 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Phase 1

* To evaluate the safety and tolerability of REGN10933+REGN10987 compared to placebo
* To evaluate the virologic efficacy of REGN10933+REGN10987 compared to placebo in reducing viral load of SARS-CoV-2

Phase 2

• To evaluate the virologic efficacy of REGN10933+REGN10987 compared to placebo in reducing viral load of SARS-CoV-2

Phase 3

* Cohort 1 (≥18 Years Old, Not Pregnant at Randomization)

  • To evaluate the clinical efficacy of REGN10933+REGN10987 compared to placebo as measured by COVID-19-related hospitalizations or all-cause death
* Cohort 2 (\<18 Years Old, Not Pregnant at Randomization)

  * To evaluate the safety and tolerability of REGN10933+REGN10987 compared to placebo
  * To further characterize the concentrations of REGN10933 and REGN10987 in serum over time
* Cohort 3 (Pregnant at Randomization) • To evaluate the safety and tolerability of REGN10933+REGN10987

Detailed description:

Arms: arm 1: Low dose or body-weight equivalent for those under 18 years of age.
Interventions: intervention 1: casirivimab+imdevimab combination therapy
Intervention descriptions: intervention 1: Administered intravenously (IV) single dose

Protocol documents:
ICF_000.pdf: 


 
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Beca use t his is a researc h st u d y wit h a n e x peri me ntal dr u g, y o u ma y or ma y n ot be nefit fr o m b ei n g i n 
t he st u d y. T h ere is als o o nl y a li mite d a m o u nt of data  a b o ut t he st u d y dr u g i n p e o ple. E v e n t h o u g h 
patie nts will be c aref ull y watc he d, t he ris ks of recei vi n g t he dr u g are u n k n o w n. S o me of t hese ris ks ma y 
be seri o us or life -t hr eate ni n g. Fi nall y, k ee p i n mi n d t hat y o u ma y ha v e ot her treat me nt o pti o ns if y o u 
c h o ose n ot t o j oi n t he st u d y.  
 
T he c h oic e t o j oi n is u p t o y o u. Y o u will n ot be p e nalize d i n a n y wa y if y o u deci de n ot t o j oi n or if y o u 
lea ve t he st u d y. T he rest of t his f or m pr o vi des m ore i nf or mati o n t o hel p y o u deci de if y o u wa nt t o j oi n. 
 
W h at is t he p ur p ose of t his f or m ?  
Y o u are bei n g as ke d if y o u w o ul d li ke t o j oi n  a researc h st u d y (als o calle d a cli nical trial). T his c o nse nt 
f or m e x plai ns w h y t he st u d y is bei n g d o ne, p ossi ble ris ks a n d be nefits t o y o u, y o ur ri g hts, a n d w hat y o u 
will ha ve t o d o if y o u j oi n. T he c h oic e is u p t o y o u, a n d y o u d o n ot ha v e t o j oi n t he st u d y if y o u d o n ot 
wa nt t o. If y o u deci de t o j oi n, y o u will be as ke d t o si g n a n d date t his f or m, stati n g t hat y o u u n derst a n d 
w hat was e x plai ne d t o y o u a n d t hat y o u a gree t o b e i n t he st u d y. T his is calle d i nf or me d c o nse nt.  
 
T he i nf or me d c o nse nt f or m ma y be deli vere d a n d si g ne d i n pa per f or mat. It ma y als o be deli vere d a n d 
si g ne d el ectr o nicall y (e C o nse nt) if l ocal la ws, re g ulati o ns, a n d st u d y site p olicies all o w t his.  
 
Please rea d t his f or m caref ull y. As k t he st u d y d oct or or staff a n y q uesti o ns y o u ha ve a b o ut  t he st u d y. 
Y o u ca n ta ke a n u nsi g n e d c o p y t o re vie w wit h y o ur pers o nal d oct or, fa mil y, a n d fri e n ds. If y o u a gree t o 
j oi n, y o u will be gi ve n a si g ne d a n d date d c o p y. N o tests will be d o ne u ntil t his f or m is si g ne d. 
 
If y o u d eci de n ot t o j oi n or wit h dra w at a n y ti me, y o u will n ot be pe nalize d or l ose a n y b e nefits t o w hic h 
y o u are ot her wise e ntitle d . 
 
W h o is s p o ns ori n g t his st u d y ?  
Re ge n er o n P har mace uticals, I nc. (“ Re ge ner o n”) is t he s p o ns or of t he st u d y. T his mea ns t h at Re ge ner o n 
is pa yi n g f or t he st u d y, a n d the st u d y d oct or will be pai d b y Re ge ner o n.  
 
Re ge n er o n, its c olla b orat ors or t h ose de vel o pi n g t he st u d y dr u g, a n d t h eir affiliates, re prese nt ati ves, 
a ge nts, a n d c o ntract ors (t he “ Re ge ner o n Parties”), are i n v ol ve d i n t he st u d y. S o me or all of t hes e gr o u ps 
ma y use t h e i nf or mati o n c ollecte d i n t he st u d y t o carr y o ut t he researc h d es cri be d i n t his c o nse nt f or m.  
 
T his st u d y is bei n g re vi e we d b y a n i n de pe n d e nt gr o u p calle d a n i nstit uti o nal re vie w b oar d (I R B) or 
et hics c o m mittee ( E C). T his gr o u p, w hic h is n ot a par t of Re ge ner o n, l o o ks o ut f or t he safet y, welfare, 
a n d ri g hts of p e o ple ta ki n g part i n researc h st u dies. T he I R B or E C re vie wi n g t his st u d y has a p pr o ve d 
t he st u d y. 
 
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W h y is t his st u d y bei n g d o ne ?  
T h is st u d y is researc hi n g t he e x peri me ntal dr u gs R E G N 1 0 9 3 3 an d R E G N 1 0 9 8 7, gi v e n t o get her as a 
si n gle treat me nt i n pe o ple w h o ha ve t he vir us t hat ca uses C O VI D -1 9 ( c o r o navi r us d isease 2 0 1 9). T he  
st u d y is f oc use d o n patie nts w h o are w ell e n o u g h t o g o h o me after t he y h a ve bee n  c o nfir me d t o h a v e t he 
vir us . T he treat me nt will be referre d t o as “st u d y dr u g” i n t his c o nse nt f or m.  
 
T he  st u d y is tr yi n g t o a ns wer se v eral s pe cific researc h q uesti o ns. T hes e i ncl u de:  
 
•  W het her t he st u d y dr u g ca n re d uce le vels of i nfecti o n b y t he vir us  
•  W het her t he st u d y dr u g re d uces t he nee d f or me di cal visit s d ue t o C O VI D -1 9  
•  W h et her a n y seri o us si de effects ma y ha p pe n b eca use of  t he st u d y dr u g 
•  H o w m uc h st u d y dr u g is i n y o ur bl o o d at differe nt ti mes  
•  W het her t he b o d y m a kes its o w n a nti b o dies a gai nst t he st u d y dr u g  
 
W h at are R E G N 1 0 9 3 3 a n d R E G N 1 0 9 8 7 ?  
R E G N 1 0 9 3 3 a n d R E G N 1 0 9 8 7 are “ m o n ocl o nal a nti b o dies.” A nti b o dies are pr otei ns ma de b y i m m u ne 
cells i n y o ur b o d y, a n d t he y tr a vel i n t he bl o o d t o fi g ht i nfecti o ns. A m o n ocl o nal a nti b o d y is a s pecial 
ki n d of a nti b o d y t hat is ma de i n a la b orat or y. Researc h ers c a n desi g n t hese a nti b o dies t o fi g ht s pecific 
t y pes of i nfecti o ns, s uc h as vir uses. 
 
C O VI D -1 9 is ca use d fr o m i nfecti o n b y a c or o na vir us calle d S A R S -C o V -2. T here is a l ot t hat still is 
u n k n o w n a b o ut t his ne w vir us. H o we ver, c or o na vir uses are k n o w n t o use “s p i ke” pr otei ns o n t heir 
s urface t o attac h t o t he cells t he y are i nfecti n g. It is belie ve d t hat t he s pi ke pr otei n all o ws t he vir us t o 
i nfect cells i n t he n ose, t hr oat, l u n gs, a n d ot her tiss ues, lea di n g t o C O VI D-1 9 s y m pt o ms a n d ill ness.  
 
T he a nti b o dies bei n g teste d i n t his st u d y bl oc k t he s pi ke pr otei n fr o m attac hi n g t o h ost cells i n 
la b orat or y tests. 
W he n t he s pi ke pr otei n is bl oc ke d, t he vir us 
ma y n ot be a ble t o i nfect cells. 
R E G N 1 0 9 3 3 a n d R E G N 1 0 9 8 7 w or k t o get h er t o bl oc k t he s pi ke pr otei n at t w o differe nt p laces o n t he 
pr otei n. B y l o w eri n g t he a bilit y of t h e vir us t o i nfect cells, t he st u d y dr u g ma y hel p t o st o p C O VI D -1 9 
s y m pt o ms fr o m getti n g w orse. 
 
T he st u d y dr u g c o m bi nati o n is c o nsi dere d e x peri me ntal, beca use it has n ot bee n a p pr o ve d b y a n y h ealt h 
a ut h ori t y (s u c h as t he U. S. F o o d a n d Dr u g A d mi nistrati o n, or F D A) t o treat C O VI D-1 9.  
 
T he st u d y ma y e ve nt u all y test ot her st u d y dr u gs c o ntai ni n g a nti b o dies t hat w or k i n a si milar wa y. 
C urre ntl y, h o we ver, o nl y R E G N 1 0 9 3 3 a n d R E G N 1 0 9 8 7 will be teste d i n t his st u d y.  
 
H o w bi g is t he st u d y ?  
T h e st u d y will i ncl u de a b o ut 7 8 0  pe o ple w orl d wi d e . 
 
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H o w will I k n o w if I c a n j oi n t his st u d y ?  
T here are cert ai n c o n diti o ns y o u m ust meet t o e nter t he st u d y. T he st u d y d oct or will g o o ver t hese wit h 
y o u bef ore y o u ca n j oi n. T here is a  c ha nce t hat y o u ma y n ot q ualif y or be a ble t o j oi n t he st u d y. 
 
H o w will I be gi ve n t he st u d y dr u g ?  
Y o u will be gi ve n t he st u d y dr u g i nt o a vei n usi n g a nee dle. T his is calle d a n i ntra ve n o us (I V) i nf usi o n. 
Y o u will be gi ve n a n  I V i nf usi o n o nl y o nce, o n t he  first da y of t he st u d y. 
 
T he p ossi ble ris ks of bei n g gi ve n st u d y dr u g are d escri be d lat er i n t he c o ns e nt f or m. 
 
W h at will h a p pe n i n t he st u d y, a n d w h at will I h a ve t o d o if I j oi n ?  
After y o u gi ve y o ur c o ns e nt , t he st u d y d oct or will c hec k t he c o n diti o ns of t he st u d y t o s ee if y o u q u alif y. 
T his ma y i n v ol ve r u n ni n g tests. T his peri o d, calle d scree ni n g , will ha p pe n eit her o n t he sa me da y , or t he 
da y b ef ore,  y o u are gi ve n t he I V i nf usi o n  ( da y 1 of t he st u d y). 
 
O nce t h e d oct or c o nfir ms t hat y o u q uali fy , y o u will be ra n d o ml y c h ose n t o recei ve o n e of t hree p ossi ble 
I V i nf usi o ns: R E G N 1 0 9 3 3  +  R E G N 1 0 9 8 7  at a l o wer d ose  (1. 2  gra ms  of eac h a nti b o d y ), 
R E G N 1 0 9 3 3  +  R E G N 1 0 9 8 7 at a hi g her d ose  ( 4 gra ms of eac h a nti b o d y), or place b o. A place b o l o o ks 
li ke a real tr eat me nt b ut d oes n ot c o ntai n a n y acti ve me dici ne. Y o u will ha ve a n e q ual c ha nce of 
recei vi n g a n y o n e of t hes e.  
 
T his st u d y is d o u ble -bli n de d. T his mea ns t hat t h at neit her y o u n or t he st u d y d o ct or or t h e staff gi vi n g 
y o u t he i nf usi o n will k n o w w het her y o u are bei n g gi v e n st u d y dr u g or place b o.  Y o u will ha ve a o ne -i n-
t hree c h a nce of recei vi n g R E G N 1 0 9 3 3 + R E G N 1 0 9 8 7 at a l o wer d ose, a o ne-i n-t hree c ha n ce  of 
recei vi n g R E G N 1 0 9 3 3 + R E G N 1 0 9 8 7 at a hi g her d ose, a n d a o n e-i n-t hree c ha nce of recei vi n g place b o. 
 
Bef ore a n d ri g ht after t h e i nf usi o n, y o u will  ha v e bl o o d ta ke n. O nce t his is d o ne, if t here are n o si de 
effects wit hi n 2 h o urs of t he i nf usi o n , a n d if t he d oct or belie ves y o u are healt h y e n o u g h, y o u will be se nt 
h o me . 
 
As part  of t he st u d y , y o u will ha ve bl o o d ta ke n se vera l ti mes. Y o u will  als o ha ve nas o p har y n geal ( N P) 
s wa bs ta ke n. T hes e  sa m ples will be ta k e n at t he st u d y site, a d esi g n ate d m e dical ce nt er, b y ha vi n g st u d y 
staff c o me t o y o ur h o m e, or b y s o me ot her met h o d t hat will be e x plai ne d t o y o u. T he  s wa bs will  be 
ta ke n e ver y ot her d a y f or t he first t w o wee ks of t he st u d y , t he n t wice a wee k after t hat u ntil da y 2 9.  
 
T hr o u g h o ut t h e st u d y, y o u will als o re p ort o n y o ur s y m pt o ms usi n g a n electr o nic a p p e v er y d a y, a n d 
st u d y staff will c o ntact y o u wee kl y t o as k i nf or mati o n a b out y o ur healt h.  
 
T he st u d y will e n d o n d a y 2 9, w h e n y o u will ha ve a st u d y visit f or fi nal tests.  
 
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St u d y tests, pr oce d ures, a n d w h at y o u will be e x pecte d t o d o  
T he st u d y has certai n r ul es a b o ut visits y o u will ha ve, tests t hat nee d t o be d o ne, a n d ot her t h i n gs y o u 
will  be as ke d t o d o. S o me of t hese ma y i n v ol v e ris ks, w hic h are des cri be d bel o w.  Beca us e t he st u d y 
i n v ol ves e x peri me ntal researc h, t h ere ma y b e ot her ris ks t hat we ca n n ot pre dict a hea d of ti me.  
 
Si nce m ost of t he st u d y will ha p pe n w hile y o u are at  h o me , y o u m ust be willi n g a n d a ble t o pr o vi de  t he 
i nf or mati o n a n d sa m ples descri be d bel o w , w he n as ke d. T his will e ns ure t hat t he res earc h q uesti o ns of 
t he st u d y ca n be a ns were d. T he st u d y d o ct or or staff will gi ve y o u m or e i nf or mati o n t o hel p y o u d o t his. 
 
N as o p h ar y n ge al ( N P) s w a bs  
T o meas ure i nfecti o n b y t he vir us, sa m ples will be c ollecte d b y t a ki n g w hat are calle d N P s w a bs . T he 
st u d y d oct or or staff will ta ke t hese sa m ples. E ac h ti me a sa m ple is c oll ecte d, a s wa b will be ge ntl y 
i nserte d a b o ut t hree i nc hes i nt o o ne n ostril u ntil t he s wa b reac hes t he b ac k of y o ur t hr oat. T h e s wa b will 
be r otate d a fe w ti mes a n d re m o ve d. T his will t he n be re peate d i n t he ot her n ostril usi n g a fres h s wa b.  
 
P ossi ble risks: C ollecti n g N P s wa b sa m ples ca n be u nc o mf orta ble, b ut  n ot pai nf ul. Y o u ma y ga g or feel 
t he ur ge t o s neeze or c o u g h w hile t he sa m ple is bei n g c ollect e d. Y o u ma y als o ha v e a mi n or n ose blee d 
after t he s a m ple is ta ke n.  
 
As descri be d l ater i n t his c o nse nt f or m, pleas e n ote t hat t he res ults of y o ur tests, i ncl u di n g vir us 
i nfecti o n meas ur e d wit h N P s wa bs, will n ot be pr o vi de d t o y o u. 
 
Bl o o d dr a ws  
Bl o o d will be ta ke n t o c hec k y o ur healt h a n d carr y o ut t he researc h descri be d i n t his c o nse nt f or m. T he 
a m o u nt of bl o o d ta ke n d uri n g a visit will ra n ge fr o m a p pr o xi matel y 6  milliliters ( half ta bles p o o n) t o 7 9  
milliliters ( 5  ta bles p o o ns). 
 
P ossi ble ris ks: Bl o o d dra ws ma y ca us e disc o mf ort, br uisi n g, or i nfecti o n at t he site w here bl o o d was 
ta ke n. S o me pe o ple bec o me fai nt or dizz y w he n gi vi n g bl o o d. 
 
Ret ur ni n g t o t he cli nic f or  assess me nts  
I n s o me cases, y o u ma y nee d t o visit t he st u d y cli nic o ne or m ore ti mes s o t hat tests a n d sa m ple 
c ollecti o ns ca n be d o n e.  
 
P ossi ble Ris ks: B y c o mi n g b ac k t o t h e cli nic, y o u ma y be e x p ose d t o ot hers w h o m a y ha v e C O VI D -1 9 
or ot her ill nesses. It is c urre ntl y n ot k n o w n w het h er ha vi n g pri or C O VI D-1 9 disease will ma ke s o me o ne 
i m m u ne fr o m getti n g it a gai n, s o it is p ossi ble t hat e ve n if y o u ha ve h a d C O VI D-1 9 a n d rec o v ere d, y o u 
c o ul d bec o me re -i nf ecte d fr o m e x p os ure t o s o me o ne w h o is still sic k. 
 
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H a vi n g me dic al visits at h o me  
I n s o me cases, it ma y b e p ossi ble ha ve a st u d y visit at y o ur h o me, rat her t ha n at t he st u d y site or ot her 
l ocati o n. T hese h o m e visits ma y b e d o ne b y a t hir d -part y c o m pa n y (a c o m pa n y n ot affiliate d wit h t he 
st u d y site or Re ge n er o n) or b y a me m ber of t h e st u d y site tea m . T h e st u d y d oct or or staff will tal k wit h 
y o u t o see if y o u q ualif y f or t hese visits. It is y o ur c h oice w het her t o all o w t hese ki n ds of visits or n ot.  
 
H a vi n g me dic al visits electr o nic all y  
Y o ur c o nse nt t o j oi n t he st u d y, as w ell as s o me of y o ur me dical visits, ma y be d o n e b y p h o n e or 
electr o nicall y ( o n a s mart p h o ne, ta blet, or c o m p uter). T his t y p e of visit is als o calle d tele me dici ne. T he 
re m ote me dical visits will all o w t he d oct or or staff t o c hec k o n y o ur healt h, s o t hat y o u ca n ha v e fe wer 
i n-pers o n visits d uri n g t h e st u d y. T h e st u d y d o ct or or staff will tell y o u m or e a b o ut t hese t y pes of visits.  
 
Re p orti n g s y m pt o ms wit h a n electr o nic s ur ve y  
T hr o u g h o ut  t he st u d y, y o u will use a n electr o nic a p p t o fill o ut s ur ve ys a b o ut a n y C O VI D-1 9 s y m pt o ms 
y o u ma y h a ve.  
 
Vit al si g ns  
Se veral of y o ur vital si g ns will be meas ure d at differe nt ti mes o n t he first da y of t he st u d y, i ncl u di n g 
y o ur b o d y te m perat ur e, bl o o d press ure, a n d bl o o d o x y ge n le vels (t he a m o u nt of o x y ge n i n y o ur bl o o d).  
Y o ur b o d y te m perat ure will be meas ure d usi n g a t her m o meter t hat g o es eit her i n y o ur m o ut h, ear, 
ar m pit, or o n y o ur f ore hea d. Y o ur bl o o d press ur e will be meas ure d usi n g a c uff t h at i nflates ar o u n d y o ur 
ar m. Bl o o d o x y ge n l e vels will be meas ure d usi n g a s mal l de vice t hat cli ps o nt o y o ur fi n ger.  
 
Pre g n a nc y test  
If y o u are a w o ma n w h o is a ble t o ha ve c hil dre n, y o u will ha ve t o ta ke a pre g na nc y test bef ore recei vi n g 
t he st u d y dr u g a n d at t he e n d of t he st u d y. T he test will be d o ne usi n g eit her a bl o o d or a uri ne sa m ple. 
Ris ks relate d t o t he st u d y dr u g a n d pre g n a nc y are descri be d lat er i n t he c o nse nt f or m.  
 
Pr o vi di n g i nf or m ati o n a b o ut y o ur he alt h t o t he st u d y d oct or a n d st aff  
At t he start of t he st u d y, t he st u d y d oct or or staff will as k y o u q u esti o ns a b o ut y o urse lf, y o ur healt h, a n d 
y o ur me di cal hist or y (i ncl u di n g pri or C O VI D -1 9 s y m pt o ms). Y o ur wei g ht a n d hei g ht will be meas ure d.  
 
T hr o u g h o ut t he st u d y, t h e d oct or or staff will als o c ollect i nf or mati o n a b o ut si de effects a n d ot her healt h 
c ha n ges relate d t o C O VI D -1 9  ill ness. T he y m a y als o as k a b o ut a n y me dici ne or s u p ple me nts y o u are 
ta ki n g ( prescri be d a nd o v er -t he-c o u nter).  
 
Re p orti n g a n y me dic al visits y o u h a ve d ue t o C O VI D -1 9  
Eac h wee k, y o u will be as ke d w het her y o u h a d a n y me dical visits relate d t o C O VI D -1 9. It i s i m p orta nt 
t hat y o u descri be a n y me dical visits y o u ha d a n d a n y details a b o ut t he visit (f or e x a m ple, w here t he visit 
occ urre d, t he dat e y o u w e nt a n d t he s y m pt o ms y o u felt). 
 
If y o u see a d oct or or h a ve a n y me dical visit d uri n g t h e st u d y, e ve n if it is n ot wit h t he st u d y d oct or or 
staff, y o u will be as ke d t o c o ntact t he st u d y staff as s o o n as p ossi ble t o tell t he m a b o ut t he visit.  
V V- T M F- 2 2 8 3 9 4 0 - 


 
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A u g 1 2, 2 0 2 0  
 
8 4 0 _ R 1 0 9 3 3 -1 0 9 8 7 -C O V -2 0 6 7 _ Mai n  I C F P h 2 _ V 9 . 0 
Pa ge 7  of 2 0  
 
Is ge n o mic m ateri al c ollecti o n re q uire d i n t his st u d y ? 
D N A is w hat ma kes u p t he ge nes y o u i n herit fr o m y o ur pare nts. It acts l i ke a n i nstr ucti o n b o o k f or t he 
cells i n y o ur b o d y a n d h el ps f or m y o ur traits (li ke e ye c ol or or hei g ht). R N A is ma de usi n g y o ur ge n es 
a n d carri es o ut t he i nstr ucti o ns of D N A. C or o na vir uses li ke t he o ne t hat ca uses C O VI D -1 9 w or k a little 
dif fere ntl y, a n d onl y c o ntai n R N A.  
 
A n i m p orta nt g oal of t he st u d y is t o see w het her t h e st u d y dr u g l o wer s t he a m o u nt of vir us y o u ha ve. T o 
d o t his , sa m ples c ollecte d fr o m y o u  will be use d t o meas ure le vels of vir us R N A. I n a d diti o n, tests will 
be d o ne  o n t he vir us R N A  t o lo o k at its se q ue nce (t he ge n etic c o d e of t he vir us ). T hese t ests will l o o k at 
w het her t he s e q ue nce ca n affect w het her or n ot  t h e st u d y dr u g w or ks. 
 
If necessar y, t he s a m ples ma y be re-a nal yz e d i n t he f ut ure. T hes e sa m ples will be st ore d f or u p t o 1 5 
years f oll o wi n g c o m pleti o n of t he st u d y. 
 
Ge n o mic Testi n g Ris ks  
T he sa m ples t h at are c ollecte d will o nl y b e use d t o st u d y vir us R N A a n d n ot h u ma n R N A. H o we ver, 
h u ma n R N A ca n n ot al w a ys be c o m pletel y re m o ve d fr o m t he sa m ples , a n d t here is a c ha n ce t hat s o m e of 
y o u r R N A s e q ue n ces c o ul d be i de ntifie d a n d a n al yze d . 
 
W hile e ver y eff ort will be ma de t o pr ot ect y o ur i de ntit y, i t is p ossi ble t hat t he R N A se q ue n ces t hat 
descri be y o ur ge nes c o ul d p ote ntiall y i d e ntif y y o u. Beca us e t he s pecifi c ge nes y o u ha v e ca n m a ke it 
m ore  or less li kel y t hat y o u mi g ht de v el o p cert ai n me dical c o n diti o ns, k n o wle d ge of t his i nf or mati o n 
c o ul d als o lea d t o u n wa nte d ps yc h ol o gic al a n d fi na ncial c o nse q ue n ces if it were release d t o y o u or a n y 
t hir d part y. T h ere ma y als o be ot her pri vac y ris ks t hat ha ve n ot pre dict e d.  
 
T here is a U. S. fe deral la w calle d t he Ge n etic I nf or mati o n N o n -Discri mi nati o n Act ( GI N A). I n ge neral, 
t his la w ma kes it ille gal f or healt h i ns ura nce c o m pa nies, gr o u p healt h pla ns a n d m ost e m pl o yers t o 
discri mi nate a gai nst y o u base d o n y o ur ge netic i nf or mati o n. T his la w d oes n ot pr otect a gai nst 
discri mi nati o n b y c o m pa nies t hat sell life, disa bilit y or l o n g -ter m care i ns ura nce b ut t he c ha nces t hat 
y o ur i nf or mati o n w o ul d be rele ase d t o t hese c o m pa nies are ver y s mall.  
 
Will a d diti o n al s a m pl es be c ollecte d ?  
As descri be d a b o ve, b iol o gic al sa m ples, i ncl u di n g sa m ples fr o m y o ur m o ut h or n ose as well as  bl o o d , 
will be c ol le cte d as part of t his st u d y. Y o ur c o d e d sa m ples will be use d b y Re ge n er o n Parties f or t h e 
p ur p oses of t he st u d y, i n cl u di n g e x pl orat or y researc h, t o i de ntif y ne w lear ni n gs, s uc h as:  
 
•  H o w t he st u d y dr u g w or ks i n t he b o d y  
•  W h y  s o m e pe o ple res p o n d better t o t he st u d y dr u g 
•  W h y s o m e pe o ple de v el o p si de effects  
•  I nf or mati o n a b o ut C O VI D-1 9  
 
V V- T M F- 2 2 8 3 9 4 0 - 


 
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A u g 1 2, 2 0 2 0  
 
8 4 0 _ R 1 0 9 3 3 -1 0 9 8 7 -C O V -2 0 6 7 _ Mai n  I C F P h 2 _ V 9 . 0 
Pa ge 8  of 2 0  
T hese sa m ples will be ke pt f or u p t o 1 5 years afte r t he st u d y e n ds. D uri n g t hat ti me, the sa m ples will be 
ke pt i n a sec ure st ora ge area at a Re ge n er o n facilit y or at a st ora ge facilit y desi g nate d b y, a n d u n der t he 
s u per visi o n of, Re ge ner o n i n t he U nite d States. U n use d sa m ples will be destr o ye d.  
 
If y o u wis h t o wit h dra w y o ur c o nse nt t o use a n d st ore y o ur sa m ples, please n otif y t he st u d y d oct or. If 
y o u wit h dr a w fr o m t he trial, b ut d o n ot wit h dra w y o ur c o ns e nt t o use a n d st ore y o ur s a m ples, y o ur 
sa m ples will c o nti n ue t o be use d as descri be d i n t his f or m. If yo u wit h dra w y o ur c o nse nt t o use t he 
sa m ple a n d y o u wis h t o ha ve t he sa m ples destr o ye d, y o ur st u d y d oct or, Re ge n er o n, a n d t he la b orat or y 
res p o nsi ble f or pr ocessi n g t he sa m ples will ma ke e ver y reas o na ble eff ort t o e ns ure y o ur sa m ples are 
destr o ye d.  H o we ver, it is i m p orta nt t hat y o u u n dersta n d t hat if y o ur sa m ple has alrea d y b ee n pr ocesse d 
a n d a nal yz e d, t he res ults a n d i nf or mati o n o btai ne d ca n n ot be destr o ye d a n d will c o nti n ue t o be a vaila ble 
t o t he Re ge n er o n Parties. 
 
W h at are t he p ossi ble ris ks a n d si de effe cts of t he st u d y dr u g ?  
T here is c urre ntl y a li mite d a m o u nt of data a b o ut t his st u d y dr u g i n pe o ple . T o dat e, n o s eri o us s afet y 
c o ncer ns ha v e bee n see n. La b orat or y st u dies i n cells a n d m o n ke ys are c urre ntl y bei n g d o ne t o l o o k f or 
p ote ntial safet y ris ks of t he st u d y dr u g. Patie nts will als o be caref ull y m o nit ore d f or a n y p ossi ble safet y 
c o ncer ns d uri n g t his st u d y, a n d y o u will be t ol d if t here are a n y i m p orta nt safet y fi n di n gs. At t his ti me, 
h o we ver, t he ris ks of t he st u d y dr u g are u n k n o w n. S o me of t hese u n k n o w n ris ks ma y b e seri o us or life -
t hreate ni n g. 
 
T he p ossi ble ris ks descri be d bel o w are base d o n w hat i s k n o w n a b o ut dr u gs t hat w or k i n a si milar wa y 
t o t he st u d y dr u g, or are gi ve n i n t he sa m e wa y (t hr o u g h I V i nf usi o n). 
 
F or y o ur s afet y, it is i m p orta nt t ha t y o u pr o m ptl y tell t he st u d y d oct or or staff a b o ut a n y si de effects t hat 
y o u are feeli n g or a n y c h a n ges i n y o ur healt h. Y o u s h o ul d als o re p ort a n y ne w me dici ne or s u p ple me nts 
y o u start ta ki n g, i ncl u di n g vita mi ns, her bal re me di es, o ver -t he-c o u nte r dr u gs, or prescri pti o n dr u gs. 
 
I ntr a ve n o us (I V) i nf usi o n ris ks a n d aller gic re acti o n ris ks  
Y o u ma y h a ve br uisi n g, pai n, or disc o mf ort at t he site w here t he st u d y dr u g is gi ve n.  
 
T here is als o a c ha n ce t hat y o u will ha v e  a n aller gic reacti o n t o t he st u d y dr u g. T his  c o ul d i ncl u d e si de 
effects t hat o cc ur d uri n g t he i nf usi o n or wit hi n a fe w h o urs t o da ys after t he i nf usi o n. T hes e reacti o ns, 
k n o w n as i nf usi o n reacti o ns, c o ul d i ncl u de ras h, hi ves, c o u g h, c hills, s weati n g, s h ort ness of br eat h, 
na usea, or feeli n g fl us h.  
 
A lt h o u g h rare, t here is a c ha nce y o u ma y ha v e  m ore seri o us s y m pt o ms, i ncl u di n g a se vere aller gic 
reacti o n (calle d a n a p h yl a xis). Se vere s y m pt o ms re q uir e i m me diate me dical care a n d c o ul d res ult i n  
per ma ne nt disa bilit y or deat h.  
 
V V- T M F- 2 2 8 3 9 4 0 - 


 
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M U S T  B E  A P P R O V E D  
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A S M O DI FI E D  
A u g 1 2, 2 0 2 0  
 
8 4 0 _ R 1 0 9 3 3 -1 0 9 8 7 -C O V -2 0 6 7 _ Mai n  I C F P h 2 _ V 9 . 0 
Pa ge 9  of 2 0  
Ris k of u ne x pecte d i m m u ne res p o nse  
It is p ossi ble t hat y o ur i m m u ne s yste m c o ul d ma ke  its o w n a nti b o dies a gai nst st u d y dr u g. T his ca n ca use 
si de effects or ma ke t h e dr u g w or k less effecti vel y.  
 
T he oretic al ris k of vir us i nfecti o n getti n g w orse  
I n s o me a ni mal st u dies, a nti b o dies a n d v acci nes ca n ma ke a n i nf ecti o n w orse. I n h u ma ns, t his h as o nl y 
bee n see n i n rare cases wit h vacci nes. T he reas o n f or t his is n ot f ull y u n derst o o d, b ut it is t h o u g ht t hat 
t his ca n ha p p e n w h e n t he a m o u nt of a nti b o d y i n circ ulati o n gets l o w. As of t o da y, t his has n ot b ee n s ee n 
wit h a nti b o dies use d a gai nst S A R S -C o V -2 (t he vir us t hat ca uses C O VI D -1 9), i n eit her a ni mal st u dies or 
h u ma ns. At t his ti me, t h o u g h, t he t he oretical ris k ca n n ot be r ule d o ut wit h t his st u d y dr u g. Si g ns a n d 
s y m pt o ms of C O VI D-1 9 i nfecti o n ma y get w orse wee ks t o m o nt hs after recei vi n g t he st u d y dr u g, a n d 
will be m o nit ore d t hr o u g h o ut t he st u d y.  
 
W h at h a p pe ns if m y p art ner or I get pre g n a nt ?  
T he st u d y dr u g h a s n ot bee n teste d i n pre g n a nt or n ursi n g w o me n  s o ta ki n g part i n t his res earc h ma y 
h urt a  pre g na nc y or fet us i n u n k n o w n wa ys . It is n ot k n o w n if t he y ca n ca use har m t o y o u or y o ur ba b y 
if y o u bec o me pre g na nt, or w h et her y o u ma y l os e y o ur pre g n a nc y. W o me n w h o j oi n t his st u d y ca n n ot 
bec o me pre g n a nt or breastfee d d uri n g t he st u d y. If y o u are pre gn a nt, y o u ca n n ot j oi n t he st u d y a n d 
ca n n ot recei ve st u d y dr u g.  
 
W o me n w h o are i n t his st u d y m ust use me dicall y acce pta ble birt h c o ntr ol f or 6 m o nt hs after recei vi n g 
t he st u d y dr u g i nf usi o n. If y o u bec o m e pre g n a nt d uri n g t hat ti me, y o u m ust tell t he st u d y do ct or ri g ht 
a wa y. T he st u d y d o ct or will f oll o w u p wit h y o u a b o ut o utc o me of y o ur pre g na n c y.  
 
Me n w h o are i n t his st u d y m ust als o use me dicall y acce pt a ble birt h c o ntr ol f or 6 m o nt hs after recei vi n g 
t he st u d y dr u g i nf usi o n, u nless y o ur part n er is u n a ble t o bec o me pre g na nt (f or e x a m ple, if y o ur part ner is 
me dicall y sterile). If y o ur part ner bec o m es pre g na nt d uri n g t hat ti me, y o u m ust tell t he st u d y d oct or. T he 
st u d y d o ct or will as k t o s pea k t o y o ur p art ner. If y o ur part n er a grees, Re ge ner o n will c ollect i nf or m ati o n 
a b o ut t he pre g na n c y a n d its o utc o me.  
 
T he st u d y d o ct or ca n a ns wer a n y q u esti o ns y o u h a ve a b o ut acce pta ble birt h c o ntr ol.  
 
W h at ot her c h oices d o I h a ve if I d o n ot j oi n t his st u d y ?  
T here are c urre ntl y n o tr eat me nts a p pr o ve d b y a n y h ealt h a ut h orit y t o tr eat C O VI D-1 9 . H o we v er, t here 
ma y b e ot her o pti o ns if y o u deci de n ot t o j oi n t his st u d y:  
 
•  T here ma y b e  st u dies i n y o ur area res earc hi n g ot her e x peri me ntal treat me nts f or C O VI D-1 9 . 
•  Y o u ca n recei ve t he sta n dar d care t hat h os pitals or d oct or’s offices i n y o ur area are usi n g t o 
tr y t o treat C O VI D-1 9 . 
•  Y o u ca n c h o ose t o recei ve n o tr eat me nt or t o treat o nl y y o ur s y m pt o ms (f or e x a m ple, wit h 
o ver -t he-c o u nter m e dici n e f or fe ver) . 
 
V V- T M F- 2 2 8 3 9 4 0 - 


 
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A u g 1 2, 2 0 2 0  
 
8 4 0 _ R 1 0 9 3 3 -1 0 9 8 7 -C O V -2 0 6 7 _ Mai n  I C F P h 2 _ V 9 . 0 
Pa ge 1 0  of 2 0  
Eac h o pti o n has p ossi ble be nefits a n d ris ks , w hic h ma y be differe nt de pe n di n g o n y o ur ill ness a n d 
o verall healt h. T here ma y be ot her o pti o ns as well. If y o u ha ve q uesti o ns a b o ut y o ur o pti o ns , tal k t o t he 
st u d y d oct or. Y o u a n d t h e d oct or ca n disc uss t he best treat me nt pla n f or y o u.  
 
Will t his st u d y be nefit me ?  
T he mai n p ur p ose of t his st u d y  is researc h. Beca use of t his, y o u ma y or m a y n ot get a n y healt h b e nefit 
fr o m bei n g i n t he st u d y. B ut, b y j oi ni n g t he st u d y y o u ma y h el p us l ear n t hi n gs a b o ut t he st u d y dr u g t hat 
c o ul d hel p ot her pe o ple w h o ha ve C O VI D -1 9.  
 
Will I be p ai d t o p artici p ate i n t his st u d y ? 
Y o u will be gi ve n $ [ X X] f or eac h da y t hat y o u s p e n d at t he i nf usi o n site. After y o u are se nt h o me, yo u 
will be gi ve n a sti pe n d of $ [ X X] f or eac h st u d y visit t hat occ urs.  
 
Will I h a ve t o s pe n d m o ne y t o be i n t his st u d y ?  
T here will be n o c ost t o y o u f or t he st u d y dr u g, st u d y d oct or’s ti me or certai n pr oce d ures a n d s u p plies 
re q uire d b y t his st u d y. H o we ver, y o u are res p o nsi ble f or t he c ost of y o ur sta n dar d me dicati o n, i n 
a d diti o n t o a n y c osts relate d t o pr oce d ures a n d s u p p lies n ot re q uire d b y t he stu d y.  
 
As part of t he st u d y, y o u ma y h a ve tra vel arra n ge me nts ma de f or y o u t o tra vel t o a n d fr o m t h e st u d y site 
or testi n g ce nters usi n g a t hir d -part y c o m pa n y. Y o u will n ot nee d t o pa y  f or t hese tra vel arra n ge me nts. 
 
W h at h a p pe ns if I g et inj ure d w hile I a m  i n t he st u d y ? 
If y o u t hi n k y o u h a ve bee n i nj ure d as a res ult of partici pati n g i n t he st u d y: 
 
•  Pr o m p tl y s ee k me dical treat me nt, a n d 
•  Call t he e mer ge nc y c o nt act n u m ber o n t he first p a ge of t his f or m  a n d st u d y d oct or  ca n treat 
y o u or refer y o u t o w here y o u ca n  o btai n treat me nt . 
 
If y o u ha v e a n i nj ur y t h at is directl y ca us e d b y t a ki n g t he st u d y dr u g or a n y pr o perl y p erf or me d st u d y 
pr oce d ures i ncl u de d i n t he st u d y ( pr oce d ures y o u recei ve o nl y beca us e of y o ur partici p ati o n i n t he 
st u d y) a n d y o u ha ve f oll o we d t he directi o ns of y o ur st u d y d oct or, 
Re ge ner o n 
will pr o vi de 
rei m b urse me nt f or reas o na ble a n d n ecess ar y me dical c osts t o treat y o ur i nj ur y t hat are n ot c o vere d b y 
y o ur me di cal or h os pital i ns ura nce, or fr o m t hir d part y or ot her pr o gra ms pr o vi di n g s uc h c o vera ge.  
 
Re ge n er o n will n ot pr o vi de m o netar y  or fi na ncial c o m pe nsati o n f or:  
 
•  O t her i nj ur y- or ill ness -relate d c osts (s uc h as l ost wa ges, disa bilit y or dis c o mf ort d ue t o a n 
i nj ur y), 
•  M e dical e x pe nses t hat  are pai d f or b y a t hir d part y,  
V V- T M F- 2 2 8 3 9 4 0 - 


 
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A u g 1 2, 2 0 2 0  
 
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Pa ge 1 1  of 2 0  
•  M e dical e x pe nses t hat ha p pe n d ue t o a vi olati o n of t he st u d y or ot her misc o n d uct or 
ne gli ge n ce, i n eac h case b y a n y a ge nt or e m pl o yee of t he I nstit uti o n c o n d ucti n g t he st u d y 
(i ncl u di n g t he st u d y staff), or 
•  M e dical e x pe nses f or i nj ur y or ill ness u nrel ate d t o t he st u d y dr u g a n d u nrelate d  t o t he pr o per 
perf or ma n ce of a n y ot her pr oce d ure re q uire d b y t h e st u d y or Re ge n er o n’s writte n i nstr ucti o ns 
t o t he I nstit uti o n c o n d u cti n g t he st u d y, i ncl u di n g, wit h o ut li mitati o n, me dical e x pe nses 
ass ociate d wit h a pre -e xisti n g me dical c o n diti o n.  
 
T his res earc h is c o v ere d b y t h e P u blic Rea di ness a n d E mer ge nc y Pre pare d ness ( P R E P) Act. T he P R E P 
Act li mits y o ur a bilit y t o s ue if y o u are i nj ure d b y t he st u d y dr u g or st u d y pr oce d ures. H o we ver, y o u 
ma y be a ble t o see k c o m pe nsati o n fr o m t he H u ma n Res o urces a n d Serv ices A d mi nistrati o n ( H R S A ) 
C o u nter meas ure I nj ur y C o m pe nsati o n Pr o gra m f or cert ai n seri o us p h ysi cal i nj uries. T he declarati o n is 
availa ble at:  
 
htt ps:// w w w. g o vi nf o. g o v/c o nte nt/ p k g/ F R -2 0 2 0 -0 3 -1 7/ p df/ 2 0 2 0 -0 5 4 8 4. p df  
 
N o f u n ds ha ve bee n set asi de t o pr o vi de y o u wit h a n y f urt her m o netar y or fi na ncial c o m pe ns ati o n i n 
case of i nj ur y. B y a greei n g t o partici pate i n t his st u d y, y o u d o n ot wai ve a n y of y o ur ri g hts  t o p urs ue a 
clai m t hr o u g h t he le gal s yste m . F or m ore i nf or m ati o n, please c o ntact t he st u d y d o ct or or a me m ber of 
t he st u d y staff. 
 
C a n I le a ve t he st u d y after I j oi n ?  
Yes. Y o u ca n c h a n ge y o ur mi n d a n d lea ve t he st u d y at a n y ti me. Y o u d o n ot nee d t o gi ve a reas o n. If 
y o u l ea ve t he st u d y, y o ur me dical care o utsi de of t he st u d y will n ot be affecte d b y y o ur decis i o n. Y o u 
will n ot be pe nalize d or l ose a n y be nefits t hat y o u w o ul d recei v e if y o u were n ot i n t he st u d y.  
 
If y o u deci de t o le a ve, it is i m p orta nt t o let t he st u d y d o ct or k n o w as s o o n as p ossi ble s o y o u ca n st o p 
safel y. If y o u alrea d y receive d  t he st u d y dr ug, y o u will be as ke d t o c o m e bac k f or a f oll o w -u p visit s o 
t hat tests ca n be d o ne t o c hec k y o ur healt h. Y o u will als o be as ke d t o ret ur n all st u d y-relate d ite ms a n d 
de vices t o t h e st u d y site. T he st u d y d oct or or st u d y staff m a y als o as k t o h a ve a fi nal p h o ne call t o c hec k 
y o ur healt h.  
 
Y o u will be t ol d of a n y i m p orta nt ne w i nf or mati o n a b o ut t he st u d y dr u g, or a n y c h a n ges t o t he st u d y, 
t hat ma y affect y o ur decisi o n t o sta y i n t he st u d y. 
 
Is it p ossi ble t h at I mi g ht be as ke d t o le a ve t he st u d y ? 
Yes. Y o u ca n b e ta k e n o ut of t he st u d y wit h o ut y o ur c o nse nt at a n y ti me a n d f or a n y reas o n, i ncl u di n g : if 
t he st u d y is n o l o n ger i n y o ur best me dical i nterest, if y o u e x perie nce u n us ual or seri o us si de effects, if 
y o u b ec o me pre g na nt, or if y o u d o n ot f oll o w t he st u d y r ul es. T he st u d y ma y als o be st o p pe d b y 
Re ge n er o n, a n I R B/ E C, or a healt h a ut h orit y s uc h as t he U. S. F D A.  
 
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D A T A P R O T E C TI O N: Y O U R RI G H T S A N D C H OI C E S  
W h at i nf or m ati o n will t he st u d y st aff c ollect fr o m or a b o ut me i n c o n necti o n wit h 
t his st u d y ? 
As part of t his  st u d y, t he st u d y d oct or a n d st u d y st aff (“res earc hers”) will c ollect a n d re vie w i nf or m ati o n 
a b o ut y o u t hat c o ntai ns y o ur na me a n d ot her pers o nal i nf or mati o n.  I n a d diti o n, y o ur treati n g p h ysicia ns 
a n d ot her h ealt hcare pr o vi ders ma y  discl ose i nf or mati o n fr o m y o ur me dical rec or ds t o t h e res earc hers. 
T he i nf or mati o n c ollect e d fr o m or a b o ut y o u (“ pers o nal i nf or mati o n ”) f or t his st u d y i n cl u des:  
 
•  Y o ur me dical i nf or mati o n, i ncl u di n g h o w y o u feel, me dical a n d s ur gical hist or y, y o ur f o o d 
i nta ke, s m o ki n g a n d alc o h ol ha bits, me n o pa usal hist or y ( w o me n o nl y), p h ysical acti vit y, 
se x ual ha bits or be ha vi or, c o ntrace pti o n a n d pre vi o us a n d c urre nt me dicati o ns  
•  Ot her pers o nall y i de ntif yi n g i nf or mati o n, i ncl u di n g y o ur na m e a n d ot her i nf or mati o n (s uc h 
as y o ur a ge, race or et h nici t y, ge n d er a n d c o u ntr y l ocati o n) 
•  Res ults of e x a mi nati o ns a n d la b orat or y t ests  
•  Bi ol o gic al sa m ples 
 
Re ge n er o n  or its re pres e ntati ves ma y c o n d uct site visits t o m o nit or a n d e ns ure t hat t he trial is e x ec ute d 
acc or di n g t o t he st u d y pr ot oc ol a n d a p plica ble l ocal  la ws a n d re g ulati o ns. 
 
W h o else will be a ble t o l o o k at m y pers o n al  i nf or m ati o n ? 
T he researc hers will use a n d discl ose y o ur pers o nal i nf or mati o n  t o t he f oll o wi n g or ga nizati o ns:  
 
•  Re ge n er o n, its c olla b orat ors or t h ose d e vel o pi n g t he st u d y dr u g; a n d t heir a ffiliates, 
re pres e ntati ves, a ge nts a n d c o ntract ors (t he “ Re ge ner o n Parties ”)  
•  T he U. S. F D A, ot her U. S. g o ver n me nt a ge ncies, a n d g o ver n m e nt a ut h orities i n ot her 
c o u ntries  
•  T he I R B /E C o vers eei n g t he st u d y  
 
Y o ur pers o nal d ata ma y als o be s hare d wit h t hir d -part y c o m pa nies t hat hel p r u n t he st u d y. T his ma y 
i ncl u de c o m pa nies t hat pr o vi de tra vel ser vices, h o me healt h ser vices, as well as c o m pa nies t hat de vel o p 
s yste ms f or ele ctr o nic c o nse nt, s y m pt o m s ur ve y a p ps, a n d tele m e dici ne. T his data 
ma y i n cl u de 
pers o nall y i d e ntif yi n g i nf or mati o n, s uc h as y o ur na me, a d dress, p h o ne n u m ber, a n d e mail a d dress. T hese 
c o m pa nies are res p o nsi ble f or t he c o nfi de ntialit y of y o ur i de ntif yi n g i nf or mati o n a n d wi ll n ot s hare it 
wit h Re ge n er o n.  
 
Access t o y o ur rec or ds ma y be pr o vi de d t o re g ul at or y a ut h orities  s uc h as F D A, I R B, m o nit ors, a u dit ors, 
a n d re prese nt ati ves of Re ge n er o n, i n or der t o m o nit or, a u dit, a n d v erif y researc h pr oce d ures a n d/ or st u d y 
data. I n s o me cases, t his ma y i n v ol ve ha vi n g y o ur rec or ds re vi e we d at t he st u d y site. I n ot h er cases, y o ur 
rec or ds m a y be re vie we d re m otel y o ver t he i nter net, b ut o nl y if t he la ws a n d re g ulatio ns i n y o ur c o u ntr y 
all o w t his.  
 
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Ge nerall y, y o ur p er missi o n t o use a n d/ or s hare y o ur pers o nal i nf or mati o n  f or t he p ur p oses descri be d i n 
t his f or m d oes n ot ha v e a n e x pirati o n date, s u bject t o a p plica ble la w, u nless y o u wit h dra w y o ur 
per missi o n i n writi n g t o t he st u d y d o ct or at t he a d dress liste d o n pa ge 1  of t his f or m.  
 
W h at prec a uti o ns will be t a ke n t o pr otect m y pri v ac y ?  
E ver y eff ort will be ta k e n t o mai ntai n y o ur pri vac y. Y o ur n a me will n ot be attac he d t o rec or ds or 
sa m ples releas e d f or res earc h p ur p oses. I nstea d, y o ur rec or ds a n d sa m ples will o nl y be i de ntifie d b y a 
c o de. O nl y t he st u d y d o ct or a n d a ut h orize d pers o n nel will be a ble t o c o n nect t his c o de t o y o ur na me.  
Y o ur pers o n al i nf or mati o n will be pr otecte d b y y o ur st u d y d o ct or a n d site i n acc or da nce wit h rel e va nt 
data pr otecti o n la ws.  
 
All  data will be st ore d i n l oc ke d ca bi net files a n d restricte d-access c o m p uters. 
W hile t hese s ec urit y 
meas ures re d u ce  t he ris k of y o ur pers o nal i nf or mati o n bei n g mis use d or accesse d b y u n a ut h orize d 
i n di vi d uals, s uc h ris ks ca n n ot be eli mi nate d e ntirel y. Alt h o u g h we belie ve t hat t hese ris ks are l o w, 
a bs ol ute c o nfi de ntialit y ca n n ot be pr o mise d. H o we ver, all i nf or mati o n will be c ollecte d a n d s hare d i n 
acc or da nce wit h a p plica ble la w a n d dat a s hari n g g ui deli nes t hat Re ge ner o n  m ust f oll o w.  
 
H o w will m y pers o n al i nf or m ati o n a n d res ults fr o m t his st u d y be use d ?  
T he researc hers a n d or ga niz ati o ns liste d a b o v e will use a n d discl ose y o ur p ers o nal i nf or mati o n  i n 
c o n necti o n wit h t he st u d y t o ass ure q ualit y c o ntr ol, a nal yz e t he data, a n d c o m pl y wit h re g ul at or y d uties. 
T his i ncl u des t he s u b missi o n of t he st u d y res ults, re g ulat or y a p pr o vals of t he st u d y dr u g, t o re p ort 
a d verse e v e nts, a n d g o v er n me nt re p orti n g, if a p plica ble.  I n a d diti o n, Re ge n er o n P arties will use t he 
st u d y data t o ass ess t he s afet y a n d effic ac y of t he st u d y dr u g.  
 
Y o ur c o de d pers o n al i nf or mati o n  will be a d de d t o a c o m p uterize d data base.  T his data base will be part of 
t he st u d y res ults. Data a n d res ults fr o m t his st u d y will be prese nte d at meeti n gs or p u blis he d i n j o ur nals.  
T o f ulfill re g ulat or y re q uire me nts a n d i n d ustr y g ui deli nes, t he res ults fr o m t his st u d y will als o be 
pr o vi de d t o q ualifie d researc h ers w h o re q u est it f or le giti mate researc h p ur p oses. 
W hile y o ur c o de d 
i nf or mati o n ma y be s hare d wit h t hese researc h ers or p u blicati o ns, y o ur i de ntit y (s uc h as y o ur n a me, 
a d dress a n d e mail) will n ot be s hare d wit h t hes e researc h ers a n d will n ot be i n a n y prese ntati o n or 
p u blicati o n.  
 
A s a d va nce me nts i n me dical tec h n ol o g y c o nti n ue, Re ge ner o n Parties ma y rea nal yze t he st u d y d ata a n d 
t he res ults i n f ut ure researc h pr ojects t o fi n d ne w scie ntific i nf or mati o n a b o ut t he st u d y, st u d y dr u g, 
C O VI D -1 9 , or ot her rel ate d diseases. 
 
O nce y o ur p ers o n al inf or mati o n  is discl ose d t o t he Re ge ner o n Parties a n d t o t he ot her or ga nizati o ns 
i de ntifie d a b o ve, it ma y be s u bject t o f urt her discl os ure a n d n o l o n ger pr otecte d b y fe d eral pri v ac y la w. 
 
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Will I h a ve access t o m y res ults ?  
T he  res ults pr o d uce d as part of t his st u d y are f or researc h p ur p oses o nl y. T he res ults are n ot re vi e we d 
f or me dical dia g n osis of a n y dise ase. Beca use t he res ults o btai ne d d uri n g t h e c o urse of t he res earc h ha ve 
o nl y cli nic al res earc h val ue a n d are n ot f or me di cal dia g n osis, Re ge n er o n  d oe s n ot pr o vi de i n di vi d ual 
res ults t o y o u. I n s o me circ u msta nces, Re ge n er o n  ma y pr o vi de certai n res ults t o y o ur st u d y d o ct or. If, 
d uri n g t he c o urse of t he st u d y, t he st u d y d oct or l ear ns i nf or m ati o n relate d t o y o ur healt h fr o m t he st u d y 
pr oce d ures, t he st u d y d oct or ma y disc uss t his i nf or mati o n a n d y o ur o pti o ns wit h y o u.  
 
W h at are m y pri v ac y ri g hts ?  
 
Y o ur Ri g ht t o A ccess a n d/ or C orrect Y o ur I nf or m ati o n : Y o u h a ve t h e ri g ht t o access, t hr o u g h y o ur 
st u d y d oct or, all of t he i nf or mati o n c ollecte d a b o ut y o u i n y o ur m e dical rec or d, a n d t o as k f or 
c orrecti o ns, acc or di n g t o t he r ules of t he st u d y site. Y o u ha ve t he ri g ht t o re q uest i nf or mati o n o n h o w t he 
pers o nal i nf or mati o n  re p orte d t o Re ge ner o n  are b ei n g use d a n d wit h w h o m t he data ha ve bee n s hare d. 
Please n ote t hat y o ur ri g ht t o access certai n i nf or mati o n i n y o ur me dical rec or ds ma y b e s us pe n de d 
d uri n g y o ur partici pati o n i n t he st u d y. T heref ore, if y o u w o ul d li ke i m me diate access t o y o ur rec or ds, 
y o u ma y n ot be a ble t o c o nti n ue partici pati n g i n t he st u d y.  
 
Y o ur Ri g ht t o O bject/ Wit h dr a w : I n or der t o p artici pate i n t his st u d y, Re ge ner o n  m ust c ollect a n d use 
y o ur pers o n al i nf or mati o n . Y o ur decisi o n t o all o w t he c ollecti o n a n d use of y o ur h ealt h i nf or mati o n is 
c o m pletel y v ol u ntar y b ut if y o u d o n ot all o w it, y o u ma y n ot par tici pate i n t he st u d y. If y o u c h a n ge y o ur 
mi n d a b o ut y o ur pers o n al i nf or mati o n  bei n g use d, y o u ca n v ol u ntaril y wit h dra w fr o m t he st u d y at a n y 
ti me. If y o u c h o ose t o wit h dra w y o ur per missi o n, y o u will n ot be p u nis he d i n a n y wa y or l ose a n y ri g ht 
t o access care, treat me nt, or ser vices o utsi de of t he st u d y.  
 
If y o u wit h dra w y o ur per missi o n t o use y o ur p ers o nal i nf or mati o n , t he p ers o nal i nf or mati o n  c oll ecte d 
pri or t o y o ur wit h dra wal will still be pr ocesse d al o n g wit h ot her data c ollecte d as p art of t he st u d y i n  
or der t o preser ve t he i nte grit y of t he res ults a n d i n acc or da nce wit h re g ul at or y re q uir e me nts. T he 
i nf or mati o n c ollecte d a b o ut y o u u p t o t he p oi nt w he n y o u disc o nti n ue fr o m t he st u d y, or i nf or mati o n 
o btai ne d after y o u wit h dra w i n c o n necti o n wit h a safet y iss u e relate d t o t he st u d y, will c o nti n ue t o be 
use d, i ncl u di n g la b res ults, cli nic n otes, a n d a n y ot her i nf or mati o n c ollecte d. H o we v er, n o ne w 
i nf or mati o n will be c ollecte d u nless y ou s pecifi call y c o nse nt t o t hat.  
 
Y o ur Ri g ht t o Re q uest Deleti o n : If y o u wit h dra w fr o m t he st u d y, y o u ma y als o re q uest t hat t he 
pers o nal i nf or mati o n  alrea d y c ollecte d fr o m y o u i n c o n necti o n wit h t he st u d y be delet e d. H o we ver, y o ur 
ri g ht t o deleti o n is li mite d d ue t o re g ulat or y re q uire me nts a n d t o preser ve scie ntific i nte grit y, as y o ur 
pers o nal i nf or mati o n  m ust be ma na ge d i n s pecific wa ys i n or der f or t he researc h t o be relia ble a n d 
acc urate. T he st u d y res ults a n d c o de d data will be ke pt as l o n g as t he y are nee de d f or res earc h p ur p oses, 
a n y re g ulat or y re q uir e me nts, a n d Re ge ner o n ’s d at a rete nti o n sc h e d ule.  
 
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Please be a w are t hat beca use Re ge ner o n  o nl y mai ntai ns c o de d st u d y data, it ge nerall y ca n n ot res p o n d 
directl y t o i n di vi d ual re q uests re gar di n g y o ur pri vac y ri g hts. T h eref ore, y o u s h o ul d a d dress a n y of t hese 
re q uests re gar di n g t hese ri g hts t o t he st u d y site usi n g t he c o ntact i nf or mati o n o n t he first p a ge of t his 
c o nse nt f or m. If y o u ha v e a n y q u esti o ns, c o ncer ns, or c o m plai nts as t o h o w y o ur p ers o nal i nf or mati o n  
has  
bee n  
ha n dle d,  
y o u  
ca n  
c o ntact 
Re ge ner o n ’s  
Dat a  
Pr otecti o n  
Offi cer  
at 
Data Pr otecti o n @ Re ge n er o n.c o m . 
 
Will m y i nf or m ati o n be o n t he i nter net ?  
A descri pti o n of t his cli nical trial will be a vaila bl e o n htt p:// w w w. Cli nical Trials. g o v , as re q uir e d b y U. S. 
La w . T his We b 
site will n ot i ncl u de i nf or mati o n t hat ca n i de ntif y y o u. At most, t he We b 
site will 
i ncl u de a s u m mar y of t h e res ults. Y o u ca n s earc h t his We b site at a n y ti me. S o me re g ulat or y a ut h orities 
a n d et hics c o m mittees ma y m a ke i nf or m ati o n  a vaila ble o n t heir we bsites.  
 
W h at if s o met hi n g is de vel o pe d fr o m t his rese arc h ?  
B y pa rtici p ati n g i n t his st u d y, y o u d o n ot ac q uir e a n y o w ners hi p ri g hts i n t he sa m ples y o u c o ntri b ut e or 
i n a n y me dical or ge n etic tests, dr u gs or ot her c o m mercial pr o d ucts t hat ma y be de v el o pe d  t hr o u g h t his 
researc h. 
 
W h o d o I c all if I h a ve q uesti o ns ?  
T he pe o ple t o c o ntact f or a n y q uesti o ns , c o ncer ns, c o m plai nts or pr o ble ms i n t he st u d y are liste d o n t he 
first pa ge of t his c o nse nt. Y o u ma y as k q uesti o ns bef ore y o u si g n t he c o nse nt, at a n y ti me d uri n g y o ur 
partici pati o n i n t he st u d y, a n d after y o u are fi nis he d wit h t he st u d y.  
 
T his researc h is bei n g o versee n b y a n I nstit uti o nal Re vie w B oar d (“I R B”). A n I R B is a gr o u p of pe o ple 
w h o perf or m i n de pe n de nt re vie w of researc h st u dies. Y o u ma y tal k t o t he m at ( 8 0 0) 5 6 2 -4 7 8 9, 
hel p @ wir b.c o m if:  
 
o  Y o u ha ve q uesti o ns, c o nce r ns, or c o m plai nts t hat are n ot bei n g a ns were d b y t he researc h tea m. 
o  Y o u are n ot getti n g a ns wers fr o m t he researc h tea m.  
o  Y o u ca n n ot reac h t he researc h tea m.  
o  Y o u wa nt t o tal k t o s o me o ne else a b o ut t he researc h.  
o  Y o u ha ve q uesti o ns a b o ut y o ur ri g hts as a rese arc h s u bject. 
 
Pr ot oc ol Title:  
A Master Pr ot oc ol Assessi n g t he Safet y, T ol era bilit y, a n d 
Efficac y of A nti -S pi ke ( S) S A R S -C o V -2 M o n ocl o nal A nti b o dies 
f or t he Treat me nt of A m b ulat or y Patie nts  wit h C O VI D -1 9  
Pr ot oc ol N u m ber:  
 
S p o ns or:  
 
Rese arc h Site:  
R 1 0 9 3 3 -1 0 9 8 7 -C O V -2 0 6 7  
 
Re ge n er o n P har mace uticals, I n c.  
 
[Site ] 
 
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P artici p a nt’s A gree me nt  
 
•  I ha v e rea d a n d u n d ersta n d t his I nf or me d C o nse nt F or m. T his st u d y has bee n e x plai ne d t o me 
i n detail a n d all of m y q uesti o ns ha ve bee n a ns w ere d t o m y s atisfacti o n. I h a ve been gi ve n 
a m ple ti me t o deci de w h et her t o partici pat e.  
•  I a ut h orize t he c ollecti o n, use, discl os ure a n d st ora ge of m y p ers o nal i nf or mati o n  a n d 
bi ol o gical sa m ples f or t h e p ur p oses of t his st u d y as descri be d i n t his f or m.  
•  I v ol u nteer t o partici p ate i n t his researc h st u d y.  
•  I h a ve b ee n i nf or m e d of m y pri vac y ri g hts relat e d t o t he c ollecti o n, use a n d discl os ure of m y 
pers o nal i nf or mati o n  a n d c o nse nt t o s uc h c ollecti o n, use a n d discl os ure.  
•  I a m free t o wit h dra w m y c o nse nt t o t he c ollecti o n, use, a n d discl os ure of my p ers o nal 
i nf or mati o n at a n y ti m e wit h o ut pe nalt y a n d wit h o ut affecti n g m y 
me dical treat me nt; 
h o we ver, I will n ot be a ble t o c o nti n ue m y p artici pati o n i n t he res earc h st u d y after I wit h dr a w 
c o nse nt, a n d data alrea d y c ollecte d will c o nti n ue t o be i ncl u de d i n st u d y a nal ys es, i n 
acc or da nce wit h re g ulat or y re q uire m e nts.  
•  I a gree t hat m y G P/ pers o nal p h ysicia n ca n b e i nf or me d of m y partici pati o n i n t his st u d y. 
•  B y si g ni n g t his f or m, I h a ve n ot wai v e d a n y of t he le gal ri g hts t hat I ot h er wise w o ul d ha ve as 
a partici pa nt i n a researc h st u d y. I u n derst a n d t hat I will recei ve a si g ne d c o p y of t his f or m 
f or m y rec or ds. 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Na me of St u d y Partici pa nt  
( Pri nt Na me) 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Si g nat ure  
 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Date  
( D D M M M Y Y Y Y) 
 
St u d y I n vesti g at or or Pers o n O bt ai ni n g C o nse nt  
I h a ve f ull y i nf or m e d t he partici pa nt a b o ut t he st u d y: 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Na me of St u d y I n vesti gat or or Pers o n 
O btai ni n g C o nse nt ( Pri nt Na me)  
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Si g nat ure  
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Date 
( D D M M M Y Y Y Y) 
 
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I R B A p pr o v e d Te m plate 
M U S T  B E  A P P R O V E D  
F O R  SI T E S  B E F O R E  U S E  
A S M O DI FI E D  
A u g 1 2, 2 0 2 0  
 
8 4 0 _ R 1 0 9 3 3 -1 0 9 8 7 -C O V -2 0 6 7 _ Mai n  I C F P h 2 _ V 9 . 0 
Pa ge 1 7  of 2 0  
Wit ness Si g n at ure  
 
☐ 
N ot A p plica ble: wit ness a gree m e nt is n ot re q uire d.  
☐ 
A p plica ble: wit ness a gree me nt a n d si g n at ure are pr o vi de d bel o w.  
 
As a n i m partial t hir d part y, I wit nesse d t he e ntire c o ns e nt disc ussi o n.  I attest t hat t he a b o ve-n a me d 
partici pa nt recei ve d a ver bal a n d writte n descri pti o n of t he st u d y.  T his i n di vi d ual ha d s ufficie nt ti me t o 
c o nsi der t his i nf or mati o n, ha d a n o p p ort u nit y t o as k q uesti o ns, a n d v ol u ntaril y a gree d t o partici pat e i n 
t his st u d y. 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Na me of I m p artial Wit ness  
( Pri nt Na me) 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Si g nat ure  
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Date 
( D D M M M Y Y Y Y) 
V V- T M F- 2 2 8 3 9 4 0 - 


 
I R B A p pr o v e d Te m plate 
M U S T  B E  A P P R O V E D  
F O R  SI T E S  B E F O R E  U S E  
A S M O DI FI E D  
A u g 1 2, 2 0 2 0  
 
8 4 0 _ R 1 0 9 3 3 -1 0 9 8 7 -C O V -2 0 6 7 _ Mai n  I C F P h 2 _ V 9 . 0 
Pa ge 1 8  of 2 0  
* * F or Sites i n C alif or ni a * *  
A U T H O RI Z A TI O N T O U S E A N D DI S C L O S E I N F O R M A TI O N F O R 
R E S E A R C H P U R P O S E S   
 
W h at i nf or m ati o n m a y be use d a n d gi ve n t o ot hers ?  
T he st u d y d oct or will get y o ur pers o nal a n d me dical i nf or mati o n.  F or e xa m ple:  
•  Past a n d prese nt me dical rec or ds  
•  Researc h rec or ds  
•  Rec or ds a b o ut p h o ne calls ma de as part of t his researc h  
•  Rec or ds a b o ut y o ur st u d y visits.  
 
W h o m a y use a n d gi ve o ut i nf or m ati o n a b o ut y o u ?  
T he st u d y d oct or a n d t he st u d y staff.  [T he y ma y als o s hare t he researc h i nf or mati o n wit h  
[e nter S M O c o m pa n y na me], a n a ge nt f or t he st u d y d oct or. delete if t he site d oes n ot ha ve 
a n S M O] 
 
W h o mi g ht get t his i nf or m ati o n ? 
T he s p o ns or of t his researc h.  “ S p o ns or” mea ns a n y pers o ns or c o m pa nies t hat are:  
•  w or ki n g f or or wit h t he s p o ns or, or  
•  o w ne d b y t he s p o ns or.  
 
Y o ur i nf or m ati o n m a y  be gi ve n t o:  
•  T he U. S. F o o d a n d Dr u g A d mi nistrati o n ( F D A),  
•  De part me nt of Healt h a n d H u ma n Ser vices ( D H H S) a ge ncies,  
•  G o ver n me ntal a ge ncies i n ot her c o u ntries,  
•  T he i nstit uti o n w here t he researc h is bei n g d o ne,  
•  G o ver n me ntal a ge ncies t o w h o m certai n diseases (re p orta ble diseases) 
m ust be 
re p orte d, a n d 
•  I nstit uti o nal Re vie w B oar d (I R B)  
 
V V- T M F- 2 2 8 3 9 4 0 - 


 
I R B A p pr o v e d Te m plate 
M U S T  B E  A P P R O V E D  
F O R  SI T E S  B E F O R E  U S E  
A S M O DI FI E D  
A u g 1 2, 2 0 2 0  
 
8 4 0 _ R 1 0 9 3 3 -1 0 9 8 7 -C O V -2 0 6 7 _ Mai n  I C F P h 2 _ V 9 . 0 
Pa ge 1 9  of 2 0  
W h y will t his i nf or m ati o n be use d a n d/ or gi ve n t o ot hers ?  
•  t o d o t he researc h,  
•  t o st u d y t he res ults, a n d  
•  t o ma ke s ure t hat t he researc h was d o ne ri g ht.   
 
If t he res ults of t his st u d y are ma de p u blic, i nf or mati o n t hat i de ntifies y o u will n ot be 
use d.  
 
W h a t if I deci de n ot t o gi ve per missi o n t o use a n d gi ve o ut m y he alt h i nf or m ati o n ? 
T he n y o u will n ot be a ble t o be i n t his researc h st u d y.  
 
M a y I re vie w or c o p y m y i nf or m ati o n ?  
Yes, b ut o nl y after t he researc h is o ver.  
 
M a y I wit h dr a w or re v o ke (c a ncel) m y p er missi o n ?  
T his per missi o n will be g o o d u ntil Dece m ber 3 1, 2 0 7 0 . 
 
Y o u ma y wit h dra w or ta ke a wa y y o ur per missi o n t o use a n d discl ose y o ur healt h 
i nf or mati o n at a n y ti me.  Y o u d o t his b y se n di n g writte n n otice t o t he st u d y d oct or.  If 
y o u wit h dra w y o ur per mi ssi o n, y o u will n ot be a ble t o sta y i n t his st u d y. 
 
W he n y o u wit h dra w y o ur per missi o n, n o ne w healt h i nf or mati o n i de ntif yi n g y o u will be 
gat here d after t hat date.  I nf or mati o n t hat has alrea d y bee n gat here d  ma y still be use d a n d 
gi ve n t o ot hers.   
 
Is m y he alt h i nf or m ati o n pr otecte d after it h as bee n gi ve n t o ot hers ?  
T here is a ris k t hat y o ur i nf or mati o n will be gi ve n t o ot hers wit h o ut y o ur per missi o n.  
 
V V- T M F- 2 2 8 3 9 4 0 - 


 
I R B A p pr o v e d Te m plate 
M U S T  B E  A P P R O V E D  
F O R  SI T E S  B E F O R E  U S E  
A S M O DI FI E D  
A u g 1 2, 2 0 2 0  
 
8 4 0 _ R 1 0 9 3 3 -1 0 9 8 7 -C O V -2 0 6 7 _ Mai n  I C F P h 2 _ V 9 . 0 
Pa ge 2 0  of 2 0  
A ut h oriz ati o n:  
I ha ve bee n gi ve n t he i nf or mati o n a b o ut t he use a n d discl os ure of m y healt h i nf or mati o n for 
t his researc h st u d y.  M y q uesti o ns ha ve bee n a ns were d. 
 
I a ut h orize t he use a n d discl os ure of m y healt h i nf or mati o n t o t he parties liste d i n t he 
a ut h orizati o n secti o n of t his c o nse nt f or t he p ur p oses descri be d a b o ve.  
 
A U T H O RI Z A TI O N SI G N A T U R E:  
 
 
 
 
 
 
Si g n at ure of S u bject  
 
D ate  
V V- T M F- 2 2 8 3 9 4 0 - 

SAP_002.pdf: 
Regeneron Pharmaceuticals, Inc. 
Protocol: R10933-10987-COV-2067 
Statistical Analysis Plan 
Date: 12 MAR 2021 
CONFIDENTIAL 
Page 1 of 61 
STATISTICAL ANALYSIS PLAN 
PHASE 3  
VERSION: FINAL V1.0 
A MASTER PROTOCOL ASSESSING THE SAFETY, TOLERABILITY, AND 
EFFICACY OF ANTI-SPIKE (S) SARS-COV-2 MONOCLONAL ANTIBODIES FOR 
THE TREATMENT OF AMBULATORY PATIENTS WITH COVID-19 
Compound: 
REGN10933+REGN10987 (REGN-CoV2; REGEN-COV) 
Protocol Number: 
R10933-10987-COV-2067 
Clinical Phase: 
Phase 1/2/3 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatisticians: 
Clinical Trial Manager: 
Study Medical Directors: 
Version/Date: 
Original (Version 1.0) / 12 Mar 2021 
VV-RIM-00147241-1.0 Approved - 12 Mar 2021 GMT-5:00
PPD
PPD
PPD
PPD
PPD
PPD
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Regeneron Pharmaceuticals, Inc. 
Protocol: R10933-10987-COV-2067 
Statistical Analysis Plan 
Date: 12 MAR 2021 
 
CONFIDENTIAL 
Page 2 of 61 
The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting. 
 
 
See appended electronic signature page 
Study Biostatisticians  
 
 
 
See appended electronic signature page 
Study Medical Director 
 
 
See appended electronic signature page 
Study Clinical Pharmacologist 
) 
 
See appended electronic signature page 
Study Bioanalytical Scientist 
 
 
See appended electronic signature page 
Project Biostatistician  
) 
 
See appended electronic signature page 
Head of BDM 
 
                                        VV-RIM-00147241-1.0 Approved - 12 Mar 2021 GMT-5:00
PPD
PPD
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PPD
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PPD


Regeneron Pharmaceuticals, Inc. 
Protocol: R10933-10987-COV-2067 
Statistical Analysis Plan 
Date: 12 MAR 2021 
 
CONFIDENTIAL 
Page 3 of 61 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................7 
1. 
EXECUTIVE SUMMARY ..........................................................................................9 
1.1. 
Background/Rationale ................................................................................................10 
1.2. 
Study Objectives .........................................................................................................10 
1.2.1. 
Primary Objectives .....................................................................................................10 
1.2.2. 
Secondary Objectives .................................................................................................10 
1.2.3. 
Exploratory Objectives ...............................................................................................11 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol ................................12 
1.2.5. 
Revision History for SAP Amendments .....................................................................12 
2. 
INVESTIGATION PLAN ..........................................................................................13 
2.1. 
Study Design and Randomization ..............................................................................13 
2.2. 
Sample Size and Power Considerations for Phase 3 ..................................................16 
3. 
ANALYSIS POPULATIONS ....................................................................................18 
3.1. 
Efficacy Analysis Sets ................................................................................................18 
3.2. 
Safety (SAF) Analysis Set ..........................................................................................19 
3.3. 
Pharmacokinetics Analysis Sets .................................................................................19 
3.4. 
Immunogenicity Analysis Sets ...................................................................................19 
4. 
ANALYSIS VARIABLES .........................................................................................20 
4.1. 
Demographics and Baseline Characteristics ...............................................................20 
4.2. 
Medical History ..........................................................................................................20 
4.3. 
Prior / Concomitant Medications or Procedures .........................................................21 
4.4. 
Rescue Medication/or Prohibited Medication During Study ......................................22 
4.5. 
Efficacy Endpoints ......................................................................................................22 
4.5.1. 
Primary Efficacy Endpoint .........................................................................................22 
4.5.2. 
Secondary Efficacy Endpoints ....................................................................................22 
4.5.3. 
Pharmacokinetics ........................................................................................................25 
4.5.4. 
Immunogenicity ..........................................................................................................25 
4.5.5. 
Exploratory Endpoints ................................................................................................25 
4.6. 
Safety Variables ..........................................................................................................25 
4.6.1. 
Adverse Events and Serious Adverse Events .............................................................26 
4.6.2. 
Adverse Events of Special Interest .............................................................................26 
                                        VV-RIM-00147241-1.0 Approved - 12 Mar 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R10933-10987-COV-2067 
Statistical Analysis Plan 
Date: 12 MAR 2021 
 
CONFIDENTIAL 
Page 4 of 61 
4.6.3. 
Laboratory Safety Variables .......................................................................................27 
4.6.4. 
Vital Signs ..................................................................................................................27 
4.7. 
Pharmacokinetic Variables .........................................................................................27 
4.8. 
Pharmacodynamic and Other Biomarker Variables ...................................................27 
4.9. 
Immunogenicity Variables ..........................................................................................27 
5. 
STATISTICAL METHODS .......................................................................................28 
5.1. 
Demographics and Baseline Characteristics ...............................................................28 
5.2. 
Medical History ..........................................................................................................28 
5.3. 
Prior / Concomitant Medications or Procedures .........................................................28 
5.4. 
Prohibited Medications ...............................................................................................28 
5.5. 
Subject Disposition .....................................................................................................28 
5.6. 
Extent of Study Treatment Exposure and Compliance ...............................................29 
5.6.1. 
Measurement of Compliance ......................................................................................29 
5.6.2. 
Exposure to Investigational Product ...........................................................................29 
5.7. 
Analyses of Efficacy Variables ..................................................................................29 
5.7.1. 
Analysis of Primary Efficacy Variables .....................................................................29 
5.7.2. 
Analysis of Secondary Efficacy Variables .................................................................30 
5.7.3. 
Adjustment for Multiple Comparisons .......................................................................32 
5.8. 
Analysis of Safety Data ..............................................................................................34 
5.8.1. 
Adverse Events ...........................................................................................................35 
5.8.2. 
Clinical Laboratory Measurements.............................................................................36 
5.8.3. 
Analysis of Vital Signs ...............................................................................................36 
5.9. 
Analysis of Pharmacokinetics, Pharmacodynamics and Biomarker Data ..................36 
5.9.1. 
Analysis of Drug Concentration Data .........................................................................36 
5.9.2. 
Analysis of Pharmacokinetics and Pharmacokinetics/Pharmacodynamics ................36 
5.10. 
Analysis of Immunogenicity Data ..............................................................................37 
5.10.1. 
Analysis of ADA Data ................................................................................................37 
5.10.2. 
Analysis of NAb Data .................................................................................................38 
5.11. 
Association of Immunogenicity with Exposure and Safety .......................................38 
5.11.1. 
Immunogenicity and Exposure ...................................................................................38 
5.11.2. 
Immunogenicity and Safety ........................................................................................38 
6. 
DATA CONVENTIONS ............................................................................................39 
                                        VV-RIM-00147241-1.0 Approved - 12 Mar 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R10933-10987-COV-2067 
Statistical Analysis Plan 
Date: 12 MAR 2021 
 
CONFIDENTIAL 
Page 5 of 61 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................39 
6.2. 
Data Handling Convention for Efficacy Variables .....................................................39 
6.3. 
Data Handling Convention for Missing Data .............................................................39 
6.4. 
Visit Windows ............................................................................................................39 
6.5. 
Pooling of Centers for Statistical Analyses ................................................................41 
7. 
INTERIM ANALYSIS ...............................................................................................42 
8. 
SOFTWARE ...............................................................................................................43 
9. 
REFERENCES ...........................................................................................................44 
10. 
APPENDIX.................................................................................................................45 
10.1. 
Schedule of Time and Events .....................................................................................45 
Schedule of Events: Phase 3 (Cohort 1 Patients; Cohort 3 Patients ≥18 Years) ...........................45 
Schedule of Events: Phase 3 (Cohort 2 Patients; Cohort 3 Patients <18 Years) ...........................48 
10.2. 
Criteria for Potentially Clinically Significant Values (PCSV) ...................................53 
10.3. 
Symptom Evolution of COVID-19 (SE-C19) ............................................................61 
 
                                        VV-RIM-00147241-1.0 Approved - 12 Mar 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R10933-10987-COV-2067 
Statistical Analysis Plan 
Date: 12 MAR 2021 
 
CONFIDENTIAL 
Page 6 of 61 
LIST OF TABLES 
Table 1: 
REGN10933+REGN10987 IV Doses for Each Weight Group, Phase 3 
Cohort 2 (Ages 0 to <18 Years) ..................................................................................14 
Table 2: 
Estimated sample sizes at each analysis time point for Phase 3 patients with 
at least 1 risk factor for severe COVID-19 .................................................................16 
Table 3: 
NCI-CTCAE Severity Grading System for Adverse Events ......................................26 
Table 4: 
Hierarchical testing order ...........................................................................................33 
Table 5: 
Example Alpha Spending Function for Analysis of Primary Endpoint .....................34 
Table 6: 
Time Window for Summary of NP Swab for SARS-CoV-2 RT-qPCR 
(Cohort 1 Patients; Cohort 3 Patients ≥ 18 Years) .....................................................40 
Table 7: 
Time Window for Summary of NP Swab for SARS-CoV-2 RT-qPCR 
(Cohort 2 Patients; Cohort 3 Patients < 18 Years) .....................................................40 
Table 8: 
Time Window for Summary of Laboratory and Biomarker Variables except 
Serum for Serology (Cohort 1 Patients; Cohort 3 Patients ≥ 18 Years) .....................40 
Table 9: 
Time Window for Summary of Laboratory and Biomarker Variables except 
Serum for Serology (Cohort 2 Patients and Cohort 3 Patients <18 Years with 
Body Weight ≥ 10 kg) ................................................................................................40 
Table 10: Time Window for Summary of Serum for Serology (Cohort 1 Patients; 
Cohort 3 Patients ≥ 18 Years; Cohort 2 patients and Cohort 3 Patients <18 
Years with Body Weight ≥ 10 kg) ..............................................................................41 
Table 11: Time Window for Summary of Laboratory and Biomarker Variables (Cohort 
2 Patients with Body Weight < 10 kg)........................................................................41 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram, Phase 3 (Cohort 1 Patients; Cohort 3 Patients ≥18 
Years) ..........................................................................................................................15 
Figure 2: 
Study Flow Diagram, Phase 3 (Cohort 2 Patients; Cohort 3 Patients <18 
Years) ..........................................................................................................................15 
 
 
                                        VV-RIM-00147241-1.0 Approved - 12 Mar 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R10933-10987-COV-2067 
Statistical Analysis Plan 
Date: 12 MAR 2021 
 
CONFIDENTIAL 
Page 7 of 61 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
Abbreviation 
Definition 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
COVID-19 
Coronavirus Disease 2019 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
CRP 
C-reactive protein 
ECG 
Electrocardiogram 
FAS 
Full Analysis Set 
ICH 
International Council for Harmonisation 
IWRS 
Interactive Web Response System 
IV 
Intravenous 
mFAS 
Modified full analysis set 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effects Model for Repeated Measures 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse 
Events 
OP 
Oropharyngeal 
NP 
Nasopharyngeal 
PCR 
Polymerase Chain Reaction 
PCSV 
Potentially Clinically Significant Value 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PT 
Preferred Term 
RBC 
Red Blood Cell 
RMST 
Restricted Mean Survival Time 
                                        VV-RIM-00147241-1.0 Approved - 12 Mar 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R10933-10987-COV-2067 
Statistical Analysis Plan 
Date: 12 MAR 2021 
 
CONFIDENTIAL 
Page 8 of 61 
Abbreviation 
Definition 
RNA 
Ribonucleic Acid 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper Limit Normal 
US 
United States (of America) 
WBC 
White blood cell 
WHO 
World Health Organization 
WHODD 
World Health Organization Drug Dictionary 
 
                                        VV-RIM-00147241-1.0 Approved - 12 Mar 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R10933-10987-COV-2067 
Statistical Analysis Plan 
Date: 12 MAR 2021 
 
CONFIDENTIAL 
Page 9 of 61 
1. 
EXECUTIVE SUMMARY 
The purpose of the statistical analysis plan (SAP) is to ensure the integrity of the study results by 
pre-specifying the statistical approaches for the analysis of study data prior to a database lock of 
this phase 1/2/3 adaptive study R10933-10987-COV-2067 of anti-Spike SARS-CoV-2 
monoclonal antibodies in ambulatory patients with COVID-19.  
Study R10933-10987-COV-2067 is an adaptive phase 1/2/3, randomized, double-blinded, 
placebo-controlled 
trial 
to 
evaluate 
the 
efficacy 
and 
safety 
of 
co-administered 
REGN10933+REGN10987 combination therapy (“REGN10933+REGN10987”; REGN-COV2; 
REGEN-COV) in outpatient (ie, ambulatory) adults with COVID-19. An initial descriptive 
analysis of phase 1/2 data from the first 275 patients enrolled in this study was conducted based 
on a database lock on 23 September 2020. The primary phase 2 analysis was conducted based on 
a database lock on 24 October 2020, in which virologic efficacy was evaluated in the next 524 
patients enrolled in the symptomatic cohort and clinical efficacy was evaluated in the combined 
analysis groups comprised of the first 799 randomized symptomatic patients. These analyses 
informed the phase 3 study design and provided insight into how the phase 3 analysis plan should 
be organized.  
This version of the SAP implements the final phase 3 analysis plan for the study according to 
protocol amendment 8. The phase 3 portion of the study consists of patients separated into 3 
cohorts: cohort 1 (symptomatic patients ≥18 years of age after 799 symptomatic patients from 
phase 1/2, not pregnant at randomization), cohort 2 (<18 years of age, not pregnant at 
randomization), and cohort 3 (pregnant at randomization). The analyses described herein apply 
only to the three cohorts in phase 3. 
Based on the concept that the effects of REGN10933+REGN10987 are mediated by anti-viral 
activity and that benefit would be best observed by focusing analyses on patients who had not 
cleared virus at baseline and are at high risk for severe COVID-19, efficacy analyses will be 
conducted in a subset of the full analysis set (FAS), termed the modified full analysis set (mFAS), 
which includes patients who have detectable SARS-CoV-2 RNA by RT-qPCR in nasopharyngeal 
swabs at randomization and at least 1 risk factor for severe COVID-19. Analyses in the FAS that 
are not dependent on having detectable virus at baseline will be provided as supportive analysis.  
(The FAS represents all patients randomized and analyzed as randomized; it is equivalent to the 
ITT population for this study).  
The Independent Data Monitoring Committee (IDMC) recently made a recommendation to stop 
enrollment into the placebo group based on clear efficacy. The Sponsor stopped enrolling patients 
in the placebo group as of 25 February 2021, and the study continues to enroll patients 1:1 into 
either of the REGN10933+REGN10987 treatment arms (1200 mg or 2400 mg). Based on the 
IDMC's recommendation, the Sponsor has decided to perform the final primary efficacy analysis 
of the REGN10933+REGN10987 2400 mg treatment group versus placebo, where the primary 
endpoint will be the proportion of patients with a hospitalization related to COVID-19 or all-cause 
death. The efficacy analysis will be conducted in phase 3, cohort 1 patients with at least 1 risk 
factor for severe COVID-19 who were randomized on or before 17 January 2021, with a data cut 
date of 18 Feburary 2021, ensuring all patients had an opportunity to reach day 29. This will be 
the final primary efficacy analysis for the REGN10933+REGN10987 2400 mg treatment group 
compared to placebo because it is estimated that there is sufficient power for the analysis of the 
                                        VV-RIM-00147241-1.0 Approved - 12 Mar 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R10933-10987-COV-2067 
Statistical Analysis Plan 
Date: 12 MAR 2021 
 
CONFIDENTIAL 
Page 10 of 61 
proportion of patients with hospitalization related to COVID-19 or all-cause death endpoint. An 
interim analysis of the REGN10933+REGN10987 1200 mg treatment versus placebo comparisons 
using patients randomized on or before 17 January 2021 will also be performed. The final analysis 
of REGN10933+REGN10987 1200 mg versus placebo comparisons will be based on all phase 3 
patients randomized on or before 24 February 2021. 
1.1. 
Background/Rationale 
This study is an adaptive phase 1/2/3, randomized, double-blinded, placebo-controlled trial to 
evaluate the efficacy and safety of co-administered REGN10933+REGN10987 combination 
therapy (“REGN10933+REGN10987”) in outpatient (ie, ambulatory) adults with COVID-19. 
Treatments referenced in the protocol that were not utilized in the study will not be analyzed and 
are not discussed in this SAP. 
1.2. 
Study Objectives  
1.2.1. 
Primary Objectives 
Cohort 1 (≥ 18 Years, Not Pregnant at Randomization) 
• The primary objective of phase 3 is to evaluate the clinical efficacy of 
REGN10933+REGN10987 compared to placebo, as measured by COVID-19-related 
hospitalizations or all-cause death. 
Cohort 2 (< 18 Years, Not Pregnant at Randomization) 
• To evaluate the safety and tolerability of REGN10933+REGN10987 compared to 
placebo 
• To further characterize the concentrations of REGN10933 and REGN10987 in serum 
over time 
Cohort 3 (Pregnant at Randomization) 
• To evaluate the safety and tolerability of REGN10933+REGN10987 
1.2.2. 
Secondary Objectives 
The secondary objectives of the phase 3 are: 
Cohort 1 
• To evaluate the impact of REGN10933+REGN10987 on the resolution of self-reported 
COVID-19 symptoms compared to placebo 
• To evaluate the clinical efficacy of REGN10933+REGN10987 compared to placebo 
using various measures of COVID-19-related medically-attended visits, including 
COVID-19-related hospitalizations, emergency room visits, or all-cause death 
• To describe the virologic effects of REGN10933+REGN10987 compared to placebo 
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• To evaluate the safety and tolerability of REGN10933+REGN10987 compared to 
placebo 
• To further characterize the concentrations of REGN10933 and REGN10987 in serum 
over time 
• To assess the immunogenicity of REGN10933 and REGN10987 
Cohort 2 
• To evaluate the clinical efficacy of REGN10933+REGN10987 compared to placebo 
using various measures of COVID-19-related medically-attended visits, including 
COVID-19-related hospitalizations or all-cause death 
• To describe the virologic effects of REGN10933+REGN10987 compared to placebo 
• To assess the immunogenicity of REGN10933 and REGN10987 
Cohort 3 
• To characterize the concentrations of REGN10933 and REGN10987 in serum over 
time  
• To assess the immunogenicity of REGN10933 and REGN10987 
1.2.3. 
Exploratory Objectives 
The exploratory objectives of the phase 3 are: 
• To evaluate viral variants at baseline and post-treatment 
• To explore the potential association of baseline humoral immune response to SARS-
CoV-2 on response to REGN10933+REGN10987  
• To evaluate the effects of REGN10933+REGN10987 compared to placebo on 
generation of a humoral immune response to SARS-CoV-2 (as measured by anti-
SARS-CoV-2 N protein) 
• To explore the effects of REGN10933+REGN10987 on measures of SARS-CoV-2 
infectivity as assessed in experimental laboratory assays 
• To explore biomarkers predictive of REGN10933+REGN10987 safety, efficacy, 
and/or disease progression and COVID-19 clinical outcomes 
• To 
explore 
the 
underlying 
mechanisms 
of 
action 
and 
biology 
of 
REGN10933+REGN10987, SARS-CoV-2, and COVID-19 
• To explore relationships between REGN10933+REGN10987 exposure and selected 
efficacy endpoints, safety endpoints, and/or biomarkers 
• To evaluate the impact on self-reported symptoms of REGN10933+REGN10987 
compared to placebo 
• To assess the clinical efficacy of different dose levels of REGN10933+REGN10987, 
as measured by COVID-19-related hospitalizations or all-cause death 
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• To describe the relationship between virologic effects of REGN10933+REGN10987 
and risk of COVID-19-related medically-attended visit or all-cause death  
• To evaluate the effects of REGN10933+REGN10987 compared to placebo on the 
generation of endogenous humoral and/or cellular immune responses to SARS-CoV-2 
(optional sub-study) (cohort 1) 
• To evaluate the impact of REGN10933+REGN10987 on the resolution of self-reported 
COVID-19 symptoms compared to placebo (cohort 2 age ≥12 years) 
• To describe the clinical outcomes of patients treated with REGN10933+REGN10987 
using various measures of COVID-19-related medically-attended visits, including 
COVID-19-related hospitalizations or all-cause death (cohort 3) 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol 
There is no modification from the statistical section in the protocol amendment 8. 
1.2.5. 
Revision History for SAP Amendments 
None.  
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design and Randomization 
This is an adaptive, phase 1/2/3, randomized, double-blinded, placebo-controlled study to evaluate 
the efficacy, safety, and tolerability of REGN10933+REGN10987 combination therapy in 
ambulatory patients (ie, outpatients) with early-stage COVID-19.  
In phase 1, only symptomatic patients with COVID-19 were enrolled. In phase 2, symptomatic 
patients and asymptomatic patients were enrolled into separate cohorts. In phase 3, only 
symptomatic patients are enrolled. The phase 3 patients are enrolled into the following cohorts.  
• cohort 1 (≥ 18 years of age, not pregnant at randomization),  
• cohort 2 (< 18 years of age, not pregnant at randomization) and  
• cohort 3 (pregnant at randomization). 
Cohort 1 
Prior to protocol amendment 6, patients were randomized in a 1:1:1 allocation ratio to one of the 
treatments listed below:  
• Co-administered REGN10933+REGN10987 combination therapy, 2400 mg (1200 mg 
each of REGN10933 and REGN10987) IV single dose  
• Co-administered REGN10933+REGN10987 combination therapy, 8000 mg (4000 mg 
each of REGN10933 and REGN10987) IV single dose  
• Placebo IV single dose 
Randomization was stratified by: 
• Presence/absence of COVID-19 symptoms (ie, symptomatic versus asymptomatic 
cohort). Any asymptomatic patient enrolled are considered to be part of phase 2. 
• Country 
• Risk factors for severe COVID-19 (no risk factors for severe COVID 19 versus ≥1 risk 
factor for severe COVID-19).  
Starting with Protocol Amendment 6, patients were randomized in a 1:1:1 allocation ratio to one 
of the treatments listed below, according to a central randomization scheme using an interactive 
web response system (IWRS) and randomization was stratified by country. The stratification 
factors for presence/absence of COVID-19 symptoms and risk factors for hospitalization due to 
COVID-19 were removed because asymptomatic patients and those without risk factors were no 
longer eligible for the study: 
• Co-administered REGN10933+REGN10987 combination therapy, 1200 mg (600 mg 
each of REGN10933 and REGN10987) IV single dose 
• Co-administered REGN10933+REGN10987 combination therapy, 2400 mg (1200 mg 
each of REGN10933 and REGN10987) IV single dose 
• Placebo IV single dose 
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Starting with protocol amendment 8, cohort 1 will be randomized 1:1 to a single dose of 
REGN10933+REGN10987 1200 mg IV or REGN10933+REGN10987 2400 mg IV and 
randomization stratified by country. Patients in this cohort will no longer be randomized to 
placebo. 
Cohort 2 
Starting with Protocol Amendment 6, pediatric patients were enrolled into cohort 2, randomized 
in a 1:1:1 allocation ratio to a single IV dose of REGN10933+REGN10987 at a lower dose level, 
at a higher dose level, or to placebo, where the exact dose was tiered according to body weight to 
match REGN10933+REGN10987 2400 mg or REGN10933+REGN10987 1200 mg, as defined in 
Table 1.  
Starting with protocol amendment 8, cohort 2 will be randomized 1:1 to a single IV dose of 
REGN10933+REGN10987 high dose or REGN10933+REGN10987 low dose, as defined in 
Table 1.  Patients in this cohort will no longer be randomized to placebo. 
Table 1: 
REGN10933+REGN10987 IV Doses for Each Weight Group, Phase 3 Cohort 
2 (Ages 0 to <18 Years) 
Body Weight 
Group 
Dose Equivalent for 
REGN10933+REGN10987 1200 mg 
IV Dose (600 mg per mAb) 
Dose Equivalent for 
REGN10933+REGN10987 2400 
mg IV Dose (1200 mg per mAb) 
≥40 kg 
1200 mg (600 mg per mAb) 
2400 mg (1200 mg per mAb) 
≥20 kg to <40 kg 
450 mg (225 mg per mAb) 
900 mg (450 mg per mAb) 
≥10 kg to <20 kg 
224 mg (112 mg per mAb) 
450 mg (225 mg per mAb) 
≥5 kg to <10 kg 
120 mg (60 mg per mAb) 
240 mg (120 mg per mAb) 
≥2.5 kg to <5 kg 
60 mg (30 mg per mAb) 
120 mg (60 mg per mAb) 
<2.5 kg 
30 mg (15 mg per mAb) 
60 mg (30 mg per mAb) 
In phase 3 cohort 2, randomization will be stratified by country 
Cohort 3 
Patients in cohort 3 will be randomized in a 1:1 allocation ratio to co-administered 
REGN10933+REGN10987 combination therapy IV single dose (no placebo). Patients in cohort 3 
who are ≥18 years of age will follow the REGN10933+REGN10987 dose levels described for 
cohort 1 (1200 mg and 2400 mg). Patients in cohort 3 who are <18 years of age will follow the 
adjusted REGN10933+REGN10987 dose levels described in Table 1. 
In phase 3, cohort 3, randomization will not be stratified. 
The study design schematic before protocol amendment 8 is presented in Figure 1 and Figure 2.  
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Figure 1: 
Study Flow Diagram, Phase 3 (Cohort 1 Patients; Cohort 3 Patients ≥18 
Years) 
 
 
 
Figure 2: 
Study Flow Diagram, Phase 3 (Cohort 2 Patients; Cohort 3 Patients <18 Years) 
 
 
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2.2. 
Sample Size and Power Considerations for Phase 3 
The phase 3 sample size of the study is based on having sufficient power to analyze the primary 
endpoint of proportion of patients with a COVID-19-related hospitalization or all-cause death in 
the modified full analysis set (mFAS). Based on data from the phase 2 analysis involving the first 
799 symptomatic patients enrolled and blinded phase 3 data, the sponsor assumes an event rate of 
3.4% for COVID-19-related hospitalization or all-cause death among patients on placebo in the 
mFAS (patients with at least 1 risk factor for severe COVID-19 and a positive SARS-CoV-2 RT-
qPCR test at baseline), and that 83% of all randomized patients (FAS) will have a positive SARS-
CoV-2 RT-qPCR test at baseline.  
The following table presents estimated number of randomized patients with at least 1 risk factor 
for severe COVID-19 at each analysis time point for cohort 1 efficacy analysis. 
Table 2: 
Estimated sample sizes at each analysis time point for Phase 3 patients with 
at least 1 risk factor for severe COVID-19 
 
Placebo 
FAS1 
(mFAS) 
1200 mg 
FAS1 (mFAS) 
2400 mg 
FAS1 
(mFAS) 
8000 mg 
FAS1 (mFAS) 
Total 
FAS1 
(mFAS) 
Pre-Amendment 6 patients 
662 (550) 
Not applicable 
662 (550) 
662 (550) 
1986 (1650) 
Amendment 6/7 patients 
randomized by 
17 January 2021 
841 (698) 
841 (698) 
841 (698) 
Not applicable 
2523 (2094) 
Final analysis for 2400 mg 
vs. placebo (patients 
randomized by 
17 January 2021) 
1503 
(1248) 
 
1503 (1248) 
 
 
Interim analysis for 1200 
mg vs. placebo (patients 
randomized by 
17 January 2021) 
841 (698) 
841 (698) 
 
 
 
Amendment 6/7 patients 
randomized by 
24 February 2021 
1352 
(1122) 
1352 (1122) 
1352 (1122) 
Not applicable 
4056 (3366) 
Final analysis for 1200 mg 
vs. placebo (patients 
randomized by 
24 February 2021) 
1352 
(1122) 
1352 (1122) 
 
 
 
1 FAS estimates only include those in FAS with ≥1 risk factor for severe COVID-19. 
The final primary efficacy analysis for the 2400 mg dose group versus placebo comparison will be 
performed based on patients randomized on or before 17 January 2021, which includes 
approximately 1503 randomized patients with COVID-19 risk factors per group in the 2400 mg 
dose group and the placebo group (1248 per group in mFAS). The study will have approximately 
76% power to detect a significant treatment effect in the proportion of patients with ≥1 COVID-
19-related hospitalization or all-cause death in mFAS at a 2-sided α of 0.05, assuming 3.4% of 
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patients in the placebo group and 1.7% of patients in the 2400 mg group have an event (ie, a 50% 
reduction with R10933+R10987 treatment). If there is a greater treatment difference, such as a 
60% reduction, the study will have at least 90% power to detect a significant treatment effect in 
the proportion of patients with ≥1 COVID-19-related hospitalization or all-cause death. 
The final efficacy analysis of the 1200 mg dose group versus placebo comparison will be 
performed in approximately 1352 patients with COVID-19 risk factors per dose group 
(approximately 1122 per dose group estimated in mFAS), representing the cohort of patients 
enrolled starting in Protocol Amendment 6 (i.e., when the 1200 mg dose was introduced) through 
February 24, 2021, the last date that enrollment into the placebo group was allowed. This analysis 
will only include patients who were concurrently randomized to either the 1200 mg dose group or 
the placebo group. The study will have approximately 72% power to detect a significant treatment 
effect in the proportion of patients with ≥1 COVID-19-related hospitalization or all-cause death in 
the mFAS at a 2-sided α of 0.05 assuming 3.4% of patients in the placebo group and 1.7% of 
patient in the 1200 mg group have an event (i.e., a 50% reduction). If there is a greater treatment 
difference, such as a 60% reduction, the study will have approximately 88% power to detect a 
significant treatment effect in the proportion of patients with ≥1 COVID-19-related hospitalization 
or all-cause death. 
From 25 February 2021 onward, the Sponsor plans to randomize up to approximately 1500 patients 
1:1 to either the 1200 mg dose group or the 2400 mg dose group in addition to the patients enrolled 
under Amendment 6 or 7, to have adequate precision to estimate the difference in the proportion 
of patients with a COVID-19-related hospitalization or death between the 2 dose groups. For 
example, assuming an event rate of 1.7% in each group, with a total of approximately 2100 
concurrently randomized patients per arm (1744 per arm in mFAS) in 1200 mg and 2400 mg dose 
groups, a 2-sided 95% confidence interval for the difference will extend approximately 1% from 
the observed difference. Blinded sample size reestimation may be performed based on the pooled 
observed event rates. 
The EAST v6.0 software was used for sample size calculation. 
Phase 3 Cohort 2 and Cohort 3 
Up to approximately 180 pediatric patients in cohort 2 is planned with a goal of approximately 52 
patients exposed to each dose of study drug, which is considered adequate to describe the drug 
concentrations over time. In cohort 2, there will be an enrollment of approximately 20 patients <10 
kg (10 per treatment group) and 20 patients between ≥10 kg and <40 kg (10 per treatment group). 
In cohort 3, no minimum or maximum enrollment is planned.  
Cohorts 2 and 3 will be analyzed descriptively for safety, and may be analyzed descriptively for 
clinical and virologic outcomes. 
Note that cohort 2 and cohort 3 may continue to enroll after enrollment of cohort 1 has been 
completed. 
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3. 
ANALYSIS POPULATIONS 
In accordance with guidance from the International Conference for Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (ICH, 1998) the following population of analysis will be 
used for all statistical analyses in the phase 1/2 portion of this study. 
3.1. 
Efficacy Analysis Sets 
Cohort 1 
All symptomatic patients from the 800th randomized symptomatic patient will be included in the 
phase 3 portion of the study. The full analysis set (FAS) includes all randomized patients in phase 
3 cohort 1, including those with or without risk factors for severe COVID-19, and is based on the 
treatment allocated (as randomized). 
The modified full analysis set (mFAS) for phase 3 includes all randomized patients with a positive 
central lab-determined RT-qPCR test from nasopharyngeal (NP) swab samples at randomization, 
and with at least one risk factor for severe COVID-19 at baseline. If pre-dose virologic results 
from the qualitative test are missing, then results from post-dose sample may be used to determine 
the qualitative PCR status at baseline, as long as the sample was collected within 2 hours after 
starting the study drug infusion. The mFAS is based on the treatment allocated (as randomized). 
The seronegative mFAS is defined as all randomized patients with documented seronegative status 
(eg, SARS-CoV-2 serum antibody negative) at baseline in the mFAS.  
Both mFAS and FAS will be used for the summaries of demographic and baseline characteristics. 
The mFAS will be used for the analysis of clinical, symptoms, and virologic endpoints. The 
seronegative mFAS will be used for the analysis of certain virologic endpoints and in analyses of 
certain clinical endpoints. Data from patients with no risk factors will be summarized descriptively. 
For the analyses of 1200 mg group comparing to placebo, only patients concurrently randomized 
(ie, after Protocol Amendment 6 is implemented) will be included. 
Cohort 2 
The FAS includes all randomized patients in phase 3 cohort 2 and is based on the treatment 
allocated (as randomized). The modified full analysis set (mFAS) includes all randomized patients 
with positive RT-qPCR in NP swab samples at randomization and is based on the treatment 
allocated (as randomized). If pre-dose results from the qualitative test are missing, then results 
from post-dose sample may be used to determine the qualitative PCR status at baseline, as long as 
the sample was collected within 2 hours after starting the study drug infusion. The seronegative 
mFAS is defined as all randomized patients with documented seronegative status at baseline in the 
mFAS. 
Cohort 3 
Data on all patients in Cohort 3 (pregnant population) will be utilized in the analyses. 
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3.2. 
Safety (SAF) Analysis Set 
The safety analysis set (SAF) includes all randomized patients who received any study drug; it is 
based on the treatment received (as treated). Determination of “as treated” will be based on the 
actual study drug received on day 1. Demographic and baseline characteristics, treatment 
compliance/administration and all clinical safety variables will be analyzed using the SAF. 
3.3. 
Pharmacokinetics Analysis Sets 
The pharmacokinetics (PK) analysis population includes all patients who received any study drug 
(safety population) and who had at least 1 non-missing result following the first dose of study drug. 
Patients will be analyzed based on actual treatment received. 
3.4. 
Immunogenicity Analysis Sets 
The immunogenicity analysis set is dependent on assay availability. 
The anti-drug antibody (ADA) analysis set (AAS) includes all subjects who received any study 
drug (safety population) and had at least one non-missing ADA result from the ADA assay after 
first dose of the study drug(s). Subjects will be analyzed according to the treatment actually 
received. 
Samples positive in the ADA assay will be characterized further for ADA titers and for the 
presence of neutralizing antibody (Nab). The NAb analysis set (NAS) includes all patients who 
received any study drug and who are either negative in the ADA assay or positive for ADA with 
at least one non-missing result in the NAb assay after first dose of the study drug. Subjects who 
are negative for ADA are set to negative in the NAb analysis set 
Subjects will be analyzed according to the treatment actually received. 
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4. 
ANALYSIS VARIABLES 
4.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristic variables include the following: 
• Age at screening (years) 
• Age group (<18, 18 to <65, ≥50, ≥65, ≥75) 
• Sex (Male, Female) 
• Race (Asian, American Indian/Alaska Native, Black/African American, Native 
Hawaiian/Other Pacific Islander, White and Other) 
• Ethnicity (Hispanic or Latino, Not-Hispanic or Latino) 
• Baseline Weight (kg) 
• Baseline Height (cm) 
• Baseline Body mass index (BMI) (kg/m2) calculated from weight and height 
• Obesity (not obese, BMI <=30 kg/m2; obese, BMI >30 kg/m2) 
• Risk factor for severe COVID-19, per CRF (no risk factor, ≥1 risk factor) 
• Baseline SARS-CoV-2 results from central lab (excluding assessment at screening 
visit)  
• Baseline viral load based on RT-qPCR result (copies/mL as well as log10 copies/mL) 
• Baseline viral load categories (>107, >106, >105, etc. copies/mL) 
• Baseline qualitative RT-PCR results (positive, negative, other) 
• Baseline serostatus (positive, negative, other) 
A patient’s serostatus is considered to be positive if any anti-SARS-CoV-2 antibody 
test (eg, anti-SARS-CoV-2 IgA or IgG) is positive, negative if all available tests are 
negative, and other if serostatus is not positive or negative (eg, borderline result) or is 
unknown. 
• Baseline C-Reactive Protein (mg/L) 
• Time from onset of first COVD-19-related symptom, as determined by the investigator, 
to randomization (days) 
4.2. 
Medical History 
Medical history will include the following:  
• COVID-19 with start date as the date of onset of first symptom related to COVID-19 
• Risk factors for severe COVID-19/hospitalization due to COVID-19 as defined below 
• Whether the patient is receiving oxygen at home by nasal cannula  
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• Pregnancy or breastfeeding status, if applicable 
 
Risk factors for severe COVID-19 are defined as follows: 
a. Age ≥50 years (cohort 1 only) 
b. Obesity, defined as: 
BMI ≥30 kg/m2 (cohort 1 only) 
BMI (kg/m2) ≥95th percentile for age and sex based on CDC growth charts (cohort 2 
≥2 years only) 
c. Cardiovascular disease, including hypertension 
d. Chronic lung disease, including asthma 
e. Type 1 or type 2 diabetes mellitus 
f. Chronic kidney disease, including those on dialysis 
g. Chronic liver disease 
h. Pregnancy 
i. Immunosuppressed, based on investigator’s assessment  
Examples include cancer treatment, bone marrow or organ transplantation, immune 
deficiencies, HIV (if poorly controlled or evidence of AIDS), sickle cell anemia, 
thalassemia, and prolonged use of immune-weakening medications 
j. Any underlying genetic condition, neurologic condition, metabolic condition, or 
congenital heart disease deemed by the investigator to be a risk factor for severe 
COVID-19 (cohort 2 only) 
4.3. 
Prior / Concomitant Medications or Procedures 
Medications/Procedures will be recorded from the day of informed consent until the final study 
assessment (Day 169 or early study discontinuation or death). Medications will be coded to the 
ATC level 2 (therapeutic main group) and ATC level 4 (chemical/therapeutic subgroup), according 
to WHO Drug Dictionary (WHODD) version 202003 or later. Patients will be counted once in all 
ATC categories linked to the medication. 
Prior medications/procedures are: medications taken or procedures performed prior to 
administration of the study drug. 
Concomitant medications/procedures are: medications taken or procedures performed 
following the first dose of study drug through the final study assessment (Day 169 or early study 
discontinuation or death).  This includes medications taken that started before the study and are 
ongoing during the study. 
Only select concomitant medications will be captured in this trial. The select list of medications 
include, but are not limited to, corticosteroids, remdesivir, lopinavir-ritonavir, chloroquine, 
hydroxychloroquine, interferon beta, and convalescent serum. In addition, any concomitant 
procedures used to treat an adverse event will be captured in this trial. 
Analysis of medications data will be focused on the targeted medications (specified in the 
protocol) that are expected to be reviewed and recorded by sites. 
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4.4. 
Rescue Medication/or Prohibited Medication During Study 
Patients can receive rescue therapy for COVID-19 per local standard-of-care. Rescue treatments 
are not provided as part of the study. 
Patients are not permitted to receive any medication specified in the exclusion criteria (of the 
protocol) for study enrollment, unless medically indicated.  Patients may otherwise continue their 
normal regimen of medications and procedures.  All data collected on medications/procedures 
(pre-treatment and concomitant) will be summarized. 
4.5. 
Efficacy Endpoints 
4.5.1. 
Primary Efficacy Endpoint 
Cohort 1 
The primary clinical efficacy endpoint for phase 3 is the proportion of patients with ≥1 
COVID-19-related hospitalization or all-cause death through day 29. 
4.5.2. 
Secondary Efficacy Endpoints 
The secondary endpoints for phase 3 are: 
Cohort 1 
The key secondary endpoints for phase 3 are  
• Proportion of patients with ≥1 COVID-19-related hospitalization or all-cause death 
from day 4 through day 29 
• Time to COVID-19 symptoms resolution. 
The other secondary efficacy endpoints for phase 3 are: 
• Proportion of patients with ≥1 COVID-19-related hospitalization, emergency room 
(ER) visit, or all-cause death through day 29  
• Proportion of patients with ≥1 COVID-19-related medically-attended visit or all-cause 
death through day 29  
• Proportion of patients with COVID-19 related medically-attended visits by type of 
visit(s) (hospitalization, ER visit, urgent care, and/or physician’s office/telemedicine 
visit) through day 29 
• Proportion of patients with ≥2 COVID-19 related medically-attended visits through day 
29 
• Cumulative incidence of ≥1 COVID-19-related hospitalization or all-cause death 
through day 29 
• Cumulative incidence of COVID-19-related hospitalizations or ER visits through day 
29 
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• Cumulative incidence of patients with ≥1 COVID-19-related medically-attended visit 
or all-cause death through day 29 
• Days of hospitalization due to COVID-19 
• Proportion of patients admitted to an ICU due to COVID-19 by day 29 
• Proportion of patients requiring supplemental oxygen due to COVID-19 by day 29 
• Proportion of patients requiring mechanical ventilation due to COVID-19 by day 29 
• Total number of COVID-19-related medically-attended visits through day 29  
• Time to all-cause death 
• All-cause death by day 29, day 120, and day 169 
• Time-weighted average change from baseline in viral load (log10 copies/mL) from day 
1 to day 7, as measured by RT-qPCR in NP swab samples (patients enrolled prior to 
protocol amendment 6 only) 
• Change from baseline in viral load at each visit, as measured by RT-qPCR in NP 
samples 
Cohort 2 
The secondary endpoints for phase 3 are: 
• Proportion of patients with ≥1 COVID-19-related hospitalization or all-cause death 
through day 29 
• Proportion of patients with ≥1 COVID-19-related hospitalization or all-cause death 
from day 4 through day 29 
• Proportion of patients with ≥1 COVID-19-related hospitalization, ER visit, or all-cause 
death through day 29  
• Proportion of patients with ≥1 COVID-19-related medically-attended visit or all-cause 
death through day 29 
• Proportion of patients with ≥1 COVID-19-related medically-attended visit by type of 
visit(s) (hospitalization, ER visit, urgent care, and/or physician’s office/telemedicine 
visit) through day 29 
• Proportion of patients with ≥2 COVID-19-related medically-attended visits through 
day 29 
• Cumulative incidence of patients with ≥1 COVID-19-related hospitalization or all-
cause death through day 29 
• Cumulative incidence of patients with ≥1 COVID-19-related hospitalization, ER visit, 
or all-cause death through day 29 
• Cumulative incidence of patients with ≥1 COVID-19-related medically-attended visit 
or all-cause death through day 29 
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• Days of hospitalization due to COVID-19 
• Proportion of patients admitted to an ICU due to COVID-19 by day 29 
• Proportion of patients requiring supplemental oxygen due to COVID-19 by day 29 
• Proportion of patients requiring mechanical ventilation due to COVID-19 by day 29 
• Total number of COVID-19-related medically-attended visits through day 29 
• Time to all-cause death 
• All-cause death by day 29, day 120, and day 169. 
• Time-weighted average change from baseline in viral load (log10 copies/mL) from day 
1 to day 7, as measured by RT-qPCR in NP swab samples. 
• Change from baseline in viral load at each visit, as measured by RT-qPCR in NP 
samples 
• Immunogenicity, as measured by ADA and NAbs to REGN10933 and REGN10987 
Cohort 3 
The secondary endpoints for phase 3 are: 
• Concentrations of REGN10933 and REGN10987 in serum over time 
• Immunogenicity, as measured by anti-drug antibodies and neutralizing antibodies to 
REGN10933 and REGN10987  
Endpoint definitions 
Time to COVID-19 symptoms resolution will be defined as time from randomization to the first 
day during which the subject scored none on all symptoms except fatigue, headache, and cough, 
which can be mild/moderate or none. Patients with missing baseline assessment will not be 
included in the analysis.  
Time-weighted average of change from baseline viral load in the nasopharyngeal (NP) swab 
samples from day 1 through day 7 will be calculated for each patient with intensive viral load data 
collection (ie, those randomized under protocol amendment 5 or earlier) using the linear 
trapezoidal rule as the area under the curve for change from baseline at each time point divided by 
the time interval for the observation period. Accompanying descriptive analyses will be provided 
at the individual timepoints used to calculate the TWA. 
For example, the time-weighted average change from baseline in viral load in the nasopharyngeal 
(NP) swab samples till the last observation day tk will be calculated using formula 
𝑇𝑊𝐴[0−𝑘] = [∑(𝑡𝑖
𝑘
𝑖=1
−𝑡𝑖−1) ∗(𝐷𝑖+ 𝐷𝑖−1)/2]/(𝑡𝑘−𝑡0) 
Where  
• k=11 refers to 11 post-baseline assessments 
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• Di is the change from baseline in viral load value (log10 copies/mL) obtained at time 
ti, D0 =0 
• ti is the time (day) for which Di is measured, such as t0 = 1 (day) for baseline and {ti} = 
3, 5, 7, 9, 11, 13, 15, 18, 22, 25, 29, for i=1 to 11 where the postbaseline assessment is 
taken. 
• If the Di is not available per protocol or missing due to failed test or other reasons, only 
the time points with non-missing values will be included into the calculation. For 
example, we will calculate the TWA till day 7. In this case, data is not available at day 
1, 2, 4, and 6 per the protocol schedule of events. Suppose the scheduled assessment 
result is missing at day 5 due to a failed test but non-missing at day 3 and day 7, then 
𝑇𝑊𝐴[0−7] = [(𝑡3 −𝑡0) ∗(𝐷3 + 𝐷0)/2 + (𝑡7 −𝑡3) ∗(𝐷7 + 𝐷3)/2]/(𝑡7 −𝑡0) 
Baseline is defined as the last non-missing value prior to the study drug infusion.  Patients with 
missing baseline will be excluded from the analysis of virologic endpoints. Virologic data after 
start of study drug infusion will be used as post-baseline assessments. 
4.5.3. 
Pharmacokinetics 
• Concentrations of REGN10933 and REGN10987 in serum and select PK parameters 
4.5.4. 
Immunogenicity 
• Immunogenicity as measured by anti-drug antibodies (ADA) to REGN10933 and 
REGN10987 
4.5.5. 
Exploratory Endpoints 
Exploratory endpoints for phase 3 are: 
• Viral load over time in patients with and without COVID-19-related medically-
attended visits 
• Change in WPAI+CIQ over time 
• Change in EQ-5D-5L over time 
• Time to COVID-19 symptoms resolution (cohort 2 ages ≥12 years) 
4.6. 
Safety Variables 
Safety endpoints 
• Proportion of patients with treatment-emergent SAEs through day 29  
• Proportion of patients with infusion-related reactions (grade ≥2) through day 4  
• Proportion of patients with hypersensitivity reactions (grade ≥2) through day 29 
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4.6.1. 
Adverse Events and Serious Adverse Events 
Serious adverse events and AESIs will be collected according to the Schedule of Events 
(Section 10.1). All adverse events are to be coded to a “Preferred Term (PT)” and associated 
primary “System Organ Class (SOC)” according to the Medical Dictionary for Regulatory 
Activities (MedDRA version 23.0 or later). 
Infusion reactions are defined as any relevant AE that occurs during the infusion or up to day 4. 
Treatment-emergent adverse events are defined as those that are not present at baseline or represent 
the exacerbation of a pre-existing condition during the observation period. 
The severity of adverse events (including test findings classified as adverse events) will be graded 
using the current version of the NCI-CTCAE v5.0 (Division of Cancer Treatment and Diagnosis 
[DCTD], 2020). 
Treatment-emergent SAEs or AESIs not listed in the NCI-CTCAE will be graded according to the 
scale in Table 3. 
Table 3: 
NCI-CTCAE Severity Grading System for Adverse Events 
Grade 
Severity 
Description 
1  
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
2  
Moderate 
Minimal, local, or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (ADL)* 
3  
Severe 
Severe or medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL† 
4  
Life-threatening 
Life threatening consequences; urgent intervention indicated 
5  
Death 
Death related to adverse events 
*Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
† Self-care ADL refers to bathing, dressing, and undressing, feeding self, using the toilet, taking medications, and 
not bedridden.  
4.6.2. 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) are AEs (serious or non-serious) of scientific and 
medical interest specific to this drug program, for which ongoing monitoring and rapid 
communication by the investigator to the sponsor will be appropriate.  
Treatment-emergent adverse events of special interest for this study are grade ≥2 hypersensitivity 
and grade ≥2 infusion-related reactions and any treatment-emergent adverse event that led to a 
medically-attended visit (phase 3 only), regardless of whether the visit is related to COVID-19. 
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4.6.3. 
Laboratory Safety Variables 
The clinical laboratory data consists of blood chemistry (including C-Reactive Protein, liver 
function tests, creatinine and other), hematology, urinalysis, infection testing, SARS-CoV-2 RT-
PCR and other (as specified in the protocol). 
Clinical laboratory values will be converted to standard international (SI) units and grouped by 
function in summary tables. Conventional unit may be provided. Functions are defined as follows: 
• Liver function including ALT, AST, alkaline phosphatase, total bilirubin, 
• Renal function including creatinine, uric acid, 
• Electrolytes including sodium, potassium, 
• C-Reactive Protein (CRP), 
• Creatine Phosphokinase (CPK) 
• Metabolic parameters including total proteins, albumin, 
• White blood cells (WBCs) including WBCs count and differential count (neutrophils, 
lymphocytes, eosinophils, basophils, monocytes), 
• Red blood cells (RBCs) and platelets including red blood cells count, hemoglobin, 
hematocrit and platelets count, 
• Coagulation parameters including INR, PT, aPTT 
• Other 
4.6.4. 
Vital Signs 
Vital signs, including temperature, blood pressure, heart rate, and SpO2 are recorded at multiple 
time points according to Schedule of Time and Events table (See Section 10.1). 
4.7. 
Pharmacokinetic Variables 
The PK variables are the concentrations of REGN10933 andREGN10987 in serum and time when 
a sample was collected as specified in the Schedule of Events table (please refer to table 10.1 in 
the appendix). (See Section 10.1). 
4.8. 
Pharmacodynamic and Other Biomarker Variables  
Exploratory biomarker variables may be reported outside of the clinical study report (CSR).   
4.9. 
Immunogenicity Variables 
The immunogenicity variables are ADA status, titer, NAb status, and time-point/visit. Samples 
will be collected at the visits as specified in Section 10.1. 
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5. 
STATISTICAL METHODS 
For continuous variables, descriptive statistics will include the following: the number of patients 
reflected in the calculation (n), mean, median, standard deviation (SD), Q1, median, Q3, minimum, 
and maximum. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
5.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics variables given in Section 4.1 will be summarized 
descriptively by treatment group, and all groups combined using full analysis set (FAS), mFAS 
and safety set for each cohort. 
5.2. 
Medical History 
Medical history will be summarized by SOC and PT and by treatment group and all groups 
combined using FAS for each cohort. 
5.3. 
Prior / Concomitant Medications or Procedures 
Prior or concomitant medications/procedures will be summarized by treatment groups using FAS 
for each cohort.  Summaries will present patient counts (and percentages) for all medications, 
dictionary coded by WHODRUG, by decreasing frequency of the overall group incidence (or high 
dose group incidence in tables where the overall is not presented) of ATC followed by ATC level 
2, ATC level 4 and preferred term.  Focus of the results will be on the list of targeted medications 
(Section 4.3). 
5.4. 
Prohibited Medications  
Number and percentage of patients with prohibited medications will be summarized by treatment 
groups in the FAS population for each cohort, similar to the concomitant medications. 
5.5. 
Subject Disposition 
The following will be provided using FAS and mFAS for each cohort: 
• The total number of screened patients: signed the ICF 
• The total number of randomized patients: received a randomization number 
• The total number of patients who discontinued the study, and the reasons for 
discontinuation 
• The total number of patients who discontinued from study treatment, and the reasons 
for discontinuation 
• A listing of patients treated but not randomized, patients randomized but not treated, 
and patients randomized but not treated as randomized 
• A summary of analysis sets including FAS, mFAS, SAF, PK, immunogenicity (ADA), 
and exploratory biomarkers (Section 3). 
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5.6. 
Extent of Study Treatment Exposure and Compliance 
5.6.1. 
Measurement of Compliance 
Proportion of patients with fully completed infusions of study drug will be reported as the 
treatment compliance since the patients will only receive one infusion during the study.  Treatment 
compliance and proportion of patients with infusion interruptions will be summarized by treatment 
group using descriptive statistics based on the SAF population for each cohort.  
5.6.2. 
Exposure to Investigational Product 
Exposure to study drug will be examined for each patient as recorded on the Study Drug 
Administration-IV CRF. The following variables will be analyzed by treatment group: 
• Duration of intravenous infusion 
• Total volume of drug administered (units: mL) 
• Number of patients with total planned dose administered (yes/no) 
If no, reason for not administration of total planned dose (equipment failure, adverse 
event, other) 
• Number of patients with infusion interruptions 
The number and percentage of patients randomized and exposed to double-blind study drug will 
be presented for each treatment group. 
5.7. 
Analyses of Efficacy Variables 
5.7.1. 
Analysis of Primary Efficacy Variables 
Cohort 1 
The primary efficacy analysis for the clinical endpoint, proportion of patients with 
COVID-19-related hospitalization or all-cause death through day 29, will be performed based on 
the mFAS. 
The analyses of proportion of patients with COVID-19-related hospitalization or all-cause death 
through day 29 will be performed for the following null and alternative statistical hypotheses: 
• H0: The risk of having COVID-19-related hospitalization or all-cause death through 
day 29 for REGN10933+REGN10987 2400 mg group is the same as that for placebo 
• H1: The risk of having COVID-19-related hospitalization or all-cause death through 
day 29 for REGN10933+REGN10987 2400 mg group is not the same as that for 
placebo 
The proportion of patients with COVID-19-related hospitalization or all-cause death through day 
29 will be compared between each dose group and placebo using the stratified Cochran-Mantel-
Haenszel (CMH) test with country as a stratification factor. P-values from the stratified CMH test 
and 95% confidence intervals for the risk ratio and relative risk reduction (1-risk ratio) using 
Farrington-Manning method will be presented. Exact method for p-values and confidence intervals 
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will be used if the expected frequencies in all cells are not at least 5. As key secondary analyses, 
the same analyses will be performed for the proportion of patients with COVID-19-related 
hospitalization or all-cause death through day 29 for patients with high baseline viral load (>106 
copies/mL) in the mFAS and for seronegative mFAS, and for proportion of patients with a COVID-
19-related hospitalization or all-cause death from day 4 through day 29 in the mFAS. The 
comparison of 1200 mg dose group to placebo will include only the subset of placebo patients 
concurrently randomized with 1200 mg dose group. Sensitivity analyses will be performed using 
FAS. Additional subgroup analysis will also be performed by baseline serostatus (negative, 
positive, other) and by baseline viral load categories (>104 copies/mL, >105 copies/mL, >106 
copies/mL, >107 copies/mL). 
5.7.2. 
Analysis of Secondary Efficacy Variables 
Patient-reported symptoms endpoint 
Cohort 1 
Time to symptoms resolution of COVID-19 symptoms (Fever, Sore throat, Cough, Shortness of 
breath/difficulty breathing, Chills, Nausea, Diarrhea, Headache, Red/watery eyes, Body aches 
such as muscle pain, Loss of taste/smell, Fatigue, Loss of appetite, Dizziness, Pressure/tightness 
in chest, Chest pain, Stomach ache, Runny nose, Sputum/phlegm) will be analyzed using the 
stratified log-rank test with randomization strata as stratification factor. The analyses will be 
performed for mFAS. Estimates of median times and associated 95% confidence intervals using 
the Kaplan-Meier method will be reported. The hazard ratio and its 95% CI for time to symptoms 
resolution of COVID-19 symptoms endpoint will be estimated by the Cox regression model with 
terms for treatment group, randomization strata. P-value from the stratified log-rank test will be 
reported. Subgroup analyses may be performed among patients with more than one risk factor, 
with high baseline viral load, or who are seronegative at baseline.  
Patients who do not experience resolution of symptoms will be censored at the last observation 
time point. Patients who died or had COVID-19-related hospitalization prior to day 29 will be 
censored at day 29. Patients with a baseline raw score ≤3 will be censored at day 0. Patients with 
missing baseline assessment will not be included in the analysis. 
Clinical endpoints 
Cohort 1 
The proportion endpoints, such as proportions of patients with a COVID-19-related 
hospitalization/ER or all-cause death and proportion of patients with a COVID-related MAV or 
all-cause death, will be compared between each dose group and placebo using stratified Cochran-
Mantel-Haenszel (CMH) test with country as a stratification factor. P-values from the stratified 
CMH test and 95% confidence intervals for risk ratio and relative risk reduction (1-risk ratio) using 
Farrington-Manning method will be presented. Exact method for p-values and confidence intervals 
will be used if the expected frequencies in all cells are not at least 5. The analyses will be performed 
based on observed data for the mFAS, seronegative mFAS, and FAS. Similar analysis will be 
performed for the proportion of patients with COVID-19-related hospitalization or ER or urgent 
care visits as well as proportions of patients with each type of COVID-19-related MAVs. Risk 
difference and its 95% confidence interval based on stratified Newcombe method for the 
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proportion endpoints between 1200 mg and 2400 mg dose groups will calculated based on patients 
concurrently randomized, i.e., under Amendment 6, 7 or 8, for the mFAS. 
Analyses will be performed for the cumulative incidence of patients having a COVID-19-related 
hospitalization or all-cause death through day 29 based on the time to first COVID-19-related 
hospitalization or all-cause death using the stratified log-rank test with randomization strata 
(country) as stratification factor for mFAS. Estimates of cumulative event rate at different time 
points and associated 95% confidence intervals using the Kaplan-Meier method will be reported. 
The hazard ratio and its 95% CI for patients having event will be estimated by the Cox regression 
model with terms for treatment group (2400 mg dose groups versus placebo), and randomization 
strata. The p-value from the stratified log-rank test for risk of having events will be reported. 
Similar analysis will be performed comparing 1200 mg dose group to placebo including only the 
subset of patients concurrently randomized. A patient who has no COVID-19-related 
hospitalization will be censored at last known date of contact up to day 29. A patient who dies on 
or before day 29 will be considered as having an event at the date of death. A patient with multiple 
COVID-19 related hospitalization visits and/or who dies will be counted as having one event with 
time computed at the first event.  
Similar secondary analyses will be performed for cumulative incidence of patients having a 
COVID-19-related hospitalization, ER visit, or all-cause death and cumulative incidence of 
patients having a COVID-19-related MAV or all cause death through day 29 for the mFAS.  
Additional landmark analysis for time to event endpoint such as cumulative incidence of 
hospitalization or death may be performed if the proportional hazard assumption is considered not 
valid.  
Sensitivity analyses will be performed using FAS. 
Additional analyses will be performed to examine the relationship between viral load and COVID-
19-related MAVs in patients who underwent an intensive sampling schedule. Viral load over time 
will be compared between patients with and without a COVID-19-related MAV. 
Cohort 2 and 3 
Proportion of patients with COVID-19-related hospitalization or ER or urgent care visits or all-
cause death as well as proportions of patients with each type of MAVs for cohort 1 patients with 
no risk factor, cohort 2 and 3 will be descriptively summarized. 
Virologic endpoints 
Cohort 1 
For phase 3, virologic analyses will be descriptive.  
To assess the time course of treatment effect in viral load, the change from baseline in viral load 
(log10 copies/mL) at each visit for mFAS will be analyzed using a mixed-effect model for repeated 
measures (MMRM) with terms for baseline viral load, baseline serostatus, country, treatment, visit, 
treatment by baseline viral load interaction, baseline viral load by visit interaction, and treatment-
by-visit interaction. Within-patient errors will be modeled with an unstructured, heterogeneous 
autoregressive (1), or compound symmetry covariance matrix in that order if a model does not 
converge. The least squares means estimates for the mean at each visit and mean change from 
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baseline to each visit as well as the difference of these estimates between each treatment arm and 
placebo will be provided along with the corresponding standard error, p-value, and associated 95% 
confidence interval. Subgroup analysis of the change from baseline in viral load at each visit will 
also be performed by baseline serostatus (negative, positive, other) and by baseline viral load 
categories (>10^4 copies/mL, >10^5 copies/mL, >10^6 copies/mL, >10^7 copies/mL). 
The time-weighted average change from baseline in viral load (log10 copies/mL) from day 1 to 
post-baseline visit timepoints will be analyzed using the same method as the phase 2 primary 
virologic endpoint (see Phase 2 primary anlysis SAP) based on mFAS for seronegative patients 
and seropositive patients separately. This analysis will only be performed for patients randomized 
prior to amendment 6. The variable is analyzed using an Analysis of Covariance (ANCOVA) 
model with treatment group and country as fixed effects and baseline viral load and treatment by 
baseline viral load interaction as covariates. Similar analysis will be performed for mFAS with 
baseline serostatus as an additional term to the ANCOVA model. The least squares means 
estimates for the time-weighted average mean change from baseline in viral load for each treatment 
group, as well as the difference comparing each anti-spike mAb treatment arm versus placebo, will 
be presented along with the corresponding p-value, standard error, and associated 95% confidence 
interval. Subgroup analysis of the TWA change from baseline in viral load at each visit will also 
be performed by baseline viral load categories (>10^4 copies/mL, >10^5 copies/mL, >10^6 
copies/mL, >10^7 copies/mL). 
Proportion endpoints based on observed virologic data will be compared between groups using 
similar method as the proportion clinical endpoints based on mFAS.  
Cohort 2 and 3 
Virologic data for cohort 1 patients with no risk factor, cohort 2 and 3 will be summarized 
descriptively. 
5.7.3. 
Adjustment for Multiple Comparisons 
Cohort 1 
The analysis of the primary endpoint (proportion of patients with ≥1 COVID-19-related 
hospitalization or all-cause death through day 29) and key secondary endpoint (time to symptom 
resolution) will be conducted at the overall α = 0.05. The endpoints will be tested hierarchically in 
the following order, adjusting for interim analysis. 
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Table 4: 
Hierarchical testing order  
Hierarchy 
Number 
Description 
1 
Proportion of patients with ≥1 COVID-19-related hospitalization or all-cause death 
through day 29 in the mFAS for REGN10933+REGN10987 2400 mg group versus 
placebo 
2 
Proportion of patients with ≥1 COVID-19-related hospitalization or all-cause death 
through day 29 in the mFAS for REGN10933+REGN10987 1200 mg group versus 
placebo  
3 
Proportion of patients with ≥1 COVID-19-related hospitalization or all-cause death 
through day 29 in the mFAS patients with baseline viral load >106 copies/mL for 
REGN10933+REGN10987 2400 mg group versus placebo  
4 
Proportion of patients with ≥1 COVID-19-related hospitalization or all-cause death 
through day 29 in the mFAS patients who are seronegative at baseline for 
REGN10933+REGN10987 2400 mg group versus placebo  
5 
Proportion of patients with ≥1 COVID-19-related hospitalization or all-cause death 
through day 29 in the mFAS patients with baseline viral load >106 copies/mL for 
REGN10933+REGN10987 1200 mg group versus placebo  
6 
Proportion of patients with ≥1 COVID-19-related hospitalization or all-cause death 
through day 29 in the mFAS patients who are seronegative at baseline for 
REGN10933+REGN10987 1200 mg group versus placebo  
7 
Proportion of patients with ≥1 COVID-19-related hospitalization or all-cause death 
from day 4 through day 29 in the mFAS for REGN10933+REGN10987 2400 mg 
group versus placebo 
8 
Proportion of patients with ≥1 COVID-19-related hospitalization or all-cause death 
from day 4 through day 29 in the mFAS for REGN10933+REGN10987 1200 mg 
group versus placebo  
9 
Time to COVID-19 symptoms resolution in the mFAS for 
REGN10933+REGN10987 2400 mg group versus placebo  
10 
Time to COVID-19 symptoms resolution in the mFAS for 
REGN10933+REGN10987 1200 mg group versus placebo 
 
The final analysis of the primary efficacy endpoint, i.e., proportion of patients with ≥1 
COVID-19-related hospitalization or all-cause death through day 29 for the 2400 mg group versus 
placebo comparison will be performed based on patients randomized on or before 17 January 2021 
in the mFAS, at α level of 0.05.  
If the 2400 mg group versus placebo comparison for the primary endpoint is positive, an interim 
analysis of the primary efficacy endpoint for the 1200 mg group versus placebo comparison (#2 in 
Table 4) will be performed at α level of 0.01 based on patients randomized on or before 
17 January 2021 in the mFAS. If the comparison is positive, this analysis will be considered as the 
final analysis of the proportion of patients with ≥1 COVID-19-related hospitalization or all-cause 
death through day 29 for the 1200 mg group versus placebo comparison. Final analysis of the 
primary and key endpoints for the comparisons 3 to 10 (Table 4) will be performed based on 
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patients randomized on or before 17 January 2021 in the mFAS in the hierarchical order above at 
α level of 0.05. 
If the interim analysis of the primary efficacy endpoint for the 1200 mg group versus placebo 
comparison (#2 in Table 4) is negative at α level of 0.01, no tests will be performed for the primary 
and key endpoints for the comparisons 3 to 10 in Table 4 based on patients randomized on or 
before 17 January 2021. Final analysis of the proportion of patients with ≥1 COVID-19-related 
hospitalization or all-cause death through day 29 for the 1200 mg group versus placebo comparison 
(#2 in Table 4) and other comparisons 3 to 10 will be performed based on all patients randomized 
on or before 24 February 2021 and tested hierarchically at an alpha level adjusted based on the 
information fraction at the interim analysis using Gamma family alpha spending function, e.g., at 
0.047 level as illustrated in the example in Table 5. Additional details are provided in section 7. 
Table 5 provides an example alpha spending boundary for the interim analysis and final analysis 
of the primary and key secondary endpoints. Under amendment 6 and 7, a total of 2524 patients 
were randomized to the 1200 mg, 2400 mg, and placebo groups on or before 17 January 2021 for 
the planned interim analysis, and 4056 patients were randomized on or before 24 February 2021 
for the final analysis of 1200 mg versus placebo comparisons. With these sample sizes utilized in 
each analysis, the information fraction is approximately 62% (gamma=-4), assuming the 
proportions of RT-qPCR-positive patients in the FAS are the same at the interim and final analysis. 
The resulting overall alpha for the final analysis would then be 0.047 if the interim analysis is 
negative at 0.01 level. 
Table 5: 
Example Alpha Spending Function for Analysis of Primary Endpoint 
Information Time 
Value 
Overall α for Proportion 
Analysis = 0.05 
62% of the mFAS patients completing day 
29 
α (2-sided) 
0.01 
Final analysis 
α (2-sided) 
0.047 
 
Cohort 2 and 3 
Analysis cohort 2 and cohort 3 will be descriptive. No multiplicity adjustment will be applied. 
5.8. 
Analysis of Safety Data 
The analysis of safety data will be performed on the SAF, as defined in Section 3.2. 
The safety analysis will be based on the reported SAEs and AESIs and other safety information 
(clinical laboratory evaluations and vital signs).  
Thresholds for Potential Clinically Significant Values (PCSV) in laboratory variables, vital signs 
and ECG are defined in Section 10.2. 
The summary of safety results will be presented for each treatment group for each cohort. 
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5.8.1. 
Adverse Events  
Definitions 
For safety variables, 2 periods are defined: 
• The pretreatment period is defined as the time from signing the ICF to before study 
drug administration 
• The observation period is defined as the time of study drug administration to the last 
study visit 
Treatment-emergent SAEs and AESIs are defined as those that are not present at baseline or 
represent the exacerbation of a pre-existing condition during the observation period. 
Analysis 
All SAEs and AESIs reported in this study will be coded using the currently available version of 
the Medical Dictionary for Regulatory Activities (MedDRA®). Coding will be to lowest level 
terms. The preferred term (PT), and the primary system organ class (SOC) will be listed. 
Summaries by treatment group will include the following: 
• The number (n) and percentage (%) of patients with at least 1 treatment-emergent 
serious adverse events (SAEs) through day 29 by system organ class and PT 
• The number (n) and percentage (%) of patients with at least 1 infusion-related reactions 
(grade ≥2), through day 4 by PT 
• The number (n) and percentage (%) of patients with at least 1 hypersensitivity reactions 
(grade ≥2), through day 29 by PT 
Summaries of SAEs and AESIs by treatment group will include: 
• The number (n) and percentage (%) of patients with at least 1 event by SOC and PT 
• SAEs and AESIs by severity (according to the grading scale outlined in Section 4.6.1), 
presented by SOC and PT 
• SAEs and AESIs by relationship to treatment (related, not related), presented by SOC 
and PT 
• Treatment-emergent SAEs and AESIs  
• The number (n) and percentage (%) of patients with Grade 3 or Grade 4 
treatment-emergent adverse events (cohort 2 and cohort 3 <18 years only). 
Deaths and other SAEs will also be listed and summarized by treatment arm. 
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5.8.2. 
Clinical Laboratory Measurements  
Laboratory measurements include clinical chemistry and hematology results, and will be converted 
to standard international units and US conventional units. Summaries of laboratory variables based 
on standard international units will include: 
• Descriptive statistics of laboratory result and change from baseline to Day 29. 
Summary statistics will include the number of patients, mean, median, standard 
deviation, quartiles, minimum, and maximum. 
• Number and percentage of patients with a potentially clinically significant value 
(PCSV) at any post-randomization time point will be summarized for each clinical 
laboratory test for all patients and separately for patients in whom the PCSV criterion 
was normal or missing at baseline. 
• Shift tables based on baseline normal/abnormal and other tabular and graphical 
methods may be used to present the results for parameters of interest. 
Listing of all laboratory parameters normal range and abnormal flag by patient and visit will be 
provided. 
5.8.3. 
Analysis of Vital Signs 
Vital signs (including temperature, blood pressure, pulse, and respiration) will be summarized by 
baseline and change from baseline to each scheduled assessment time with descriptive statistics.  
The graphs of mean (or median) value of some vital sign parameter vs. visit will also be plotted. 
5.9. 
Analysis of Pharmacokinetics, Pharmacodynamics and Biomarker 
Data  
5.9.1. 
Analysis of Drug Concentration Data 
Cohort 1 PK Sub-study 
The concentrations of REGN10933 and REGN10987 in serum over time will be summarized 
descriptively for each of the treatment groups. 
Cohort 2 Pediatric Patients 
The concentrations of REGN10933 and REGN10987 in serum over time will be summarized 
descriptively by body weight tier and treatment group. 
Cohort 3 Pregnant Women 
The concentrations of REGN10933 and REGN10987 in serum over time will be summarized 
descriptively for each of the treatment groups. 
5.9.2. 
Analysis of Pharmacokinetics and Pharmacokinetics/Pharmacodynamics 
Exposure-response analyses for virologic, other select efficacy and safety endpoints, and/or 
biomarkers may be performed, as appropriate. 
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5.10. 
Analysis of Immunogenicity Data 
5.10.1. 
Analysis of ADA Data 
Immunogenicity variables will be summarized using descriptive statistics. 
Immunogenicity will be characterized by the ADA responses and titers observed in subjects in the 
ADA analysis set.  
ADA response categories and titer categories are defined as follows: 
ADA response categories: 
• ADA Negative, defined as ADA negative response in the ADA assay at all time points, 
regardless of any missing samples. 
• Pre-existing immunoreactivity, defined as either an ADA positive response in the ADA 
assay at baseline with all post first dose ADA results negative, OR a positive response 
at baseline with all post first dose ADA responses less than 9-fold over baseline titer 
levels. 
• Treatment-emergent response, defined as an ADA positive response in the ADA assay 
post first dose when baseline results are negative or missing. The treatment-emergent 
responses will be further characterized as Persistent, Indeterminate or Transient. 
− Persistent Response – Treatment-emergent ADA positive response with two or 
more consecutive ADA positive sampling time points, separated by at least 16-
week period (based on nominal sampling time), with no ADA negative samples in 
between, regardless of any missing samples. 
− Indeterminate Response –Treatment-emergent ADA positive response with only 
the last collected sample positive in the ADA assay, regardless of any missing 
samples. 
− Transient Response –Treatment-emergent ADA positive response that is not 
considered persistent or indeterminate, regardless of any missing samples. 
• Treatment-boosted response, defined as a positive response in the ADA assay post first 
dose that is greater than or equal to 9-fold over baseline titer levels, when baseline 
results are positive 
Titer categories (Maximum titer values) 
• Low (titer <1,000) 
• Moderate (1,000 ≤ titer ≤ 10,000) 
• High (titer >10,000) 
The following analysis will be provided: 
• Number (n) and percent (%) of ADA-negative subjects (pre-existing immunoreactivity 
or negative in the ADA assays at all time points) by treatment arms  
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• Number (n) and percent (%) of treatment-emergent ADA positive subjects by treatment 
arms and ADA titer categories 
− Number (n) and percent (%) of persistent treatment-emergent ADA positive 
subjects 
− Number (n) and percent (%) of indeterminate treatment-emergent ADA positive 
subjects 
− Number (n) and percent (%) of transient treatment-emergent ADA positive subjects 
• Number (n) and percent (%) of treatment-boosted ADA positive subjects by treatment 
arms and ADA titer categories  
Listing of all ADA titer levels will be provided for subjects with pre-existing, treatment-emergent 
and treatment-boosted ADA response. 
5.10.2. 
Analysis of NAb Data 
The absolute occurrence (n) and percent of subjects (%) with NAb status in the NAb analysis set 
will be provided by treatment groups. 
5.11. 
Association of Immunogenicity with Exposure and Safety 
5.11.1. 
Immunogenicity and Exposure 
Potential association between immunogenicity variables and systemic exposure to REGN10933, 
and REGN10987 will be explored by treatment groups. Plots of drug concentration time profiles 
may be provided to examine the potential impact of ADA response status, and titer on these 
profiles.  
5.11.2. 
Immunogenicity and Safety  
Potential association between immunogenicity variables and safety may be explored with a 
primary focus on the following safety events during the TEAE period:  
• 
Infusion reactions  
• 
Hypersensitivity (SMQ: Hypersensitivity [Narrow]) 
• 
Anaphylaxis (SMQ: Anaphylaxis [Narrow]). 
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6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis.  
6.1. 
Definition of Baseline for Efficacy/Safety Variables 
Definitions of baseline for efficacy variables are defined in Section 4.5. 
For safety variables, baseline will be the latest available valid measurement taken prior to the 
administration of study drug.  
6.2. 
Data Handling Convention for Efficacy Variables  
Not applicable. 
6.3. 
Data Handling Convention for Missing Data 
If pre-dose virologic results from the qualitative test are missing, then results from post-dose 
sample may be used to determine the qualitative PCR status at baseline, as long as the sample was 
collected 2 hours or less after starting study drug infusion. 
For categorical variables, patients with missing data will be included in calculations of 
percentages.  Number of patients with missing data will be presented. 
Handling of Medications with missing/partial dates 
To determine whether a medication is prior or concomitant medication, the missing medication 
start date is estimated as early as possible up to first dose date, and the missing medication end 
date is estimated as late as possible up to Day 29. If the medication start date is missing, the onset 
day will not be imputed in medication listings. 
Handling of Adverse events Severity and Relatedness 
If the intensity of a SAE, AESI and grade 3 or 4 AEs is missing, it will be classified as “Grade 3” 
in the frequency tables by CTC grade of SAE and AESIs. If the assessment of relationship of the 
investigational product is missing, it will be classified as related to the investigational product. 
Date of infusions 
Date of infusion is the non-missing administration date filled in the Study Drug Administration-IV 
CRF. If the first dose of study drug administration date is missing (even after site is queried), then 
the dosing date will be imputed with the randomization date.  If any subsequent study drug 
administration date is missing, the date of dispensation of study drug from IRT will be used. 
6.4. 
Visit Windows 
Data analyzed by-visit-analysis will be summarized by the study scheduled visits described in 
Appendix 10.1, “Schedule of Event”. The analysis visit windows will be exhaustive so that all 
available values obtained from unscheduled visits, early termination visit (ETV) and end of 
treatment (EOT)/end of study (EOS) have the potential to be summarized. No analysis visit 
windows will be applied for the study scheduled visits nor for drug concentration/immunogenicity 
data. 
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The following analysis visit windows will be used to map the unscheduled visits, ETV and EOT 
visits for NP Swab for SARS-CoV-2 RT-qPCR, based on the study day during the double blind 
period: 
Table 6: 
Time Window for Summary of NP Swab for SARS-CoV-2 RT-qPCR (Cohort 
1 Patients; Cohort 3 Patients ≥ 18 Years) 
Visit Label 
Targeted Study Day 
Analysis Window in Study Day 
Baseline 
1 
≤ 1 
Day 7 
7 
[2, 10] 
Day 15 
15 
[11, 22] 
Day 29 
29 
[23, 32] 
Table 7: 
Time Window for Summary of NP Swab for SARS-CoV-2 RT-qPCR (Cohort 
2 Patients; Cohort 3 Patients < 18 Years)  
Visit Label 
Targeted Study Day 
Analysis Window in Study Day 
Baseline 
1 
≤ 1 
Day 3 
3 
[2, 4] 
Day 7 
7 
[5, 10] 
Day 15 
15 
[11, 22] 
Day 29 
29 
[23, 32] 
The following analysis visit windows will be used to map the unscheduled visits, ETV and EOT 
visits for laboratory and biomarker variables based on the study day during the double blind period: 
Table 8: 
Time Window for Summary of Laboratory and Biomarker Variables except 
Serum for Serology (Cohort 1 Patients; Cohort 3 Patients ≥ 18 Years) 
Visit Label 
Targeted Study Day 
Analysis Window in Study Day 
Baseline 
1 
≤ 1 
Day 7 
7 
[2, 11] 
Day 15 
15 
[12, 22] 
Day 29 
29 
[23, 32] 
Table 9: 
Time Window for Summary of Laboratory and Biomarker Variables except 
Serum for Serology (Cohort 2 Patients and Cohort 3 Patients <18 Years with 
Body Weight ≥ 10 kg) 
Visit Label 
Targeted Study Day 
Analysis Window in Study Day 
Baseline 
1 
≤ 1 
Day 7 
7 
[2, 11] 
Day 15 
15 
[12, 22] 
Day 29 
29 
[23, 32] 
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Table 10: 
Time Window for Summary of Serum for Serology (Cohort 1 Patients; 
Cohort 3 Patients ≥ 18 Years; Cohort 2 patients and Cohort 3 Patients <18 
Years with Body Weight ≥ 10 kg) 
Visit Label 
Targeted Study Day 
Analysis Window in Study Day 
Baseline 
1 
≤ 1 
Day 29 
29 
[2, 32] 
Table 11: 
Time Window for Summary of Laboratory and Biomarker Variables 
(Cohort 2 Patients with Body Weight < 10 kg) 
Visit Label 
Targeted Study Day 
Analysis Window in Study Day 
Baseline 
1 
≤ 1 
Day 7 
7 
[2, 18] 
Day 29 
29 
[19, 32] 
In the event of multiple measurements of the same test in the same window, if the measurements 
are from different categories, the priority order is scheduled, early termination visit then 
unscheduled visit. For the measurements in the same category, the value measured nearest to the 
target day will be assigned to the window; if they are at the same distance to the target day, the 
latest one will be used. Extra assessments (laboratory data or vital signs associated with 
non-protocol clinical visits or obtained in the course of investigating or managing adverse events) 
will be included in listings, but not summaries except for the endpoint determination.  If more than 
one laboratory value is available for a given visit, the first observation will be used in summaries 
and all observations will be presented in listings. 
The determination of baselines and values at the end of treatment for both efficacy and safety 
variables will be based on scheduled available assessments and unscheduled available 
assessments.  
6.5. 
Pooling of Centers for Statistical Analyses 
Not applicable. 
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7. 
INTERIM ANALYSIS 
Cohort 1 
The final analysis of the primary efficacy endpoint, i.e., proportion of patients with ≥1 
COVID-19-related hospitalization or all-cause death through day 29 for the 2400 mg group versus 
placebo comparison will be performed based on patients randomized on or before 
17 January 2021. If the 2400 mg group versus placebo comparison is positive, an interim analysis 
of the primary endpoint for the 1200 mg group versus placebo comparison will be performed at α 
level of 0.01 based on patients randomized on or before 17 January 2021. If the interim analysis is 
positive for the 1200 mg group versus placebo comparison, this analysis will be considered as the 
final analysis and final analysis of the other key secondary analyses will be performed based on 
patients randomized on or before 17 January 2021. If the interim analysis is negative for the 1200 
mg group versus placebo comparison, no further tests will be conducted for other key secondary 
endpoints at the interim analysis, and final analysis of the primary endpoint for the 1200 mg group 
versus placebo comparison and other key secondary analyses will be performed based on patients 
randomized on or before 24 February 2021. 
The Gamma family alpha spending function (Hwang, Shih, DeCani 1990) based on the primary 
endpoint of proportion of patients with ≥1 COVID-19-related hospitalization or all-cause death 
through day 29 for the 1200 mg versus placebo comparison will be used to control for type I error 
for the planned interim analysis and the final analysis. The parameter for the Gamma family 
spending function will be calculated based on the information fraction of the interim analysis such 
that the alpha level at the interim analysis is equal to 0.01. If the interim analysis is not significant 
at 0.01 level for an endpoint, the remaining alpha level will be calculated based on the gamma 
parameter and information fraction. The information fraction will be determined based on the 
sample size in the mFAS at the interim analysis and final analysis of the primary endpoint for the 
1200 mg group versus placebo comparison as follows: number of patients randomized to 1200 mg 
or placebo on or before 17 January 2021 in the mFAS divided by number of patients randomized 
to 1200 mg or placebo on or before 24 February 2021 (i.e., the day before the placebo treatment 
group was dropped per IDMC recommendation) in the mFAS. 
Cohort 2 and 3 
An interim descriptive analysis of phase 3 cohort 2 and 3 may be conducted for regulatory purposes 
when the phase 3 cohort 1 primary analysis is performed. 
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8. 
SOFTWARE 
All analyses will be done using SAS Version 9.4. 
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9. 
REFERENCES 
1. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A Trial of Lopinavir-Ritonavir in 
Adults Hospitalized with Severe Covid-19. N Engl J Med 2020; 382(19):1787-99. 
2. Coronavirus 
Disease 
2019 
(COVID-19) 
Situation 
Report 
– 
90. 
https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports/. 
Published 2020a. [Accessed] 20 April 2020. 
3. ICH. (1998, February 5). ICH Harmonized tripartite guideline: Statistical principles for 
clinical trials (E9). International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use. 
4. Hwang IK, Shih WJ, and DeCani JS. Group sequential designs using a family of type 1 
error probability spending functions. Statistics in Medicine, 9:1439–1445, 1990. 
5. Kim DH, Uno H, Wei LJ. Restricted mean survival time as a measure to interpret clinical 
trial results. JAMA cardiology. 2017 Nov 1;2(11):1179-80. 
6. World Health Organization (WHO). Report of the WHO-China Joint Mission on 
Coronavirus 
Disease 
2019 
(COVID-19). 
World 
Health 
Organization. 
https://www.who.int/docs/default-source/coronaviruse/who-china-joint-mission-on-
covid-19-final-report.pdf. Published 2020b. [Accessed] 10 March 2020. 
7. Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus 
Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From 
the Chinese Center for Disease Control and Prevention. Jama 2020b. 
8. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A Novel Coronavirus from Patients 
with Pneumonia in China, 2019. N Engl J Med 2020; 382(8):727-33. 
9. Altman DG, Bland JM. Measurement in medicine: the analysis of method comparison 
studies. The Statistician 32 (1983), 307-317. 2. 
10. Lin Li. A concordance correlation coefficient to evaluate reproducibility. Biometrics 45 
(1989), 255-268. 
 
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10. 
APPENDIX 
10.1. 
Schedule of Time and Events  
Schedule of Events: Phase 3 (Cohort 1 Patients; Cohort 3 Patients ≥18 Years) 
Day 
Screening/Baseline Visit1 
Follow Up3 
EOS3 
-1 to 1 
2 
3 
4 
7 15 22 29 60 90 120 
169 
Screen Pre-Dose Dose Post-Dose 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 10 
11 
12 
Window (Days) 
 
 
 
 
 
 
 
±1 ±3 ±3 ±3 ±3 ±3 ±712,14 ±714 
 
 
 
 
 
Screening/Baseline Only 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PGx sub-study consent (optional)4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunoprofiling sub-study consent (optional)4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Antigen or molecular diagnostic test for SARS-CoV-25 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history (including COVID-19 illness, risk factors) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight and height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization (treatment assignment) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment  
Study drug administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy  
Query for COVID-19-related medically-attended visit details 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
NP swab for SARS-CoV-2 RT-qPCR 
 
X 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
Safety  
Vital signs 
 
X6 
 
X6 
 
 
 
 
 
 
 
 
 
 
 
Treatment-emergent grade ≥2 IRRs7,8 
 
 
X 
X 
← cont. mon. → 
 
 
 
 
 
 
 
 
TEAEs that led to any medically-attended visit7,8 
 
 
 
X 
← continuous monitoring → 
 
 
 
 
Treatment-emergent grade ≥2 hypersensitivity7,8 
 
 
X 
X 
← continuous monitoring → 
 
 
 
  
Treatment-emergent SAEs7,8,16 
 
 
X 
X 
← continuous monitoring → 
Targeted concomitant medications7, 8 
X 
 
X 
X 
← continuous monitoring → 
Concomitant procedures7,8 
X 
 
X 
X 
← continuous monitoring → 
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Day 
Screening/Baseline Visit1 
Follow Up3 
EOS3 
-1 to 1 
2 
3 
4 
7 15 22 29 60 90 120 
169 
Screen Pre-Dose Dose Post-Dose 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 10 
11 
12 
Window (Days) 
 
 
 
 
 
 
 
±1 ±3 ±3 ±3 ±3 ±3 ±712,14 ±714 
 
 
 
 
 
Vital status16 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Pregnancy test (women of childbearing potential)9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy status16 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Safety information (newborns of study participants)16 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Central Laboratory Safety Testing  
Hematology (including differential) 
X10 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
Blood chemistry (including AST, ALT, CRP, LDH) 
X10 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
Coagulation tests (D-dimer, PT/INR, aPTT) 
X10 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
Central Laboratory Immunogenicity Testing (Not Enrolled in PK Sub-Study, Not Pregnant at Randomization) 
Serum for ADA13 
X13 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Central Laboratory Drug Concentration and Immunogenicity Testing (Enrolled in PK Sub-Study, Not Pregnant at Randomization) 
Serum for drug concentration (PK)12 
X10,12 
 
 
 
 
 
 
 
 
X12 
 
 
X12 
 
Serum for ADA13 
X13 
 
 
 
 
 
 
 
 
X13 
 
 
X13 
 
Central Laboratory Drug Concentration and Immunogenicity Testing (Pregnant at Randomization) 
Serum for drug concentration (PK)12 
X10,12 
 
X12 
 
 
 
 
 
 
X12 
 
 
X12 
 
Serum for ADA13 
X13 
 
 
 
 
 
 
 
 
X13 
 
 
X13 
 
Central Laboratory Biomarker Testing  
Serum for serology 
X10 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Serum for research  
X10 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
Plasma for research  
X10 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
Exploratory Patient-reported Outcomes 
SE-C1914 
 
X 
 
 
Daily 
 
 
 
 
PGIS14 
 
X 
 
 
Daily 
 
 
 
 
PGIC14 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Item: return to usual health 
 
X 
 
 
Daily 
 
 
 
 
Item: return to usual activities 
 
X 
 
 
Daily 
 
 
 
 
EQ-5D-5L14 
 
X 
 
 
Daily 
X14 X14 X14 
X14 
WPAI+CIQ 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
Immunoprofiling (Optional Sub-Study) 
Blood for PBMCs  
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
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Day 
Screening/Baseline Visit1 
Follow Up3 
EOS3 
-1 to 1 
2 
3 
4 
7 15 22 29 60 90 120 
169 
Screen Pre-Dose Dose Post-Dose 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 10 
11 
12 
Window (Days) 
 
 
 
 
 
 
 
±1 ±3 ±3 ±3 ±3 ±3 ±712,14 ±714 
 
 
 
 
 
Pharmacogenomics (Optional Sub-Study) 
Blood for DNA4 
 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for RNA4 
X4 
 
 
 
 
 
 
 
  
 
 
 
 
ADA, anti-drug antibodies; AE; adverse event; ALT, alanine transaminase; aPTT, activated partial thromboplastin time; AST, aspartate transaminase; CRP, c-reactive protein; EOS, 
end of study; INR, international normalized ratio; IRR, infusion-related reaction; LDH, lactate dehydrogenase; NP, nasopharyngeal; PBMC, peripheral blood mononuclear cells; 
PGx, pharmacogenomics; PK, pharmacokinetics; PT, prothrombin time; SAE, serious adverse event; RT-qPCR, quantitative reverse transcription polymerase chain reaction; TEAE, 
treatment-emergent adverse event. 
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Schedule of Events: Phase 3 (Cohort 2 Patients; Cohort 3 Patients <18 Years)  
Day 
Screening/Baseline Visit1 
Follow Up3 
EOS3 
-1 to 1 
2 
3 
4 
7 
15 22 29 60 90 120 169 
 
Screen Pre-Dose Dose Post-Dose 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 10 11 
12 
Window (Days) 
 
 
 
 
 
 
 
±1 ±3 ±3 ±3 ±3 ±3 ±714 ±714 
 
 
 
 
 
Screening/Baseline Only 
 
 
 
 
Parental informed consent and informed assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Antigen or molecular diagnostic test for SARS-CoV-25 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history (including COVID-19 illness, risk factors) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight and height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization (treatment assignment) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization (PK-ADA schedule assignment)15 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment  
 
 
 
 
Study drug administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy  
 
 
 
 
Query for COVID-19-related medically-attended visit details 
 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
NP swab for SARS-CoV-2 RT-qPCR 
 
X 
 
 
 
X 
 
X 
X 
 
X 
 
 
 
 
Safety  
 
 
 
 
Vital signs (≥12 years) 
 
X6 
 
X6 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (<12 years) 
 
X6 
X6 
X6 
 
 
 
 
 
 
 
 
 
 
 
Treatment-emergent grade ≥2 IRRs7, 8 
 
 
X 
X17 
← cont. mon. → 
 
 
 
 
 
 
 
 
TEAEs that led to any medically-attended visit7, 8 
 
 
 
X17 
← continuous monitoring → 
 
 
 
 
Treatment-emergent grade ≥2 hypersensitivity7, 8 
 
 
X 
X17 
← continuous monitoring → 
 
 
 
 
Treatment-emergent grade 3 or 4 AEs8  
 
 
X 
X17 
← continuous monitoring → 
 
 
 
 
Treatment-emergent SAEs7, 8,16 
 
 
X 
X17 
`← continuous monitoring → 
Targeted concomitant medications7,8 
X 
 
X 
X17 
← continuous monitoring → 
Concomitant procedures7,8 
X 
 
X 
X17 
← continuous monitoring → 
Vital status16 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Pregnancy test (women of childbearing potential)9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy status16 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
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Day 
Screening/Baseline Visit1 
Follow Up3 
EOS3 
-1 to 1 
2 
3 
4 
7 
15 22 29 60 90 120 169 
 
Screen Pre-Dose Dose Post-Dose 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 10 11 
12 
Window (Days) 
 
 
 
 
 
 
 
±1 ±3 ±3 ±3 ±3 ±3 ±714 ±714 
 
 
 
 
 
Safety information (newborns of study participants)16 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Central Laboratory Safety Testing and Central Laboratory Biomarker Testing, Body Weight ≥20 kg  
Hematology (including differential) 
X10 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
Blood chemistry (including AST, ALT, CRP, LDH) 
X10 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
Serum for serology 
X10 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Serum for exploratory research 
X10 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
Plasma for exploratory research 
X10 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
Central Laboratory Safety Testing and Central Laboratory Biomarker Testing, Body Weight ≥10 kg to <20 kg 
Hematology (including differential) 
X10 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
Blood chemistry (including AST, ALT, CRP, LDH) 
X10 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
Serum for serology 
X10 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Central Laboratory Safety Testing and Central Laboratory Biomarker Testing, Body Weight <10 kg 
Hematology (including differential) 
X10 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
Blood chemistry (including AST, ALT, CRP, LDH) 
X10 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
Serum for serology 
X10 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central Laboratory Drug Concentration and Immunogenicity Testing (All Body Weight Tiers) 
Serum for PK-ADA (Schedule A)15 
X10,12 
 
X12 
 
X12 
 
 
 
 
X12 
 
 
 
 
Serum for PK-ADA (Schedule B)15 
X10,12 
 
X12 
 
 
 
X12 
 
 
X12 
 
 
 
 
Serum for PK-ADA (Schedule C)15 
X10,12 
 
X12 
 
 
 
 
X12 
 
X12 
 
 
 
 
Serum for PK-ADA (Schedule D)15 
X10,12 
 
X12 
 
 
 
 
 
X12 X12 
 
 
 
 
Exploratory Patient-reported Outcomes (Age ≥12 Years Only)14 
SE-C1914 
 
X 
 
 
Daily 
 
 
 
 
PGIS14 
 
X 
 
 
Daily 
 
 
 
 
PGIC14 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Item: return to usual health 
 
X 
 
 
Daily 
 
 
 
 
Item: return to usual activities 
 
X 
 
 
Daily 
 
 
 
 
EQ-5D-Y-5L14 
 
X 
 
 
Daily 
X14 X14 X14 
X14 
WPAI+CIQ 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
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Day 
Screening/Baseline Visit1 
Follow Up3 
EOS3 
-1 to 1 
2 
3 
4 
7 
15 22 29 60 90 120 169 
 
Screen Pre-Dose Dose Post-Dose 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 10 11 
12 
Window (Days) 
 
 
 
 
 
 
 
±1 ±3 ±3 ±3 ±3 ±3 ±714 ±714 
 
 
 
 
 
ADA, anti-drug antibodies; AE; adverse event; ALT, alanine transaminase; aPTT, activated partial thromboplastin time; AST, aspartate transaminase; CRP, c-reactive protein; EOS, 
end of study; INR, international normalized ratio; IRR, infusion-related reaction; LDH, lactate dehydrogenase; NP, nasopharyngeal; PGx, pharmacogenomics; PK, pharmacokinetics; 
PT, prothrombin time; SAE, serious adverse event; RT-qPCR, quantitative reverse transcription polymerase chain reaction; TEAE, treatment-emergent adverse event. 
1. Screening visit may occur on the same day as, or the day prior to, the baseline visit. 
2. [Phase 1 footnote removed] 
3. On visit days where in-person sample collections or assessments are not required, information may be collected by phone.  
4. Patients (cohort 1; cohort 3 ≥18 years old) must provide separate consent to collect blood samples as part of the optional 
pharmacogenomics (PGx) sub-study. Blood sample for RNA may be collected at day -1 or day 1 (ie, screening or pre-dose) but 
must be collected prior to randomization. Blood sample for DNA should be collected at the day -1 or day 1 visit, but may be 
collected at any visit. Refer to Section 9.2.12 for more information about the PGx sub-study. 
Patients (cohort 1; cohort 3 ≥18 years old) must provide separate consent to collect blood samples as part of the optional 
peripheral blood mononuclear cell (PBMC) sub-study. Blood samples for PBMCs must be collected at the visits indicated. Refer 
to Section 9.2.11 for more information about this sub-study. 
5. Refer to Section 9.2.1.2 for diagnostic test requirements during screening. 
6. Vital signs, including temperature, blood pressure, heart rate, and SpO2 will be collected as described in Section 9.2.4.1.  
For patients in cohort 1 and patients ≥12 years in cohort 2 and cohort 3, vital signs will be taken once before the infusion 
and once after the infusion is completed. After infusion of study drug, these patients will be observed for at least 1 hour.  
For patients in patients <12 years in cohort 2 and cohort 3, vital signs will be taken before infusion, approximately every 30 
minutes during the infusion, after the infusion is completed, approximately 1 hour post-infusion, and approximately 2 hours post-
infusion. After infusion of study drug, these patients will be observed for at least 2 hours. 
7. Treatment-emergent AESIs (grade ≥2 IRRs, grade ≥2 hypersensitivity, and TEAEs associated with any medically-attended visit) 
and treatment-emergent SAEs will be recorded until day 29. From day 30 to day 169, only treatment-emergent SAEs will be 
recorded. For patients in cohort 2 and patients <18 years in cohort 3, treatment-emergent grade 3 or 4 AEs will also be 
recorded until day 29. Refer to Section 10 for more information on reporting and recording requirements. 
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Statistical Analysis Plan 
 
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Targeted concomitant medications and concomitant procedures will also be reviewed and recorded. Refer to Section 9.2.4.3 for 
more information. 
8. Continuously-monitored events will be recorded when they occur during the corresponding time period marked on the schedule 
of events. Study visits (including phone calls) are not required solely to collect continuously-monitored assessments, if no other 
assessments are planned on that day. 
9. Pregnancy testing will be performed in women of childbearing potential (WOCBP) only and regardless of pregnancy status. A 
negative test is not required prior to study drug administration. Serum or urine pregnancy test are both acceptable. Refer to 
Section 9.2.6 for more information, including a definition of WOCBP. 
Note that a paper pregnancy report form must be completed for each patient who becomes pregnant or is pregnant at the signing 
of consent.  
10. The indicated blood samples may be collected at the either day -1 or day 1 (ie, screening or pre-dose), but must be collected prior 
to randomization. For patients in phase 3 cohort 2, efforts should be made to collect all screening/pre-dose blood samples on the 
same study visit, when feasible. 
11. [Footnote removed] 
12. Actual dosing time and drug concentration sample collection times, as applicable, will be recorded. 
At the screening/baseline visit, blood for assessment of drug concentration in serum will be taken prior to dosing and within 60 
minutes after the end of infusion (EOI). The EOI sample should be collected from the arm contralateral to that used for IV 
infusion. If not medically feasible, the EOI sample can be drawn from the same arm, but not from the infusion catheter.  
In cohort 1 and cohort 3 (≥18 years old), patients will follow different blood sample collection schedules for drug concentration 
and immunogenicity depending on whether they enrolled in the PK sub-study (cohort 1), not enrolled in the PK sub-study (cohort 
1), or are pregnant at randomization (cohort 3 patients ≥18 years old). For samples collected on day 120, the collection window 
is ±28 days. Refer to Section 9.2.8 for more information on the PK sub-study. 
13. The window for predose ADA sample collection is as close to administration of study drug as is reasonable. Actual dosing time 
and ADA sample collection times, as applicable, will be recorded.  
14. Patients in cohort 1 and patients ≥12 years in cohort 2 and cohort 3 will self-report symptoms using electronic surveys. The 
order of completion is as follows: SE-C19, PGIS, PGIC, return to usual health, return to usual activities, EQ-5D-5L, WPAI+CIQ. 
On days when a survey/questionnaire is not required it will be skipped, but the overall order will remain the same. Note that the 
WPAI+CIQ, EQ-5D-5L, and EQ-5D-Y-5L will only be administered at sites when regionally available. 
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On days 60, 90, 120, and 169, the window for electronic survey/questionnaire assessment is ±3 days. Note that study visits are 
not required on days when only electronic survey data are collected. 
15. In cohort 2 (and patients <18 years in cohort 3), each patient will be assigned at randomization by IWRS to a blood sample 
collection schedule for drug concentration and immunogenicity analysis. Actual dosing time and PK-ADA sample collection 
times will be recorded. To conserve blood volume, a single blood draw for drug concentration and immunogenicity will be 
obtained.  
16. Patients will be followed by phone at day 120 and day 169 for vital status, pregnancy status, targeted safety information, and 
additional safety information in newborns of study participants. Refer to Section 9.2.5 for more information on these follow-up 
assessments. 
17. For patients <12 years in cohort 2 and cohort 3, follow-up by phone will be conducted within 6 to 8 hours of infusion to 
collect the information indicated. 
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Statistical Analysis Plan 
 
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CONFIDENTIAL 
10.2. 
Criteria for Potentially Clinically Significant Values (PCSV) 
Parameter 
PCSV 
Comments 
Clinical Chemistry 
ALT* 
>3 and ≤ 5 ULN and baseline ≤ 3 ULN* 
>5 and ≤ 10 ULN and baseline ≤ 5 ULN 
>10 and ≤ 20 ULN and baseline ≤ 10 ULN 
>20 ULN and baseline ≤ 20 ULN 
Enzymes activities must be expressed in ULN, not in IU/L.  
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Each category is calculated independently. 
* At least one level is required; multiple levels are optional 
for phase 2/3 studies. If it is desirable to get the distribution 
across the different PCSV levels, additional shift table on 
≤3, >3 to ≤5, > 5 to ≤10, >10 to ≤20, and > 20 category for 
baseline vs. post baseline may be provided  
AST* 
>3 and ≤ 5 ULN and baseline ≤ 3 ULN* 
>5 and ≤ 10 ULN and baseline ≤ 5 ULN 
>10 and ≤ 20 ULN and baseline ≤ 10 ULN 
>20 ULN and baseline ≤ 20 ULN 
Enzymes activities must be expressed in ULN, not in IU/L.  
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Each category is calculated independently. 
* At least one level is required, multiple levels are optional 
for phase 2/3 studies. If it is desirable to get the distribution 
across the different PCSV levels, additional shift table on 
≤3, >3 to ≤5, > 5 to ≤10, >10 to ≤20, and > 20 category for 
baseline vs. post baseline may be provided 
Alkaline 
Phosphatase 
>1.5 ULN and baseline ≤ 1.5 ULN 
Enzyme activity must be expressed in ULN, not in IU/L. 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
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Parameter 
PCSV 
Comments 
Total Bilirubin* 
>1.5 and ≤ 2 ULN and baseline ≤ 1.5 ULN* 
>2 ULN and baseline ≤ 2.0 ULN 
Must be expressed in ULN, not in µmol/L or mg/L. 
Categories are cumulative. 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
* At least one level is required, multiple levels are optional 
for phase 2/3 studies. If it is desirable to get the distribution 
of significant level, additional shift table on ≤1.5, >1.5 to 
≤2.0 and > 2.0 category for baseline vs. post baseline may 
be provided 
Conjugated 
Bilirubin 
>35% Total Bilirubin and TBILI>1.5 ULN, and baseline Total 
Bilirubin ≤ 35% or TBILI ≤1.5 ULN 
Conjugated bilirubin determined on a case-by-case basis. 
ALT and Total 
Bilirubin 
ALT>3 ULN and TBILI>2 ULN, and baseline ALT ≤ 3 ULN or 
TBILI ≤ 2ULN 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
CPK* 
>3 and ≤ 10 ULN and baseline ≤ 3ULN* 
>10 ULN and baseline ≤10ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
* At least one level is required, multiple levels are optional 
for phase 2/3 studies. If it is desirable to get the distribution 
of significant level, additional shift table on ≤3, >3 to ≤10, 
and > 10 category for baseline vs. post baseline may be 
provided 
Creatinine 
≥150 μmol/L (Adults) or ≥ULN (if ULN≥150 μmol/L) and 
baseline < 150 μmol/L or <ULN (if ULN≥150 μmol/L) 
≥30% change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
3 independent criteria  
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Parameter 
PCSV 
Comments 
Creatinine 
Clearance 
(Cockcroft's 
formula) 
<15 ml/min and baseline ≥15 ml/min (end stage renal 
impairment) 
≥15 -<30 ml/min and baseline ≥30 ml/min (severe renal 
impairment) 
≥30 - < 60 ml/min and baseline ≥60 ml/min (moderate renal 
impairment) 
≥60 - < 90 ml/min and baseline ≥90 ml/min (mild renal 
impairment) 
Use is optional. 
FDA draft guidance 2010 
Four independent criteria, will provide additional shift table 
if needed 
 
Uric Acid 
Hyperuricemia: 
 
Hypouricemia: 
 
>408 μmol/L or >ULN (if ULN≥408 μmol/L) and baseline ≤408 
μmol/L or ≤ULN (if ULN≥408 μmol/L) 
<120 μmol/L or <LLN (if LLN≤120 μmol/L) and baseline ≥ 120 
μmol/L or ≥LLN (if LLN≤120 μmol/L) 
Harrison- Principles of Internal Medicine 17th Ed., 2008. 
Two independent criteria 
Blood Urea 
Nitrogen 
≥17 mmol/L or ≥ULN (if ULN≥17 mmol/L) and baseline 
<17 mmol/L or <ULN (if ULN≥17 mmol/L) 
Two independent criteria 
Chloride 
                
Hypochloremia: 
 
               
Hyperchloremia: 
 
<80 mmol/L or <LLN (if LLN≤80 mmol/L) and baseline 
≥ 80 mmol/L or ≥LLN (if LLN≤80 mmol/L) 
>115 mmol/L or >ULN (if ULN≥115 mmol/L) and baseline 
≤ 115 mmol/L or ≤ULN (if ULN≥115 mmol/L) 
Two independent criteria  
Sodium 
                  
Hyponatremia: 
 
                 
Hypernatremia: 
 
≤129 mmol/L or ≤LLN (if LLN≤129 mmol/L) and baseline 
> 129 mmol/L or >LLN (if LLN≤129 mmol/L) 
≥160 mmol/L or ≥ULN (if ULN≥160 mmol/L) and baseline 
<160 mmol/L or <ULN (if ULN≥160 mmol/L) 
Two independent criteria 
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Parameter 
PCSV 
Comments 
Potassium 
                  
Hypokalemia 
 
                  
Hyperkalemia 
 
<3 mmol/L or <LLN (if LLN≤3 mmol/L) and baseline ≥ 3 
mmol/L or ≥LLN (if LLN≤3 mmol/L) 
≥5.5 mmol/L or ≥ULN (if ULN≥5.5 mmol/L) and baseline <5.5 
mmol/L or <ULN (if ULN≥5.5 mmol/L) 
FDA Feb 2005. 
Two independent criteria 
Total Cholesterol ≥7.74 mmol/L or ≥ULN (if ULN≥7.74 mmol/L) and baseline < 
7.74 mmol/L or <ULN (if ULN≥7.74 mmol/L) 
Threshold for therapeutic intervention. 
Triglycerides 
≥4.6 mmol/L or ≥ULN (if ULN≥4.6 mmol/L) and baseline < 4.6 
mmol/L or <ULN (if ULN≥4.6 mmol/L) 
Threshold for therapeutic intervention. 
Lipasemia 
≥3 ULN and baseline < 3 ULN  
 
Amylasemia 
≥3 ULN and baseline < 3 ULN  
 
Glucose 
                
Hypoglycaemia 
 
               
Hyperglycaemia 
 
≤3.9 mmol/L and <LLN and baseline >3.9 mmol/L or ≥ LLN  
≥11.1 mmol/L (unfasted); ≥7 mmol/L (fasted) and baseline < 11.1 
mmol/L (unfasted); <7 mmol/L (fasted)  
 
ADA Jan 2008. 
HbA1c 
>8% and baseline ≤ 8%  
 
Albumin 
≤25 g/L or ≤LLN (if LLN≤25 g/L) and baseline >25 g/L or >LLN 
(if LLN≤25 g/L) 
 
CRP  
>2 ULN or >10 mg/L (if ULN not provided) and 
baseline ≤2 ULN or ≤10 mg/L (if ULN not provided)  
FDA Sept 2005. 
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Parameter 
PCSV 
Comments 
Hematology 
WBC 
<3.0 Giga/L or <LLN (if LLN≤3.0 Giga/L) and baseline ≥3.0 
Giga/L or ≥LLN (if LLN≤3.0 Giga/L) (Non-Black);  
<2.0 Giga/L or <LLN (if LLN≤2.0 Giga/L) and baseline ≥2.0 
Giga/L or ≥LLN (if LLN≤2.0 Giga/L) (Black)* 
 
≥16.0 Giga/L or ≥ULN (if ULN≥16.0 Giga/L) and baseline < 16 
Giga/L or <ULN (if ULN≥16.0 Giga/L) 
Increase in WBC: not relevant. 
*The default criteria. Summary by race (black and Non-
black) are optional. 
 
To be interpreted only if no differential count available. 
Lymphocytes 
>4.0 Giga/L or >ULN (if ULN≥4.0 Giga/L) and baseline ≤ 4.0 
Giga/L or ≤ULN (if ULN≥4.0 Giga/L) 
 
Neutrophils 
<1.5 Giga/L or <LLN (if LLN≤1.5 Giga/L) for Non-Black or 
<1.0 Giga/L or <LLN (if LLN≤1.0 Giga/L) for Black and baseline 
≥1.5 Giga/L or ≥LLN (if LLN≤1.5 Giga/L) for Non-Black or 
≥1.0 Giga/L or ≥LLN (if LLN≤1.0 Giga/L) for Black* 
 
<1.5 Giga/L or <LLN (if LLN≤1.5 Giga/L) and baseline ≥1.5 
Giga/L or ≥LLN (if LLN≤1.5 Giga/L) (Non-Black);  
<1.0 Giga/L or <LLN (if LLN≤1.0 Giga/L) and baseline ≥1.0 
Giga/L or ≥LLN (if LLN≤1.0 Giga/L) (Black) 
 
<0.5 Giga/L regardless of baseline value or racce 
International Consensus meeting on drug-induced blood 
cytopenias, 1991. 
*The default criteria. By race (black and Non-black) are 
optional. 
Monocytes 
>0.7 Giga/L or >ULN (if ULN≥0.7 Giga/L) and baseline ≤ 0.7 
Giga/L or ≤ULN (if ULN≥0.7 Giga/L) 
 
Basophils 
>0.1 Giga/L or >ULN (if ULN≥0.1 Giga/L) and baseline ≤ 0.1 
Giga/L or ≤ULN (if ULN≥0.1 Giga/L) 
 
Eosinophils 
>0.5 Giga/L or >ULN (if ULN≥0.5 Giga/L) and baseline ≤0.5 
Giga/L or ≤ULN (if ULN≥0.5 Giga/L) 
Harrison- Principles of Internal Medicine 17th Ed., 2008. 
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Parameter 
PCSV 
Comments 
Hemoglobin 
≤115 g/L or ≤LLN (if LLN≤115 g/L) for male or ≤95 g/L or 
≤LLN (if LLN≤95 g/L) for female and baseline > 115 g/L or 
>LLN (if LLN≤115 g/L) for male or > 95 g/L or >LLN (if 
LLN≤95 g/L) for Female* 
 
≤115 g/L or ≤LLN (if LLN≤115 g/L) and baseline > 115 g/L or 
>LLN (if LLN≤115 g/L) for male; 
 ≤95 g/L or ≤LLN (if LLN≤95 g/L) and baseline > 95 g/L or 
>LLN (if LLN≤95 g/L) for Female. 
 
≥185 g/L or ≥ULN (if ULN≥185 g/L) for male or ≥165 g/L or 
≥ULN (if ULN≥165 g/L) for female and baseline <185 g/L or 
<ULN (if ULN≥185 g/L) for male or <165 g/L or <ULN (if 
ULN≥165 g/L) for Female* 
 
≥185 g/L or ≥ULN (if ULN≥185 g/L) and baseline <185 g/L or 
<ULN (if ULN≥185 g/L) for Male; 
≥165 g/L or ≥ULN (if ULN≥165 g/L) and baseline < 165 g/L or 
<ULN (if ULN≥165 g/L) for Female 
 
Decrease from Baseline ≥20 g/L 
Three criteria are independent. 
 
*The default criteria. By gender (male and female) are 
optional. 
 
Criteria based upon decrease from baseline are more 
relevant than based on absolute value. Other categories for 
decrease from baseline can be used (≥30 g/L, ≥40 g/L, 
≥50 g/L). 
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Parameter 
PCSV 
Comments 
Hematocrit 
≤0.37 v/v or ≤LLN (if LLN≤0.37 v/v) for Male or ≤0.32 v/v or 
≤LLN (if LLN≤0.32 v/v) for Female and baseline > 0.37 v/v or 
>LLN (if LLN≤0.37 v/v) for Male or > 0.32 v/v or >LLN (if 
LLN≤0.32 v/v) for Female* 
 
≤0.37 v/v or ≤LLN (if LLN≤0.37 v/v) and baseline > 0.37 v/v 
or >LLN (if LLN≤0.37 v/v) for Male ; ≤0.32 v/v or ≤LLN (if 
LLN≤0.32 v/v) and baseline > 0.32 v/v or >LLN (if 
LLN≤0.32v/v) for Female 
 
≥0.55 v/v or ≥ULN (if ULN≥0.55 v/v) for Male or ≥0.5 v/v or 
≥ULN (if ULN≥0.5 v/v) for Female and baseline < 0.55 v/v or 
<ULN (if ULN≥0.55 v/v) for Male < 0.5 v/v or <ULN (if 
ULN≥0.5 v/v) for Female* 
 
≥0.55 v/v or ≥ULN (if ULN≥0.55 v/v) and baseline < 0.55 v/v or 
<ULN (if ULN≥0.55 v/v) for Male; ≥0.5 v/v or ≥ULN (if 
ULN≥0.5 v/v) and baseline < 0.5 v/v or <ULN (if ULN≥0.5 v/v) 
for Female 
Two Criteria are independent 
 
*The default criteria. By gender (male and female) are 
optional. 
RBC 
≥6 Tera/L or ≥ULN (if ULN≥6 Tera/L) and baseline < 6 Tera/L 
or <ULN (if ULN≥6 Tera/L) 
Unless specifically required for particular drug 
development, the analysis is redundant with that of Hb. 
Platelets 
<100 Giga/L or <LLN (if LLN≤100 Giga/L) and baseline ≥100 
Giga/L or ≥LLN (if LLN≤100 Giga/L) 
≥700 Giga/L or ≥ULN (if ULN≥700 Giga/L) and baseline < 700 
Giga/L or <ULN (if ULN≥700 Giga/L) 
International Consensus meeting on drug-induced blood 
cytopenias, 1991. 
Two independent criteria 
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Parameter 
PCSV 
Comments 
Urinalysis 
 
pH 
≤4.6 or ≤LLN (if LLN≤4.6) and baseline > 4.6 or >LLN (if 
LLN≤4.6) 
≥8 or ≥ULN (if ULN≥8) and baseline < 8 or <ULN (if ULN≥8) 
Two independent criteria 
Vital signs 
HR 
<45 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
To be applied for all positions except STANDING 
 
SBP 
≤95 mmHg and decrease from baseline ≥20mmHg 
≥160 mmHg and increase from baseline ≥20 mmHg 
To be applied for all positions except STANDING 
 
DBP 
≤45 mmHg and decrease from baseline ≥10 mmHg 
≥110 mmHg and increase from baseline ≥10 mmHg 
To be applied for all positions except STANDING 
Weight 
 5% increase from baseline 
5% decrease from baseline 
FDA Feb 2007  
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10.3. 
Symptom Evolution of COVID-19 (SE-C19) 
Symptom Evolution of COVID-19 (SE-C19):  The SE-C19 was developed based on the symptoms 
listed by the CDC, published literature and supported by interviews with patients with COVID-19. 
The symptom diary included a list of 23 symptoms (feverish, chills, sore throat, cough, shortness 
of breath or difficulty breathing, nausea, vomiting, diarrhea, headache, red or watery eyes, body 
aches, loss of taste or smell, fatigue, loss of appetite, confusion, dizziness, pressure or tight chest, 
chest pain, stomachache, rash, sneezing, sputum/phlegm, runny nose).  On a daily basis, patients 
indicated which of the 23 symptoms they had experienced in the last 24 hours, and then rated each 
symptom selected at its worst moment in the last 24 hours on a scale of mild, moderate or severe. 
Each symptom on the SE-C19 was captured numerically as 0 (no symptom), 1 (mild symptom), 2 
(moderate symptom), or 3 (severe symptom). For the purposes of analysis, ‘no symptom’ will be 
assigned a score of 0, ‘mild symptom’ and ‘moderate symptom’ will be assigned a score 1 
(mild/moderate symptom), and ‘severe symptom’ will be assigned a score of 2 (ie, the mild and 
moderate symptom categories will be collapsed). 
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12-Mar-2021 22:22:47 GMT+0000
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12-Mar-2021 22:28:34 GMT+0000
ESig Approval
12-Mar-2021 22:30:07 GMT+0000
                                        VV-RIM-00147241-1.0 Approved - 12 Mar 2021 GMT-5:00
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Signature Page for VV-RIM-00147241 v1.0
Signature Page for VV-RIM-00147241 v1.0 Approved
ESig Approval
12-Mar-2021 23:34:26 GMT+0000
                                        VV-RIM-00147241-1.0 Approved - 12 Mar 2021 GMT-5:00
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Prot_001.pdf: 
EudraCT: 2020-003690-21 
IND: 148069 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A MASTER PROTOCOL ASSESSING THE SAFETY, TOLERABILITY, AND 
EFFICACY OF ANTI-SPIKE (S) SARS-COV-2 MONOCLONAL ANTIBODIES 
FOR THE TREATMENT OF AMBULATORY PATIENTS WITH COVID-19 
Compound: 
REGN10933+REGN10987 
Clinical Phase: 
1/2/3 
Protocol Number: 
R10933-10987-COV-2067 
Protocol Version: 
Amendment 10 US 
Amendment 10 US Date of Issue: 
See appended electronic signature page 
Amendment 9 US Date of Issue: 
14 Jul 2021 
Amendment 8 Date of Issue: 
12 Mar 2021 
Amendment 7 Date of Issue: 
18 Dec 2020 
Amendment 6 Date of Issue: 
14 Nov 2020 
Amendment 5 Date of Issue: 
08 Aug 2020 
Amendment 4 Date of Issue: 
11 Jul 2020 
Amendment 3 Date of Issue: 
04 Jul 2020 
Amendment 2 Date of Issue: 
19 June 2020 
Amendment 1 Date of Issue: 
03 June 2020 
Original Date of Issue: 
29 May 2020 
Medical/Study Director: 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
Confidential: This submission contains confidential and proprietary commercial information and/or 
trade secrets which are subject to protection under laws and regulations worldwide including, but not 
limited to TRIPS Article 39 and regional, national or state laws whether by legislation or in equity. For 
the purposes of compliance with all applicable freedom of information laws, and regulations, and their 
equivalents anywhere in the world including but not limited to the US Freedom of Information Act 5 
U.S.C. §552, Regeneron expects that, prior to disclosure to third parties of any information and/or data 
related to, or contained within, this submission, it will be given every opportunity under applicable laws 
to protect its commercial interests and/or its trade secrets including the opportunity to object to such 
disclosure and/or provide redaction proposals. 
VV-RIM-00163381-1.0 Approved - 16 Aug 2021 GMT-5:00
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NCT04425629


Clinical Study Protocol 
 R10933-10987-COV-2067 Amendment 10 US 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 2 
 
CONFIDENTIAL 
AMENDMENT HISTORY 
Amendment 10 US 
The primary purpose of this amendment is to end enrollment of the REGN10933+REGN10988 
2400 mg IV dose level. Since 1200 mg IV is the only remaining dose in this study, treatment 
assignment for patients enrolled in this amendment and later will no longer be blinded. Additional 
modifications and clarifications have been made, including with respect to the long COVID 
portion of the study. 
Description of Change 
 
Brief Rationale   
Section(s) 
Added a note that states enrollment in 
cohort 1 was closed on 14 May 2021. 
To ensure up-to-date study 
information 
Section 6.1.3 Phase 3 
Section 7.2.1 Inclusion Criteria 
For cohort 2 and cohort 3, the 
REGN10933+REGN10987 2400 mg IV 
treatment arm will be dropped, such that 
all newly-enrolled patients in cohort 2 
and cohort 3 will receive 
REGN10933+REGN10987 at the 1200 
mg IV dose (or body-weight adjusted 
equivalent for patients who are <18 years 
of age). 
Since 1200 mg IV is the only remaining 
dose in the study, patients enrolled in 
this amendment and later will no longer 
be randomized to 1200 mg IV with a 
probability of 1, and their treatment 
assignment will no longer be blinded. 
To maximize enrollment, 
and hence data obtained, in 
the 1200 mg arm 
 
This change is not due to 
any safety concern related 
to the 2400 mg IV dose. 
Section 3.2.2.2 Phase 3 Dose Selection 
Section 6.1.3 Phase 3 
Figure 7 Study Flow Diagram, Phase 3 
(Cohort 2 Patients; Cohort 3 Patients <18 
Years) Amendment 10 US and Later [new] 
Figure 8 Study Flow Diagram, Phase 3 
(Cohort 3 Patients ≥18 Years) Amendment 
10 US and Later [new] 
Section 8.6 Method of Treatment 
Assignment 
Section 8.7 Blinding 
Section 8.8 Emergency Unblinding 
Section 8.9.1 Packaging, Labeling, and 
Storage 
Additional samples for assessment of 
drug concentration have been included as 
below:  
• Day 60 for cohort 3 patients ≥18 years  
• Day 90 for cohort 2 patients and 
cohort 3 patients <18 Years (schedules 
A and B) 
• Day 120 for cohort 2 patients and 
cohort 3 patients <18 Years (schedules 
C and D) 
To obtain additional 
REGN10933+REGN10987 
pharmacokinetics data 
Table 7 Schedule of Events: Phase 3 
(Cohort 3 ≥18 Years) 
Table 8 Schedule of Events: Phase 3 
(Cohort 2 Patients; Cohort 3 Patients <18 
Years) 
In phase 3 cohort 1 patients, any new 
medical condition(s) diagnosed after 
randomization will be captured as an 
adverse event of special interest (AESI), 
but will not require expedited reporting 
to the Sponsor. 
Patients who previously consented to 
protocol amendment 9 US but have 
already completed their end of study 
visit may be reconsented for 
retrospective collection of this 
information. 
To contextualize any 
symptoms or diagnoses that 
may confound or be 
associated with long 
COVID 
Table 6 Schedule of Events: Phase 3, 
Assessment of Long COVID (Cohort 1 
Patients) 
Section 9.1.1 Footnotes for the Schedule of 
Events Tables, #24 [new] 
Section 9.2.12 Recording New Medical 
Diagnoses or Conditions [new] 
Section 10.1.1 General Guidelines 
Section 10.1.4 Other Adverse Events of 
Special Interest that do not Require 
Expedited Reporting to Sponsor [new] 
In phase 3 cohort 1 patients, any positive 
SARS-CoV-2 local test results obtained 
outside of the study (starting from the 
day at which they consent to protocol 
amendment 9 US) will no longer require 
expedited reporting to the Sponsor. 
To provide operational 
flexibility 
Section 4.3 Exploratory Endpoints 
Section 9.2.11 Monitoring for SARS-CoV-
2 Reinfection 
Section 10.1.3 Events that Require 
Expedited Reporting to Sponsor 
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Clinical Study Protocol 
 R10933-10987-COV-2067 Amendment 10 US 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 3 
 
CONFIDENTIAL 
Description of Change 
 
Brief Rationale   
Section(s) 
Section 10.1.4 Other Adverse Events of 
Special Interest that do not Require 
Expedited Reporting to Sponsor [new] 
For all day 120 and day 169 
questionnaires in phase 3 cohort 1 
patients, a visit window of +7 days will 
be applied. For all other day 120 and day 
169 assessments and sample collections 
in these patients, a visit window of ±7 
days will be applied. 
To ensure operational 
clarity 
Table 6 Schedule of Events: Phase 3, 
Assessment of Long COVID (Cohort 1 
Patients) 
Section 9.1.1 Footnotes for the Schedule of 
Events Tables, #19 
Clarified that patients who are 
withdrawn from the study before day 29 
will be asked to allow an early 
termination visit consisting of day 29 
assessments and sample collections. 
Patients who are withdrawn from the 
study after day 29 will be asked to allow 
an early termination visit consisting of 
end-of-study assessments and sample 
collections. 
To ensure operational 
clarity. 
Section 9.1.2 Early Termination from the 
Study 
Risk-benefit information was updated. 
To provide current study 
drug information 
Section 3.3 Risk-Benefit 
Minor updates (typographical, editorial, 
administrative) were made. 
To ensure clarity, accuracy, 
and consistency 
Throughout the document 
 
 
                                        VV-RIM-00163381-1.0 Approved - 16 Aug 2021 GMT-5:00


Clinical Study Protocol 
 R10933-10987-COV-2067 Amendment 10 US 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 4 
 
CONFIDENTIAL 
Amendment 9 US 
The primary purpose of this US-specific amendment is to implement procedures to obtain a better 
understanding of long COVID and the potential impact of treatment during acute infection on the 
longer-term phase of the disease. 
Description of Change 
 
Brief Rationale   
Section(s) 
Evaluation of Long COVID 
Long COVID will be assessed through 
day 169 in phase 3 cohort 1. Patient-
reported symptoms and related outcomes 
will be evaluated. In addition, blood 
samples will be collected for biomarker 
analysis and immunoprofiling, to gain a 
better understanding of the underlying 
biology of long COVID and the impact 
of prior treatment in the acute stage of 
disease. Nasopharyngeal (NP) swab 
samples will also be collected to assess 
for the presence of SARS-CoV-2 during 
this later stage of analysis. 
To better understand the 
patient experience of long 
COVID, and to evaluate 
whether treatment of initial 
SARS-CoV-2 infection 
with study drug may 
provide subsequent clinical 
benefit in the prevention of 
long COVID 
Clinical Protocol Synopsis: Study Design 
Section 1.4 Long-Term Outcomes in 
Patients with COVID-19 
Section 2.3 Exploratory Objectives 
Section 3.2.1.6 Assessment of Long 
COVID 
Section 4.3 Exploratory Endpoints 
Section 5.6 Pharmacodynamic and Other 
Biomarker Variables 
Section 6.1.3.2 Evaluation of Long COVID 
in Phase 3 [new] 
Figure 4 Study Flow Diagram, Phase 3 
(Cohort 1) 
Table 5 Schedule of Events: Phase 3 
(Cohort 1 Patients) 
Table 6 Schedule of Events: Phase 3, 
Assessment of Long COVID (Cohort 1 
Patients) [new] 
Section 9.1.1 Footnotes for the Schedule of 
Events Tables, #14, 16; #18, 19, 20, 21, 23 
[new]  
Section 9.2.15 Assessment of Long 
COVID [new] 
Section 11.4.3.3 Exploratory Analysis 
[new] 
Table 10 Symptoms Evaluated in the 
Symptom Evolution of Long COVID-19 
(SE-LC19) Instrument 
For patients in cohort 1, any positive 
SARS-CoV-2 local test result, obtained 
from the day of consent to protocol 
amendment 9 US until day 169, will be 
recorded and reported as an AESI. 
To provide additional 
contextual information 
regarding SARS-CoV-2 
infection to inform long 
COVID analyses 
Table 5 Schedule of Events: Phase 3 
(Cohort 1 Patients) 
Table 6 Schedule of Events: Phase 3, 
Assessment of Long COVID (Cohort 1 
Patients) 
Section 9.1.1 Footnotes for the Schedule of 
Events Tables, #22 [new]  
Section 9.2.11 Monitoring for SARS-CoV-
2 Reinfection [new] 
Section 10.1.1 General Guidelines 
Section 10.1.3 Events that Require 
Expedited Reporting to Sponsor 
Clarified that although patient-reported 
outcome (PRO) data (eg, patient-reported 
questionnaires, surveys, and instruments) 
are generally not reportable as individual 
AEs, if the investigator is made aware of 
any AE that (in his or her judgement) is 
To ensure appropriate 
collection of safety-related 
data. 
Section 9.2.4.2 Adverse Event Monitoring 
Section 9.2.15 Assessment of Long 
COVID 
Section 10.1.1 General Guidelines 
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Clinical Study Protocol 
 R10933-10987-COV-2067 Amendment 10 US 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 5 
 
CONFIDENTIAL 
Description of Change 
 
Brief Rationale   
Section(s) 
related to study drug, the AE will follow 
standard AE reporting and recording. 
To ensure clarity in the Schedule of 
Events, a separate schedule has been 
developed for cohort 3, containing all 
procedures as the prior schedule for this 
cohort. 
To ensure operational 
clarity in light of changes 
made to the cohort 1 
schedule of events. 
Section 6.1.3 Phase 3 
Table 7 Schedule of Events: Phase 3 
(Cohort 3 ≥18 Years) 
Miscellaneous 
Work Productivity and Activity 
Impairment and Classroom Impairment 
Questions (WPAI+CIQ) will be collected 
pre-dose for patients who are enrolled in 
cohort 2 and cohort 3 after this 
amendment is implemented. 
To capture baseline 
assessment for comparative 
analyses. 
Table 7 Schedule of Events: Phase 3 
(Cohort 3 ≥18 Years) 
Table 8 Schedule of Events: Phase 3 
(Cohort 2 Patients; Cohort 3 Patients <18 
Years) 
Clarified that, for the optional 
pharmacogenomics sub-study, newly-
enrolled patients who consent to the sub-
study will have blood samples collected 
for both DNA and RNA; patients who 
were previously enrolled and later 
consent to the sub-study will only have a 
blood collection for DNA. 
To ensure appropriate 
collection of sub-study 
samples. 
Section 9.2.13 Pharmacogenomics Sub-
Study (Optional) 
Clarified that for post-day 29 follow-up, 
phone or telemedicine are the preferred 
methods of contact, but other modes of 
communication (eg, email) are 
acceptable if a patient cannot be 
contacted through other methods. 
To provide operational 
flexibility. 
Section 9.2.5 Post-Day 29 Follow-Up 
For patients <12 years of age, clarified 
that immunogenicity will be analyzed 
only in pre-dose and day 29 
pharmacokinetic (PK)-anti-drug 
antibodies (ADA) samples. 
To ensure accuracy of 
sample collection. 
Section 9.1.1 Footnotes for the Schedule of 
Events Tables, #15 
Clarified that unscheduled visits may 
also include collection of NP swabs, 
blood, serum, or plasma, as necessary. 
To provide schedule 
flexibility. 
Section 9.1.3 Unscheduled Visits 
Added language clarifying that 
enrollment in the phase 3 PK sub-study 
is closed. 
Sub-study has met planned 
enrollment. 
Section 9.2.8 Drug Concentration 
Measurements and Samples 
Risk-benefit information was updated to 
reflect phase 3 clinical trials in the 
treatment and prevention of COVID-19. 
To provide current study 
drug information. 
Section 3.3 Risk-Benefit 
Section 3.3.1 Summary of Efficacy and 
Safety Profile in Clinical Trials [New] 
Section 3.3.2 Summary of Risks 
Updates to background information, 
minor clarifications for consistency, 
administrative changes, and other minor 
updates (typographical, editorial, 
formatting) were made. 
To ensure clarity, accuracy, 
and consistency. 
Throughout the document 
 
 
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Clinical Study Protocol 
 R10933-10987-COV-2067 Amendment 10 US 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 6 
 
CONFIDENTIAL 
Amendment 8 
The primary purpose of this amendment is to 1) end randomization to placebo in all phase 3 
cohorts, and 2) revise the statistical analysis for cohort 1, including the primary endpoint, key 
secondary endpoints, hierarchical testing, and plan for interim/final analyses.  
Description of Change 
 
Brief Rationale   
Section(s) 
Phase 3 Randomization 
As of 25 February 2021, patients will no longer be 
randomized to placebo 
Per IDMC 
recommendation  
Table 1 Summary of Main Phase 3 
Adaptations 
Section 6.1.3 Phase 3 
Section 8.6 Method of Treatment 
Assignment 
Phase 3 Statistical Analysis 
The following summarizes the planned statistical 
analysis for phase 3 cohort 1: 
• The primary endpoint will be proportion of patients 
with ≥1 COVID-19-related hospitalization or all-
cause death through day 29 
• The key secondary endpoints will be proportion of 
patients with ≥1 COVID-19-related hospitalization 
or all-cause death from day 4 to through day 29, 
and time to COVID-19 symptoms resolution. 
Symptoms will include a subset of those captured 
in the SE-C19, as described in the main text 
• The full analysis set (FAS) includes all randomized 
patients with COVID-19 symptoms (starting from 
the 800th symptomatic patient randomized in the 
study overall), regardless of whether they have risk 
factors for severe COVID-19 
• The modified full analysis set (mFAS) includes all 
patients in the FAS with detectable SARS-CoV-2 
RNA by RT-qPCR in nasopharyngeal swabs at 
randomization and ≥1 risk factor for severe 
COVID-19. The mFAS will be used to analyze the 
primary and key secondary endpoints 
• Concurrent with the final analysis of the primary 
endpoint for the 2400 mg treatment group, an 
interim analysis will be conducted on the primary 
endpoint for the 1200 mg treatment group 
• A hierarchy is provided for the primary and key 
secondary endpoints to control for multiplicity, 
including a Gamma family spending function to 
control for alpha in the interim and final analyses 
• Other endpoints, including those assessing 
emergency room (ER) visits and other medically-
attended visits (MAVs), will be evaluated 
descriptively 
• Additional minor details were updated for 
consistency with the planned analysis 
Details of the revised statistical analysis are provided 
in the main text. 
Primary endpoint 
changed based on 
health authority 
feedback. 
 
Other changes 
implemented to 
ensure that efficacy 
assessment of 
REGN10933 + 
REGN10987 is 
conducted with the 
most clinically-
relevant endpoints  
Section 2.1 Primary Objectives 
Section 2.2 Secondary Objectives  
Section 3.2.1.5 Rationale for Phase 3 
Adaptations 
Table 1 Summary of Main Phase 3 
Adaptations 
Section 4.1 Primary Endpoints 
Section 4.2 Secondary Endpoints 
Figure 3 Study Flow Diagram, Phase 
2 (and Phase 3 Prior to Amendment 
6) 
Figure 4 Study Flow Diagram, Phase 
3 (Cohort 1 Patients; Cohort 3 
Patients ≥18 Years) 
Figure 5 Study Flow Diagram, Phase 
3 (Cohort 2 Patients; Cohort 3 
Patients <18 Years) 
Section 6.3 Planned Interim 
Analysis 
Section 11.1 Statistical Hypothesis 
Section 11.2 Justification of Sample 
Size 
Table 9 Estimated Sample Sizes at 
Each Analysis Time Point for Phase 
3 Patients with ≥1 Risk Factor for 
Severe COVID-19 
Section 11.3.1 Efficacy Analysis 
Sets 
Section 11.4.1 Patient Disposition  
Section 11.4.3.1 Primary Efficacy  
Analysis 
Section 11.4.3.2 Secondary Efficacy 
Analysis 
Section 11.4.4 Control of 
Multiplicity 
Table 11 Statistical Testing 
Hierarchy, Phase 3 Cohort 1 
Analysis 
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Clinical Study Protocol 
 R10933-10987-COV-2067 Amendment 10 US 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 7 
 
CONFIDENTIAL 
Description of Change 
 
Brief Rationale   
Section(s) 
Table 12 Statistical Testing 
Hierarchy, Phase 3 Cohort 1 
Analysis 
Section 11.5 Interim Analysis 
The full analysis set (FAS) and modified full analysis 
set (mFAS) will not require that patients be 
randomized and treated; patients who are 
randomized and not treated will also be considered 
part of the FAS or mFAS. 
Per health authority 
feedback 
Section 11.3.1 Efficacy Analysis 
Sets 
Additional details have been provided to describe the 
SE-C19 instrument.  
To provide additional 
information related to 
a key secondary 
endpoint 
Section 9.2.13 Exploratory Patient-
Reported Symptoms 
Table 7 Symptoms Evaluated in the 
SE-C19 [new] 
Clarified that, in total, up to approximately 8500 
patients will be enrolled in phase 3 cohort 1. 
To ensure an accurate 
description of 
planned enrollment 
Table 1 Summary of Main Phase 3 
Adaptations 
Section 7.1 Number of Patients 
Planned 
Added an exploratory objective to assess the clinical 
efficacy of different dose levels of REGN10933 + 
REGN10987, as measured by COVID-19-related 
hospitalizations or all-cause death. 
To better understand 
potential differences 
in clinical efficacy 
between REGN10933 
+ REGN10987 dose 
levels 
Section 2.3 Exploratory Objectives  
Time to COVID-19 symptoms resolution will be 
evaluated as an exploratory endpoint in phase 3 
cohort 2. 
To assess the 
potential impact of 
REGN10933 + 
REGN10987 on 
COVID-19 symptoms 
Section 4.3 Exploratory Endpoints 
 
Safety Assessment 
For patients who are <12 years of age, a phone call 
will be made within 6 to 8 hours after completing the 
infusion to collect targeted safety information. A 
phone call on day 2 is not required. These patients (or 
their caregivers) should continue to be instructed to 
contact the site within the first 24 hours post-infusion 
if they experience any side effects. 
This change is consistent with a memorandum that 
was previously provided to study sites. 
Per health authority 
feedback; to ensure 
appropriate post-
infusion monitoring 
for younger patients 
<12 years old 
Section 6.1.3 Phase 3 
Section 9.1.1 Footnotes for the 
Schedule of Events Tables, #17 
 
Clarified that any SAE resulting in death that occurs 
prior to study day 169 should be reported, regardless 
of patient withdrawal or early termination. 
To ensure appropriate 
capturing of vital 
status 
Section 10.1.1 General Guidelines 
Other Changes and Clarifications 
For all study phases, the viral sequencing exploratory 
endpoint has been removed. The exploratory 
objective has been revised to the following: 
• To evaluate viral variants at baseline and post-
treatment 
In addition, clarified that the results of viral 
sequencing will be reported separately from the CSR.  
To provide flexibility 
with respect to 
planned viral 
sequencing analyses 
Section 2.3 Exploratory Objectives 
Section 9.2.10.3 Virology 
Added exploratory objective for phase 3 cohort 3:  
• To describe clinical outcomes of patients treated 
with REGN10933+REGN10987 using various 
measures of COVID-19-related medically-attended 
visits or all-cause death 
To assess clinical 
outcomes among 
patients who are 
pregnant at 
randomization 
Section 2.3 Exploratory Objectives 
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Clinical Study Protocol 
 R10933-10987-COV-2067 Amendment 10 US 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 8 
 
CONFIDENTIAL 
Description of Change 
 
Brief Rationale   
Section(s) 
Clarified that cohort 2 and cohort 3 may continue to 
enroll after enrollment of cohort 1 has been 
completed. 
To clarify flexibility 
of enrollment in 
phase 3 cohorts 
Table 1 Summary of Main Phase 3 
Adaptations 
Section 11.2 Justification of Sample 
Size 
In cohort 2, there will be a minimum enrollment of 
20 patients <10 kg (10 per treatment group) and 20 
patients between ≥10 kg and <40 kg. 
Per health authority 
feedback 
Table 1 Summary of Main Phase 3 
Adaptations 
Section 11.2 Justification of Sample 
Size 
The following phase 3 operational clarifications or 
changes have been made: 
• Study visits (including phone calls) are not 
required solely to collect continuously-monitored 
assessments, if no other assessments are planned 
on that day.  
• Study visits are not required on days when only 
electronic survey data are collected  
• TEAEs that led to a medically-attended visit will 
be collected starting on day 1 post-infusion, when 
applicable (day 1 post dose collection was 
previously missing from the schedule of events) 
• In phase 3 cohort 2, vital status was incorrectly 
marked as a screening assessment. This error has 
been corrected 
• On days 60 and 90, the window for EQ-5D-5L 
(and EQ-5D-Y) assessment is ±3 days. On days 
120 and 169, the window is ±7 days  
To ensure operational 
clarity, including 
avoiding unnecessary 
study visits and 
ensuring appropriate 
capturing of relevant 
adverse events and 
concomitant 
procedures 
Section 8.10 Concomitant 
Medications and Procedures 
Table 5 Schedule of Events: Phase 3 
(Cohort 1 Patients; Cohort 3 Patients 
≥18 Years) 
Table 6 Schedule of Events: Phase 3 
(Cohort 2 Patients; Cohort 3 Patients 
<18 Years) 
Section 9.1.1 Footnotes for the 
Schedule of Events Tables, #7, 8, 14 
 
The following changes to concomitant medication 
recording have been made: 
• In addition to targeted concomitant medication, 
concomitant procedures will also be recorded when 
applicable 
• In addition to the listed targeted concomitant 
medications, “any other vaccines” and “oxygen” 
will also be recorded as applicable 
To capture additional 
clinical information 
Section 9.2.4.3 Record Targeted 
Concomitant Medications and 
Concomitant Procedures 
 
The following clarification has been made with 
respect to medically-attended visits related to 
COVID-19:  
• During each indicated collection visit (as provided 
in the schedule of events), all previously 
unrecorded COVID-19-related medically-attended 
visits and details will be recorded, beginning from 
the day of dosing up to and including the day of 
collection 
To ensure appropriate 
capturing of 
clinically-relevant 
information 
Section 9.2.3.2 COVID-19-Related 
Medically-Attended Visit Details 
Clarified that cohort 2 and cohort 3 will only be 
enrolled where permitted by local requirements. 
To provide 
enrollment flexibility 
per regional 
requirements 
Table 1 Summary of Main Phase 3 
Adaptations 
Section 7.2.1 Inclusion Criteria, #1 
Clarified that in addition to WPAI+CIQ, EQ-5D-5L, 
and EQ-5D-Y-5L, the return to usual health and 
return to usual activities surveys will only be 
administered at sites when regionally available. 
To provide 
operational flexibility 
Section 9.1.1 Footnotes for the 
Schedule of Events Tables, #14 
Neutralizing antibody (NAb) analyses will be 
conducted in phase 2 and phase 3 (all cohorts).  
To provide additional 
assessment of 
potential for 
neutralizing 
antibodies against 
Section 4.2 Secondary Endpoints 
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 R10933-10987-COV-2067 Amendment 10 US 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 9 
 
CONFIDENTIAL 
Description of Change 
 
Brief Rationale   
Section(s) 
REGN10933 + 
REGN10987 
Clarified that assessment of immunogenicity will be a 
secondary objective for cohort 2 and cohort 3 of 
phase 3, and that assessment of drug concentration 
will be a secondary objective for cohort 3 of phase 3; 
the objectives were previously listed incorrectly as 
primary objectives. 
To ensure accurate 
descriptions of 
planned analyses 
Section 2.1 Primary Objectives 
Section 2.2 Secondary Objectives  
Table 1 Summary of Main Phase 3 
Adaptations 
Section 4.1 Primary Endpoints 
Section 4.2 Secondary Endpoints 
The risk-benefit section has been updated to reflect 
the current Investigator’s Brochure (edition 5). This 
includes the addition of hypersensitivity reactions 
(including infusion-related reactions and injection 
site reactions) as an important identified risk. 
Additional contextual information related to COVID-
19 vaccination as a theoretical consideration has also 
been provided. 
To provide current 
information regarding 
the potential risks and 
benefits of 
REGN10933 + 
REGN10987  
Section 3.3 Risk-Benefit 
In light of the increasing number of therapeutic and 
preventative COVID-19 agents approved or 
conditionally authorized reference to individual 
agents has been removed. References to FDA and 
EMA have been provided as a general resource for 
currently-available agents. 
To ensure current, 
accurate, and 
consistent 
information 
Section 1.6 Current Landscape of 
Therapeutic and Preventative Agents 
for COVID-19 [deleted] 
Section 1.6 A Randomized, Placebo-
Controlled Study of Anti-SARS-
CoV-2 S Protein Monoclonal 
Antibodies in Ambulatory Patients 
with COVID-19 
Updates to background information, minor 
clarifications for consistency, and other minor 
updates (typographical, editorial) were made. 
To ensure clarity, 
accuracy, and 
consistency 
Throughout the document 
 
                                        VV-RIM-00163381-1.0 Approved - 16 Aug 2021 GMT-5:00


Clinical Study Protocol 
 R10933-10987-COV-2067 Amendment 10 US 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 10 
 
CONFIDENTIAL 
Amendment 7 
The primary purpose of this amendment is to modify the phase 3 portion of the study in response 
to health authority feedback. Related modifications (eg, with respect to patients who are pregnant) 
and other clarifications have also been implemented. 
Description of Change 
 
Brief Rationale   
Section(s) 
All-cause death was added to the cohort 1 (≥18 years) 
primary endpoint (ie, COVID-19-related medically-
attended visits or all-cause death) and to several 
secondary endpoints in cohort 1 and cohort 2 (<18 
years). The phase 3 sample size was not updated as a 
result of this change.  
Per health authority 
feedback; to capture 
an additional event 
of clinical 
importance 
Section 2.1 Primary Objectives 
Section 2.2 Secondary Objectives 
Section 3.2.1.5 Rationale for 
Phase 3 Adaptations 
Table 1 Summary of Main Phase 3 
Adaptations 
Section 4.1 Primary Endpoints 
Section 4.2 Secondary Endpoints 
Section 11.1 Statistical Hypothesis 
Section 11.2 Justification of 
Sample Size 
Section 11.4.3.1 Primary Efficacy 
Analysis 
In cohort 1, additional secondary endpoints were 
designated as key endpoints, and the statistical hierarchy 
was updated to control for multiplicity. 
To ensure rigorous 
statistical analysis 
Section 4.2 Secondary Endpoints 
Section 11.4.3.2 Secondary 
Efficacy Analysis 
Section 11.4.4 Control for 
Multiplicity 
Patients who are pregnant at randomization, regardless 
of age, will be enrolled in a separate double-blinded 
cohort (cohort 3): 
• Cohort will be randomized 1:1 to 
REGN10933+REGN1087 1200 mg or 2400 mg, tiered 
as applicable based on weight 
• Patients in the cohort will not be randomized to 
placebo 
• Randomization will not be stratified 
• Depending on their age, patients in cohort 3 will 
follow the cohort 1 (≥18 years) or cohort 2 (<18 years) 
schedule of events 
• For patients in cohort 3 who are ≥18 years, additional 
samples will be collected for drug concentration and 
immunogenicity assessment 
• Analysis will be descriptive and will focus on safety 
and PK  
To increase 
collection of safety 
and PK information 
related to 
REGN10933 + 
REGN10987 among 
patients who are 
pregnant 
Section 2.1 Primary Objectives 
Section 2.2 Secondary Objectives 
Table 1 Summary of Main Phase 3 
Adaptations 
Section 7.2.1 Inclusion Criteria, 
#9 
Section 9.1.1 Footnotes for the 
Schedule of Events Tables, #12, 
15 
The following changes will be made to cohort 2 (and 
patients <18 years in cohort 3): 
• Enrollment will be limited to patients who are 
symptomatic at randomization and have ≥1 risk factor 
for severe COVID-19 (ie, enrollment is discontinued 
for asymptomatic patients) 
• Removed the presence/absence of COVID-19 
symptoms as a stratification factor for randomization 
• Increased the frequency of vital signs assessments 
performed during and after infusion for patients <12 
years old 
• For patients who are <12 years old, an additional 
phone call will be made on day 2 (within 24 hours of 
infusion) for collection of targeted safety information, 
and these patients (or their caregivers) should be 
Per health authority 
request; to focus 
enrollment on 
patients with highest 
potential benefit and 
ensure appropriate 
safety monitoring 
during and within 24 
hours after study 
drug administration 
Section 3.2.1 Rationale for Study 
Design 
Section 3.2.1.5 Rationale for 
Phase 3 Adaptations 
Table 1 Summary of Main Phase 3 
Adaptations 
Section 6.1 Study Description and 
Duration 
Section 7.1 Number of Patients 
Planned 
Section 7.2.1 Inclusion Criteria, 
#4, 9 
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Description of Change 
 
Brief Rationale   
Section(s) 
instructed to contact the site within the first 24 hours 
post-infusion if they experience any side effects. 
• Clarified that a minimum of 6 patients <10 kg and 6 
patients between ≥10 kg and <40 kg will be enrolled 
Section 8.6 Method of Treatment 
Assignment 
Section 11.2 Justification of 
Sample Size 
Section 6.1.3 Phase 3 
Figure 5 Study Flow Diagram, 
Phase 3 (Cohort 2) 
Section 9.1.1 Footnotes for the 
Schedule of Events Tables, #6, 
#17 
Table 6 Schedule of Events: Phase 
3 (Cohort 2) 
In addition to what is currently being collected, the 
following safety information will be collected in all 
phase 3 cohorts: 
• All treatment-emergent adverse events that led to a 
medically-attended visit (hospitalization, emergency 
room visit, urgent care visit, physician’s office visit, or 
telemedicine visit), regardless of relatedness to 
COVID-19, through day 29 
• All treatment-emergent serious adverse events and 
deaths, from day 30 to day 169 
• In addition to standard collection of pregnancy 
outcome information, for newborn infants of patients 
who were treated in the study and were pregnant at 
randomization or became pregnant at any time in the 
study, the incidence and outcome of any SARS-CoV-2 
infection will be collected during day 120 and day 169 
follow-up phone calls and reported in the pregnancy 
report form 
Per health authority 
request and for more 
comprehensive 
analysis of 
medically attended 
visits and the safety 
profile of 
REGN10933 + 
REGN10987 
Section 3.2.1 Rationale for Study 
Design 
Section 3.2.1.5 Rationale for 
Phase 3 Adaptations 
Section 5.3 Safety Variables 
Section 6.1.3 Phase 3 
Table 5 Schedule of Events: Phase 
3 (Cohort 1) 
Table 6 Schedule of Events: Phase 
3 (Cohort 2)  
Section 9.1.1 Footnotes for the 
Schedule of Events Tables, #7, 16 
Section 9.2.4.2 Adverse Event 
Monitoring 
Section 9.2.5 Post-Day 29 Follow-
up by Phone 
Section 10.1.1 General Guidelines 
Section 10.1.3 Events that Require 
Expedited Reporting to Sponsor 
Clarified that viral variants suspected to confer 
decreased susceptibility to REGN10933 and/or 
REGN10987 will be evaluated in nonclinical work 
separate from this protocol. 
Per health authority 
request 
Section 9.2.10.3 Virology 
Eligibility criteria have been modified to allow planned 
use of any authorized or approved vaccine for SARS-
CoV-2, if (at the time of screening) it is planned after 90 
days following study drug administration. This screening 
allowance may be modified as applicable if CDC 
recommendations change. 
• Prior use (prior to randomization), current use (at 
randomization), or planned use (within 90 days of 
study drug administration or per current CDC 
recommendations, as applicable) of any authorized or 
approved vaccine for SARS-CoV-2 is excluded 
• Prior, current, or future plans to participate in a 
clinical research study of an investigational vaccine 
for SARS-CoV-2 is also excluded 
Per current CDC 
recommendations 
(CDC, 2020a) 
 
Section 7.2.2 Exclusion Criteria, 
#13, 14 
The followings clarifications were made with respect to 
assessment of women of childbearing potential 
(WOCBP) and women who are pregnant: 
• Pregnancy testing at screening must be performed in 
all WOCBP, regardless of pregnancy status 
To ensure accurate 
information is 
collected regarding 
pregnancy 
Section 9.2.1.4 Medical History 
Section 9.2.6 Pregnancy Test for 
Women of Childbearing Potential 
Section 10.1.3 Events that 
Required Expedited Reporting to 
the Sponsor 
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Description of Change 
 
Brief Rationale   
Section(s) 
• Pregnancy or breastfeeding status at screening must be 
collected as medical history, if applicable 
• A paper pregnancy report form must be completed for 
each patient who becomes pregnant or is pregnant at 
the signing of consent 
Definitions of risk factors for severe COVID-19 were 
changed as follows: 
• Cohort 1: clarified that body mass index (BMI) greater 
than or equal to 30 (not greater than 30) constitutes a 
risk factor for severe COVID-19 
• Cohort 1: clarified that age greater than or equal to 50 
years constitutes a risk factor for severe COVID-19 
• Cohort 2: for patients at least 2 years old, BMI ≥95th 
percentile for age and sex, based on CDC growth 
charts, will constitute a risk factor 
• Cohort 2: added a new risk factor for severe COVID-
19 as an inclusion criterion: Any underlying genetic, 
neurologic, or metabolic condition, or congenital heart 
disease deemed by the investigator to constitute a risk 
factor for severe COVID-19 (note that 
immunocompromised/on immunosuppressive 
treatment is already considered a risk factor and is 
accounted for separately) 
To clarify risk 
factors for severe 
COVID-19 and 
ensure alignment 
with CDC guidance, 
where applicable 
Section 3.2.1.5 Rationale for 
Phase 3 Adaptations 
Section 7.2.1 Inclusion Criteria, 
#9 
Updated concomitant medications list such that any 
medication used to treat an adverse event will be 
recorded 
To ensure collection 
of clinically relevant 
concomitant 
medications 
Section 9.2.4.3 Record Targeted 
Concomitant Medications 
Clarified that for the screening SARS-CoV-2 diagnostic 
test, the sample must be collected ≤72 hours of 
randomization. Samples are not valid for screening if 
collected >72 hours from randomization, even if the test 
is performed, or results reported, within the 72-hour 
window.  
To ensure 
appropriate 
screening for SARS-
CoV-2 infection 
Section 7.2.1 Inclusion Criteria 
Removed language stating that if diagnostic SARS-
CoV-2 testing was performed outside of the allowed 
window, a new test is required for study inclusion. 
Language was retained in error. Per study exclusion 
criteria, patients will be excluded if they have a positive 
SARS-CoV-2 antigen or molecular diagnostic test from 
a sample collected >72 hours prior to randomization  
To ensure accurate 
information 
Section 9.2.1.2 Diagnostic Test 
for SARS-CoV-2 
Provided example of monoclonal antibody 
(bamlanivimab) that is considered exclusionary for study 
enrollment 
For clarity 
Section 7.2.2 Exclusion Criteria, 
#2, 3 
Members of the clinical site study team and their 
immediate family members are now excluded from 
enrolling in the study  
To ensure integrity 
of study data and 
analysis 
Section 7.2.2 Exclusion Criteria, 
#14 
In cohort 1, the following blood samples will no longer 
be collected: 
• Serum for cytokines and CK-MB 
• Plasma for hsTroponin 
Note that the descriptions of exploratory biomarker, 
analyses, as well as exploratory patient-reported 
symptom analyses conducted during prior study phases 
or time periods have been retained in protocol for 
historical purposes. 
To reduce burden of 
blood sample 
collections 
Table 5 Schedule of Events: Phase 
3 (Cohort 1) 
Section 9.2.10 Exploratory 
Pharmacodynamic/Biomarker 
Analyses 
Section 9.2.13 Exploratory 
Patient-Reported Symptoms 
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Description of Change 
 
Brief Rationale   
Section(s) 
Blood chemistry samples that are collected will not be 
analyzed for ferritin. 
To reduce sample 
analyses with less 
relevant clinical 
significance 
Table 5 Schedule of Events: Phase 
3 (Cohort 1) 
Table 6 Schedule of Events: Phase 
3 (Cohort 2) 
Section 9.2.7 Laboratory Testing 
Columns have been added to explicitly indicate 
collection of EQ-5D-5L and EQ-5D-Y-5L at day 60 and 
day 90. This was previously indicated by a footnote in 
the schedule of events. 
To improve schedule 
clarity 
Section 9.1.1 Footnotes for the 
Schedule of Events Tables, #14 
WPAI+CIQ, EQ-5D-5L, and EQ-5D-Y-5L will only be 
administered at sites when regionally available. 
To provide 
operational 
flexibility 
Section 9.1.1 Footnotes for the 
Schedule of Events Tables, #14 
Added that an interim analysis of phase 3 cohort 2 may 
be conducted for regulatory purposes when the phase 3 
cohort 1 primary analysis is performed. 
To provide more 
details for the phase 
3 statistical analysis 
plan  
Section 11.5 Interim Analysis 
Removed incorrectly marked medical history assessment 
on day 7. 
To ensure accuracy 
Table 6 Schedule of Events: Phase 
3 (Cohort 2) 
Removed and/or simplified schedule of events footnotes 
that contained information relevant to phase 1 and phase 
2, which are now closed. 
To simplify 
interpretation of 
phase 3 schedule of 
events 
Section 9.1.1 Footnotes for the 
Schedule of Events Tables, #2, 3, 
4, 6, 7, 9, 11, 12, 14, 15 
Clarified that approximately 600 patients will be 
enrolled in the PK sub-study 
To ensure accuracy 
Section 9.2.8 Drug Concentration 
Measurements and Samples 
Updated phase 1 endpoint to align with phase 1/2 
statistical analysis plan. 
To ensure accurate 
description of 
statistical analysis 
that was performed 
Section 4.1 Primary Endpoints 
Updates to background information and other minor 
updates were made. 
To ensure current, 
accurate, and 
consistent 
information 
Throughout the document 
Amendment 6 
The purpose of this amendment is to adapt the phase 3 portion of the study based on data from 
phase 1 and phase 2. Major adaptations include changes to the patient population, treatment arms, 
objectives/endpoints, and sample size. 
The following table outlines all changes made to the protocol and the affected sections. 
Description of Change 
 
Brief Rationale   
Section(s) 
Patient Eligibility (Major Phase 3 Adaptation) 
• Females who are pregnant or breastfeeding can 
enroll in the study 
• Patients from 0 to <18 years will be enrolled as a 
separate cohort (cohort 2), where permitted by 
local requirements. Patients ≥18 years of age will 
be enrolled in cohort 1 
• Patients in cohort 1 must have ≥1 risk factor for 
severe COVID-19. Patients in cohort 2 must have 
≥1 risk factor for severe COVID-19 or live with a 
housemate who has ≥1 risk factor for severe 
COVID-19 
To adapt the phase 3 
portion of the study based 
on phase 2 data and to 
evaluate REGN10933 + 
REGN10987 in younger 
patients and 
pregnant/breastfeeding 
women with COVID-19 
Section 3.2.1.5 Rationale for 
Phase 3 Adaptations [new] 
Section 5.1 Demographic and 
Baseline Characteristics 
Section 6.1 Study Description 
and Duration 
Section 7.2.1 Inclusion Criteria, 
#1, 2, 9 
Section 7.2.2 Exclusion 
Criteria, #10, 11, 12 
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CONFIDENTIAL 
Description of Change 
 
Brief Rationale   
Section(s) 
• Patients with a known positive SARS-CoV-2 
serology test will be excluded  
• Patients with a positive SARS-CoV-2 antigen test 
or molecular diagnostic test from a sample 
collected >72 hours prior to randomization will be 
excluded 
• Patients with active infection with influenza or 
other non-SARS-CoV-2 respiratory pathogen, 
confirmed by a diagnostic test, will be excluded 
 
Note: A subset of patients in phase 3 were enrolled 
prior to the phase 3 adaptations implemented in 
protocol amendment 6. These patients will not be 
consented to protocol amendment 6 and will 
continue to follow the protocol schedule to which 
they were last consented. 
Section 9.2.5 Post-Day 29 
Follow-up by Phone 
Section 9.2.6 Pregnancy Test 
for Women of Childbearing 
Potential 
Section 10.1.3 Events That 
Require Expedited Reporting to 
Sponsor 
Section 11.4.1 Patient 
Disposition 
Section 13.2 Informed Consent 
Treatment Arms (Major Phase 3 Adaptation) 
• For cohort 1, the REGN10933+REGN10987 8000 
mg IV treatment arm will be dropped. The 
REGN10933 + REGN10987 2400 mg IV 
treatment arm and placebo arm will be retained. A 
new treatment arm will be added to assess 
REGN10933+REGN10987 1200 mg IV 
• For cohort 2, the highest dose tested will be 
REGN10933 + REGN10987 2400 mg IV. Weight-
tiered dosing will be used in this cohort  
To adapt the phase 3 
portion of the study based 
on phase 2 data  
Section 3.2.1.2 Adaptive 
Master Protocol Design 
Section 3.2.1.5 Rationale for 
Phase 3 Adaptations [new] 
Section 3.2.2 Rationale for 
Dose Selection 
Section 6.1.3 Phase 3 [new] 
Section 8.1 Investigational and 
Reference Treatments 
Section 8.6 Method of 
Treatment Assignments  
Objectives/Endpoints (Major Phase 3 Adaptation) 
• For cohort 1, the primary endpoint will be 
COVID-19-related medically-attended visits 
(MAVs). Key pre-specified secondary endpoints 
include various types of COVID-19-related MAVs 
and related outcomes  
• For cohort 2, the primary endpoints will be 
safety/tolerability and drug concentrations in 
serum over time  
• For cohort 2, secondary analyses will be 
descriptive 
• Virologic analyses for both cohorts will be 
secondary and descriptive 
• Cohort 1 will enroll up to 300 patients in an 
optional sub-study to assess, as an exploratory 
objective, the potential impact of 
REGN10933+REGN10987 on the endogenous 
immune response 
To adapt the phase 3 
portion of the study based 
on phase 2 data  
Section 2.1 Primary Objectives 
Section 2.2 Secondary 
Objectives 
Section 2.3 Exploratory 
Objectives 
Section 3.2.1.5 Rationale for 
Phase 3 Adaptations [new] 
Section 4.1 Primary Endpoints 
Section 4.2 Secondary 
Endpoints 
Section 6.1.3 Phase 3 [new] 
Table 5 Schedule of Events: 
Phase 3 (Cohort 1) [new] 
Table 6 Schedule of Events: 
Phase 3 (Cohort 2) [new] 
Section 9.1.1 Footnotes for the 
Schedule of Events Tables 
(Phase 1, Phase 2, and Phase 3), 
footnote #4 
Section 9.2.11 Immunoprofiling 
Sub-Study (Optional) [new] 
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CONFIDENTIAL 
Description of Change 
 
Brief Rationale   
Section(s) 
Sample Size (Major Phase 3 Adaptation) 
• Enrollment in phase 3 cohort 1 is anticipated to be 
approximately 5400 patients  
• Phase 3 cohort 1 will continue until at least 80 
hospitalizations or ER visits are observed in 
patients enrolled under protocol amendment 6 (or 
subsequent amendment) into the primary analysis 
population (patients in modified full analysis set 
[mFAS] with at least 1 risk factor) and the total 
number of hospitalizations or ER visits during the 
study in the primary analysis population is more 
than 120 
• Phase 3 cohort 2 will enroll up to approximately 
180 patients 
To adapt the phase 3 
portion of the study based 
on phase 2 data  
Section 3.2.1.5 Rationale for 
Phase 3 Adaptations [new] 
Section 7.1 Number of Patients 
Planned 
Section 11.2 Justification of 
Sample Size 
Other Phase 3 Adaptations  
Phase 3 cohort 1 schedule of events will be adapted 
to include the following major changes from phase 2: 
• Patients will be followed up by phone on days 120 
and 169 (end of study) for assessments including 
vital status  
• Virologic assessments will be more limited in 
scope. Nasopharyngeal (NP) swabs will only be 
collected on days 1, 7, 15, and 29  
• For targeted safety information, treatment-
emergent serious adverse events (SAEs), if 
determined by the investigator to be related to 
study drug, will be recorded from day 30 to day 
169  
• A subset of patients will be enrolled in a PK sub-
study at selected participating sites. 
Note: A subset of patients in phase 3 were enrolled 
prior to the phase 3 adaptations implemented in 
protocol amendment 6. These patients will not be 
consented to protocol amendment 6 and will 
continue to follow the protocol schedule to which 
they were last consented. 
Per health authority 
feedback, and to adapt the 
phase 3 study design based 
on phase 2 data  
Section 6.1 Study Description 
and Duration 
Section 6.1.3 Phase 3 [new] 
Figure 4 Study Flow Diagram, 
Phase 3 (Cohort 1) [new] 
Figure 5 Study Flow Diagram, 
Phase 3 (Cohort 2) [new] 
Section 9.2.5 Post-Day 29 
Follow-up by Phone 
Table 5 Schedule of Events: 
Phase 3 (Cohort 1) [new] 
Section 9.1.1 Footnotes for the 
Schedule of Events Tables 
(Phase 1, Phase 2, and Phase 3), 
footnotes #7, 11, 12, 13, 14, 15 
Section 9.2.8 Drug 
Concentration Measurements 
and Samples 
Section 10.1.1 General 
Guidelines 
Section 10.1.2 Reporting 
Procedure 
 
Phase 3 cohort 2 will follow similar schedule of 
events as cohort 1, with key exceptions as follows: 
• Blood sample collection schedules for laboratory 
and biomarker analyses will vary according to 
body weight 
• Additional NP swab sample will be collected on 
day 3 
• Blood sample collection schedules for 
pharmacokinetics and immunogenicity will utilize 
sparse sampling and vary based on randomly 
assigned sampling schedules 
• Limited biomarker samples will be collected 
• Patient-reported electronic surveys/questionnaires 
will only be collected in patients ≥12 years  
• Treatment-emergent grade ≥3 AEs will be 
collected through day 29 
To ensure appropriate 
assessment of safety and 
efficacy of REGN10933 + 
REGN10987 and to adjust 
blood volumes 
appropriately for younger 
pediatric patients 
Section 6.1.3 Phase 3 [new] 
4 Study Flow Diagram, Phase 3 
(Cohort 1) [new] 
Figure 5 Study Flow Diagram, 
Phase 3 (Cohort 2) [new] 
Section 7.2.1 Inclusion Criteria, 
#1a 
Section 8.1 Investigational and 
Reference Treatments 
Section 8.6 Method of 
Treatment Assignment 
Table 6 Schedule of Events: 
Phase 3 (Cohort 2) [new] 
Section 9.1.1 Footnotes for the 
Schedule of Events Tables 
(Phase 1, Phase 2, and Phase 3), 
footnotes #7, 11, 13, 14, 15 
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CONFIDENTIAL 
Description of Change 
 
Brief Rationale   
Section(s) 
Section 9.2.5 Post-Day 29 
Follow-up by Phone 
Section 9.2.9 Immunogenicity 
Measurements and Samples 
Details of COVID-19-related medically-attended 
visits were revised. 
To ensure appropriate 
assessment of the clinical 
efficacy of REGN10933 + 
REGN10987  
Section 9.2.3.2 COVID-19-
Related Medically-Attended 
Visit Details 
Risk factors for hospitalization due to COVID-19 
were removed as a stratification factor for 
randomization. Patients in both cohorts will be 
stratified by country, and (in cohort 2 only) by the 
presence or absence of COVID-19 symptoms. 
Both cohorts in phase 3 
will have ≥1 risk factor for 
severe COVID-19 
Section 8.6 Method of 
Treatment Assignments  
Immunogenicity will be assessed by anti-drug 
antibodies (ADA) and neutralizing antibody (NAb) 
analyses, as a secondary endpoint in cohort 1 and a 
primary endpoint in cohort 2. 
To ensure comprehensive 
assessment of potential 
immunogenic response 
following REGN10933 + 
REGN10987 
administration  
Section 2.1 Primary Objectives 
Section 2.2 Secondary 
Objectives 
Section 4.1 Primary Endpoints 
Section 4.2 Secondary 
Endpoints 
Section 5.5 Immunogenicity 
Variables 
Section 9.2.9 Immunogenicity 
Measurements and Samples 
Section 11.3.4 Immunogenicity 
Analysis Sets 
Section 11.4.8 Analysis of 
Immunogenicity Data 
Patient eligibility criteria were updated to: 
• Clarify the acceptable timing for a historical record 
of positive SARS-CoV-2 test result 
• Clarify informed consent requirements for cohort 2 
patients 
• Add that patients must be able to understand and 
complete study-related questionnaires (cohort 1 
and cohort 2 patients aged ≥12 years only) 
• Clarify that patients must not have been admitted 
to a hospital for COVID-19 prior to 
randomization, or hospitalized (inpatient) for any 
reason at randomization 
• Clarify exclusions related to prior, current, or 
planned COVID-19 treatments 
To ensure appropriate 
enrollment and data 
analysis for phase 3 and to 
provide operational clarity 
and flexibility  
Section 7.2.1 Inclusion Criteria, 
#2, 6, 8 
Section 7.2.2 Exclusion 
Criteria, #1, 3; #8, 9 [removed]; 
#10, 11, 12, 13 [added] 
For phase 3 cohort 1 efficacy analysis, the Sponsor 
may request the IDMC to perform 1 or more interim 
analyses for efficacy 
To ensure appropriate 
assessment of potential 
efficacy signals 
Section 11.5 Interim Analysis 
Other Changes and Clarifications 
For patients in this study who are also index cases of 
household contacts in the R10933-10987-COV-2069 
prophylaxis study, data from this study may be used 
as part of analyses on the COV-2069 study. 
To assess the potential 
impact of 
REGN10933+REGN10987 
treatment of an index case 
participating in this study 
on infection rates in 
household contacts 
participating in COV-
2069. 
Section 6.1.3 Phase 3 
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CONFIDENTIAL 
Description of Change 
 
Brief Rationale   
Section(s) 
Prior to unblinding for interim analysis of phase 1/2 
and analysis of phase 2, changes were made to the 
statistical analysis plan, including endpoints and 
analysis descriptions. These changes have been 
updated in the protocol 
To ensure consistency and 
accuracy of the study 
statistical plans. 
Section 3.2.1.3 Rationale for 
Phase 1 and Phase 2 Objectives  
Section 4.1 Primary Endpoints 
Section 4.2 Secondary 
Endpoints 
Section 6.3 Planned Interim 
Analysis 
Section 11.5 Interim Analysis 
Emergency unblinding procedures were clarified, 
including manual unblinding in case of IWRS 
unavailability. 
Per health authority 
request 
Section 8.8 Emergency 
Unblinding 
Baseline blood samples may be collected at either 
day -1 or day 1 (ie, screening or pre-dose) prior to 
randomization. For patients in phase 3 cohort 2. 
To provide operational 
flexibility.  
Section 9.1.1 Footnotes for the 
Schedule of Events Tables 
(Phase 1, Phase 2, and Phase 3), 
#12 
Study monitoring plan was updated to allow off-
site/remote monitoring of study sites. 
Per health authority 
request; to provide 
flexibility for site 
monitoring due to COVID-
19. 
Section 12.2.1 Monitoring of 
Study Sites 
Risk-benefit language was updated. 
To provide updated risk-
benefit information for the 
program and 
considerations for a 
broader patient population 
Section 3.3 Risk-Benefit 
Descriptions of the statistical plan were updated as 
follows: 
• Statistical hypotheses and analysis set definitions 
were updated 
• Details regarding control of multiplicity were 
added 
• Phase 3 efficacy analysis methods were added 
• For phase 3, plans for interim analyses were added 
To update descriptions of 
the statistical plan 
Section 3.1 Hypotheses  
Section 6.3 Planned Interim 
Analysis 
Section 11 Statistical Plan 
Section 11.1 Statistical 
Hypotheses 
Section 11.3.1 Efficacy 
Analysis Sets 
Section 11.4.3.1 Primary 
Efficacy Analysis 
Section 11.4.3.2 Secondary 
Efficacy Analysis 
Section 11.4.4 Control of 
Multiplicity 
Descriptions of viral sequencing parameters were 
updated to expand beyond analyses of potential viral 
resistance. 
For accuracy 
Section 9.2.10.3 Virology 
Detailed descriptions of exploratory patient-reported 
symptoms were added. 
To provide context for 
patient-reported symptom 
assessments 
Section 9.2.13 Exploratory 
Patient-Reported Symptoms 
REGN10989 monotherapy will no longer be 
considered as part of this adaptive master protocol. 
References to REGN10989 have correspondingly 
been removed throughout the protocol. 
Based on preclinical viral 
resistance data showing 
viral escape following 
monotherapy with anti-
SARS-CoV-2 monoclonal 
antibodies, this study to 
assess combination 
therapies and will no 
Throughout the document 
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CONFIDENTIAL 
Description of Change 
 
Brief Rationale   
Section(s) 
longer include 
monotherapy arms.  
References to phase 1 and phase 2 were removed 
from the study synopsis. 
For operational clarity, 
since phase 1 and phase 2 
are now closed 
Clinical Study Protocol 
Synopsis 
References to “low dose” and “high dose” were 
removed. 
To ensure clarity with the 
addition of different dose 
levels in phase 3 
Throughout the document 
Updates to background information, administrative 
updates, and other minor updates to align with phase 
3 adaptations were made. 
To ensure current, 
accurate, and consistent 
information 
Throughout the document 
 
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CONFIDENTIAL 
Amendment 5 
Description of Change 
 
Brief Rationale   
Section(s) 
Added new cohort of patients in phase 2 to 
evaluate asymptomatic patients with SARS-
CoV-2 infection. Total planned enrollment 
for phase 2 has been increased to 1300 
patients to accommodate this cohort. 
To broaden patient 
eligibility and enable 
broader assessment of 
potential treatment impact 
on viral burden and other 
measures 
Section 3.2.1.3 Rationale for Primary 
Objectives 
Section 3.2.1.5 Stratification According 
to Risk of Hospitalization Due to 
COVID-19 
Section 6.1 Study Description and 
Duration 
Section 6.1.2 Phase 2 
Figure 3 Study Flow Diagram, Phase 2 
Section 7.1 Number of Patients Planned 
Section 7.2.1 Inclusion Criteria, #4 
Section 8.6 Method of Treatment 
Assignment 
Section 11.2 Justification of Sample 
Size 
Section 11.4.3.1 Primary Efficacy 
Analysis 
Section 11.4.3.2 Secondary Efficacy 
Analysis 
In phase 2, added new secondary clinical 
endpoint to assess development of symptoms 
consistent with COVID-19. 
 
To assess the impact of 
treatment on the 
development of COVID-
19 symptoms in patients 
who are initially 
asymptomatic with SARS-
CoV-2 infection 
Section 4.1 Secondary Endpoints 
In phase 2, added new secondary clinical 
endpoint to assess duration of symptoms 
consistent with COVID-19. 
To assess the impact of 
treatment on the duration 
of symptoms 
Section 4.1 Secondary Endpoints 
Removed screening requirement that patients 
have ≥1 of the following symptoms at 
randomization: fever, cough, shortness of 
breath. 
To broaden patient 
eligibility and to facilitate 
assessment of potential 
treatment impact on other 
clinical manifestations of 
COVID-19 
Section 7.2.1 Inclusion Criteria, #3 
[deleted] 
At screening, diagnostic testing for SARS-
CoV-2 infection will allow antigen tests in 
addition to molecular tests. 
To provide operational 
flexibility 
Section 7.2.1 Inclusion Criteria, #3 
Table 4 Schedule of Events: Phase 2 
Section 9.2.1.2 Diagnostic Test for 
SARS-CoV-2 
Revised exclusion criteria medications to 
exclude patients with prior, current, or 
planned future use of EUA-approved 
medications (eg, remdesivir), convalescent 
serum, IVIG, other anti-SARS-CoV2 
antibodies, or systemic steroids, thereby 
allowing antecedent use of other COVID-19 
investigational medications such as 
hydroxychloroquine and azithromycin. 
Clarified that excluded agents are permitted 
only if medically indicated. 
To broaden patient 
eligibility 
Figure 3 Study Flow Diagram, Phase 2 
Section 7.2.2 Exclusion Criteria, #3 
Section 7.2.2 Exclusion Criteria, #4 
[consolidated with #3], #5, [deleted] 
Section 8.10.1 Prohibited and Permitted 
Medications 
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In phase 2, added blood samples for 
hematology, blood chemistry, and 
coagulation tests on days 7 and 15. In phase 
2, added blood samples for cardiac 
biomarkers at baseline and on days 7, 15, and 
29. 
To enable more 
comprehensive analysis of 
safety and efficacy by 
including additional 
biomarkers of 
inflammation and cardiac 
and/or other organ injury 
Section 5.6 Pharmacodynamic and 
Other Biomarker Variables 
Section 6.1.2 Phase 2 
Table 4 Schedule of Events: Phase 2 
Section 9.1.1 Footnotes for the 
Schedule of Events Tables (Phase 1 and 
Phase 2), #10 
Section 9.2.7 Laboratory Tests 
Section 9.2.10.8 Serum and Plasma for 
Cardiac Biomarkers [section added] 
Removed post-dose collection of SE-C19 and 
PGIS and extended daily collection of SE-
C19 and PGIS until day 29 
To ensure that assessments 
are only captured once in 
each 24 hour period , and 
to provide additional 
information on patient-
reported symptoms at later 
time points 
Table 4 Schedule of Events: Phase 2 
Minor clarifications were made to 
descriptions of other biomarker analyses. 
To better describe planned 
analyses 
Section 9.2.10.4 Serological 
Immunoassays for Anti-SARS-CoV-2 
Antibodies 
Section 9.2.10.5 Serum and Plasma for 
Research 
Section 9.2.10.7 Cytokines 
Clarified collection of medical history: 
COVID-19, if applicable, with start date as 
date of onset of first symptoms. 
To ensure appropriate 
collection of symptom 
onset 
Section 9.2.1.4 Medical History 
Information regarding review of sentinel 
safety group (part A) was added. 
To update safety 
information for the 
program 
Section 3.2.1.1 Phase 1 Sentinel Safety 
Group 
Updated phase 2 interim analysis plans. 
To allow flexibility of 
interim analyses  
Section 6.3 Planned Interim Analysis 
Section 11.4.4 Control of Multiplicity  
Section 11.5 Interim Analysis 
Minor editorial updates made to reflect 
addition of asymptomatic cohort. 
To ensure accuracy and 
consistency 
Section 1.3 Outpatient Care as a 
Potential COVID-19 Treatment Setting 
Section 1.6 A Randomized, Placebo-
Controlled Study of Anti-SARS-CoV-2 
S Protein Monoclonal Antibodies in 
Ambulatory Patients with COVID-19 or 
Asymptomatic SARS-CoV-2 Infection 
Section 3.1 Hypotheses  
Section 3.2.1 Rationale for Study 
Design 
Removed a duplicate secondary endpoint for 
phase 3; other minor editorial and 
administrative updates were made. 
To ensure accuracy and 
consistency 
Section 1.1 Emergence of SARS-CoV-2 
and COVID-19 
Section 4.1 Secondary Endpoints 
Section 8.6 Method of Treatment 
Assignment 
Section 9.1.1 Footnotes for the 
Schedule of Events Tables (Phase 1 and 
Phase 2), #4 
 
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Amendment 4 
Description of Change  
Brief Rationale  
 
Section(s) 
Nasal swabs and saliva samples will no 
longer be collected in phase 2 and are no 
longer planned for phase 3. Only 
nasopharyngeal (NP) swabs will be 
collected in phase 2 and phase 3.  
To allow adequate assessment 
of virologic efficacy, as NP 
swab is the current gold 
standard to detect SARS-
CoV-2 
Clinical Study Protocol Synopsis: 
Objectives, Study Design, Endpoints, 
Procedures and Assessments 
Section 2.2 Secondary Objectives 
Section 4.1 Secondary Endpoints 
Section 6.1.2 Phase 2 
Figure 2 Study Flow Diagram, Phase 1 
Figure 3 Study Flow Diagram, Phase 2 
Table 4 Schedule of Events: Phase 2 
Section 9.2.3.1 Nasopharyngeal Swab, 
Nasal Swab, and Saliva Collection 
Section 11.4.3.2 Secondary Efficacy 
Analysis 
Phase 2 sample size has been increased to 
enable additional enrollment. 
To allow adequate assessment 
of virologic efficacy 
Figure 3 Study Flow Diagram, Phase 2 
Section 7.1 Number of Patients 
Planned 
Section 11.2 Justification of Sample 
Size 
Interim analysis plan was updated to allow 
more flexibility in timing. 
To allow flexibility of interim 
analyses 
Section 6.3 Planned Interim Analysis 
Section 9.2.3.1 Nasopharyngeal Swab, 
Nasal Swab, and Saliva Collection 
Section 11.5 Interim Analysis 
A modified full analysis set (mFAS) was 
added and includes all randomized patients 
with a positive RT-qPCR for SARS-CoV-2 
in NP swab at randomization. 
To allow adequate assessment 
of virologic efficacy 
Section 11.3.1 Efficacy Analysis Sets 
Section 11.4.3.1 Primary Efficacy 
Analysis 
Section 11.4.3.2 Secondary Efficacy 
Analysis 
An additional secondary virologic endpoint 
has been added. 
To allow adequate assessment 
of virologic efficacy 
Section 4.1 Secondary Endpoints 
The following clarifications have been 
made to the phase 2 Schedule of Events: 
• Clarified that at concomitant 
medications are continuously monitored 
• Visit windows have been added 
• Removed incorrect vital sign 
assessments marked in dosing column 
• Clarified footnote describing phone visit 
requirements  
• Day 2 column shading was removed, as 
day 2 does not include a phone visit 
To improve clarity of study 
schedule  
Section 9.1.1 Footnotes for the 
Schedule of Events Tables (Phase 1 
and Phase 2), #3 
Table 4 Schedule of Events: Phase 2 
 
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CONFIDENTIAL 
Amendment 3 
Description of Change  
Brief Rationale  
 
Section(s) 
Primary virologic efficacy in phase 2 
will be assessed using 
nasopharyngeal (NP) swab samples. 
NP swab sample collection has been 
correspondingly added. 
Provisional phase 3 secondary 
endpoints have also been updated for 
potential inclusion of NP swab 
samples. 
To ensure adequate assessment of 
virologic efficacy. 
Section 2.2 Secondary Objectives 
Section 4.1 Primary Endpoint 
Section 4.1 Secondary Endpoints 
Table 4 Schedule of Events: Phase 2 
Section 6.1.2 Phase 2 
Section 6.1.3 Phase 3 
Figure 3 Study Flow Diagram, 
Phase 2 
Section 9.2.3.1 Saliva, Nasal Swab, 
and Nasopharyngeal Swab Collection 
Section 11.4.3.2 Secondary Efficacy 
Analysis 
Additional patients may be enrolled 
in phase 1 to replace patients who 
have missing or negative baseline 
virologic sample(s) or are missing ≥1 
follow-up virologic sample(s). 
To ensure adequate assessment of 
virologic efficacy. 
Section 7.1 Number of Patients 
Planned 
Section 7.4 Replacement of Patients  
 
Amendment 2 
Description of Change 
Brief Rationale  
 
Section(s) 
Grade 3 or 4 treatment-emergent AEs will 
be collected (phase 1 only) 
Per health authority request 
Section 3.2.1.3 Rationale for Primary 
Objectives 
Section 5.3 Safety Variables 
Section 6.1.1 Phase 1 
Table 3 Schedule of Events: Phase 1  
Section 9.1.1 Footnotes for the 
Schedule of Events Tables (Phase 1 
and Phase 2), #7 
Section 9.1.3 Unscheduled Visits 
Section 9.2.4.2 Adverse Event 
Monitoring 
Section 10 Safety Evaluation and 
Reporting (and sub-sections therein) 
Section 11.4.5.1 Adverse events 
Clarified objective, endpoint, and 
procedure for assessing viral resistance 
Per health authority request 
Section 2.3 Exploratory Objectives 
Section 4.3 Exploratory Endpoints  
Section 9.2.10.3 Virology  
Clarified EC and IC terminology related to 
dose rationale 
To clarify in vitro data 
descriptions 
Section 3.2.2 Rationale for Dose 
Selection 
Included secondary objective and endpoint 
to assess correlations in viral shedding 
across sample types 
To understand differences in 
assessing virologic efficacy 
using distinct sampling 
sources 
Section 2.2 Secondary Objectives 
Section 4.1 Secondary Endpoints 
Section 11.4.3.1 Primary Efficacy 
Analysis 
Nasopharyngeal swab sampling added to 
day 11, 15, 18, and 25 (phase 1 only) 
To provide matching sample 
types across time points 
Section 6.1.1 Phase 1 
Table 3 Schedule of Events: Phase 1  
Figure 2 Study Flow Diagram, Phase 1 
Figure 3 Study Flow Diagram, Phase 2 
Study will be conducted in the US and 
other countries 
To broaden reach of study 
Section 6.1 Study Description and 
Duration 
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Description of Change 
Brief Rationale  
 
Section(s) 
Added country as a stratification factor for 
randomization in phase 2 
To ensure balance in study 
populations 
Section 8.6. Method of Treatment 
Assignment 
Section 11.4 Statistical Methods 
Screening for SARS-CoV-2 infection can 
be performed by any validated molecular 
diagnostic assay; historical record ≤72 
hours of randomization is acceptable 
To clarify acceptable 
screening criteria  
Section 7.2.1 Inclusion Criteria, #2 
Table 3 Schedule of Events: Phase 1  
Table 4 Schedule of Events: Phase 2 
Section 9.1.1 Footnotes for the 
Schedule of Events Tables (Phase 1 
and Phase 2), #5 
Section 9.2.1.2 Molecular Diagnostic 
Test for SARS-CoV-2 
For assessment of COVID-19 symptom 
onset during screening, symptoms are 
defined per investigator discretion 
To clarify inclusion criterion 
Section 7.2.1 Inclusion Criteria, #4 
Endpoints in phase 1 related to intensive 
care unit (ICU) and mechanical ventilation 
moved to exploratory; other statistical 
clarifications made to primary and 
secondary efficacy analysis, multiplicity 
control, and interim analysis 
To ensure consistency with 
planned statistical analysis 
Section 4.1 Secondary Endpoints 
Section 4.3 Exploratory Endpoints 
Section 11.1 Statistical Hypothesis 
Section 11.2 Justification of Sample 
Size 
Section 11.4.3.2 Secondary Efficacy 
Analysis 
Section 11.4.4 Control of Multiplicity 
Section 11.5 Interim Analysis 
Updated study stopping criteria 
To provide additional details 
for study stopping and/or 
adaptations 
Section 6.1.4.2 Study Stopping 
Criteria 
The Independent Data Monitoring 
Committee (IDMC) will review both safety 
and efficacy data during the study 
To clarify the planned IDMC 
review process 
Section 6.2.1 Independent Data 
Monitoring Committee 
Any unused or leftover biological samples 
collected during the study may be used for 
exploratory research; maximum time 
period of allowable storage (for both 
exploratory research samples and 
pharmacogenomic samples) may be shorter 
per regional laws and regulations 
To clarify the intended use 
and storage of samples 
Section 9.2.8 Drug Concentration 
Measurements and Samples  
Section 9.2.9 Immunogenicity 
Measurements and Samples 
Section 9.2.10 Exploratory 
Pharmacodynamic/Biomarker 
Analyses 
 Section 9.2.12 Pharmacogenomic 
Analysis (Optional) 
The following operational changes and 
clarifications have been made: 
• Phone visits have a window of ±1 day 
• Day 29 visit may occur at any in-person 
location 
• Clarified that home-based visits may be 
done by home health staff 
To provide additional 
flexibility for sample 
collection and assessments 
Section 6.1.1 Phase 1 
Section 6.1.2 Phase 2 
Table 3 Schedule of Events: Phase 1  
Table 4 Schedule of Events: Phase 2 
Section 9.1.1 Footnotes for the 
Schedule of Events Tables (Phase 1 
and Phase 2), #3 
Early termination visit will consist of day 
29 assessments, with follow-up phone 
contact on day 29 
To clarify early termination 
assessments 
Section 1 Early Termination from the 
Study 
Updated the list of targeted concomitant 
medications to be recorded 
To ensure consistency with 
eCRF 
Section 9.2.4.3 Record Targeted 
Concomitant Medications 
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Description of Change 
Brief Rationale  
 
Section(s) 
Respiratory rate will only be measured in 
phase 1; temperature will not be measured 
rectally  
To clarify required 
assessments  
Section 9.1.1 Footnotes for the 
Schedule of Events Tables (Phase 1 
and Phase 2), #6 
Section 9.2.4.1 Vital Signs 
Updated description of SE-C19 survey 
To clarify the scoring system 
used  
Section 9.2.10.8 Exploratory Patient-
Reported Symptoms 
Removed delineation of visit locations in 
Schedule of Events; visits may occur at any 
in-person location except where additional 
phone visits are indicated  
To improve clarity of study 
schedule and design 
Table 3 Schedule of Events: Phase 1  
Table 4 Schedule of Events: Phase 2 
Section 9.1.1 Footnotes for the 
Schedule of Events Tables (Phase 1 
and Phase 2), #3 
Clarifications of study procedures 
To improve clarity of 
procedures and planned 
analyses 
Section 9.2.1.4 Medical History 
Section 9.2.7 Laboratory Testing 
Section 9.2.10.2 Serum and Plasma 
Biomarkers 
Section 9.2.10.4 Serological 
Immunoassays for Anti-SARS-CoV-2 
Antibodies 
Section 9.2.10.5 Serum and Plasma for 
Research 
Section 9.2.10.4 Complement 
Section 9.2.10.7 Cytokines 
Minor typographical, grammatical, 
editorial, and formatting updates 
To ensure clarity, accuracy, 
and consistency 
Throughout the document 
 
Amendment 1 
Description of Change  
Brief Rationale 
Section(s) 
Mandatory sequestering is only applicable 
to patients in the phase 1 sentinel safety 
group 
Clarification of study 
design 
Section 6.1 Study Description and Duration 
Figure 2 Study Flow Diagram, Phase 1 
Table 3 Schedule of Events: Phase 1  
Table 4 Schedule of Events: Phase 2 
Section 9.1.1 Footnotes for the Schedule of 
Events Tables (Phase 1 and Phase 2), #2, 
#3 
Section 9.2.3.2 COVID-19-related 
Medically-Attended Visit Details 
Day 1 vital sign requirements (including 
pulse oximetry) added for patients in the 
phase 1 sentinel safety group 
Per health authority 
request 
Table 3 Schedule of Events: Phase 1  
Table 4 Schedule of Events: Phase 2 
Section 9.1.1 Footnotes for the Schedule of 
Events Tables (Phase 1 and Phase 2), #8 
Additional vital sign procedural details 
provided 
To ensure study 
consistency with health 
authority request 
Section 9.2.4.1 Vital Signs 
Independent Data Monitoring Committee 
(IDMC) description updated 
Operational details to be 
provided in the IDMC 
charter 
Section 6.2.1 Independent Data Monitoring 
Committee 
Editorial updates implemented 
To ensure clarity, 
accuracy, and consistency 
Section 8.7 Blinding 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ACE2 
Angiotensin-converting enzyme 2 
ADA 
Anti-drug antibody 
ADE 
Antibody-dependent enhancement 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
CK-MB 
Creatine kinase-MB 
Cmax 
Maximum concentration 
COVID-19 
Coronavirus disease 2019 
CRO 
Contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
EC 
Ethics Committee 
EC50 
Effective concentration of 50% viral neutralization 
EC99 
Effective concentration of 99% viral neutralization 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EOS 
End of study 
EUA 
Emergency Use Authorization 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FIH 
First-in-human 
FcγR 
Fc gamma receptor 
GCP 
Good clinical practice 
GLP 
Good laboratory practice 
IRB 
Institutional Review Board 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ICU 
Intensive care unit 
IDMC 
Independent data monitoring committee 
INR 
International normalized ratio 
IRT 
Interactive response technology 
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IRWS 
Interactive web response system 
IV 
Intravenous 
IVIG 
Intravenous immunoglobulin 
LDH 
Lactate dehydrogenase 
mAb 
Monoclonal antibody 
MAV 
Medically-attended visit 
MERS-CoV 
Middle East respiratory syndrome coronavirus 
mFAS 
Modified full analysis set 
NAb 
Neutralizing antibodies 
NCI 
National Cancer Institute 
NLR 
Neutrophil-lymphocyte ratio 
NT-proBNP 
N-terminal pro B-type natriuretic peptide 
PK 
Pharmacokinetic 
PT 
Prothrombin time  
RBD 
Receptor binding domain 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
REGN10933+REGN10987 Co-administered REGN10933+REGN10987 combination 
therapy 
RT-qPCR 
Quantitative reverse transcription polymerase chain reaction 
SARS-CoV 
Severe acute respiratory syndrome coronavirus 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SE-C19 
Symptom Evolution of COVID-19 
SE-LC19 
Symptom Evolution of Long COVID-19 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
TWA 
Time-weighted average 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................2 
Amendment 10 US ...........................................................................................................................2 
Amendment 9 US .............................................................................................................................4 
Amendment 8 ...................................................................................................................................6 
Amendment 7 .................................................................................................................................10 
Amendment 6 .................................................................................................................................13 
Amendment 5 .................................................................................................................................19 
Amendment 4 .................................................................................................................................21 
Amendment 3 .................................................................................................................................22 
Amendment 2 .................................................................................................................................22 
Amendment 1 .................................................................................................................................24 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................25 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................35 
1. 
INTRODUCTION ......................................................................................................42 
1.1. 
Emergence of SARS-CoV-2 and COVID-19 .............................................................42 
1.2. 
Clinical Outcomes in Hospitalized Patients with COVID-19 ....................................42 
1.3. 
Ambulatory Care as a Potential COVID-19 Treatment Setting .................................42 
1.4. 
Long-Term Outcomes in Patients with COVID-19 ....................................................43 
1.5. 
The Role of Spike (S) Protein in SARS-CoV-2 Pathogenesis ...................................43 
1.6. 
REGN10933+REGN10987: Human Monoclonal Antibodies that Target 
SARS-CoV-2 S Protein ..............................................................................................43 
1.7. 
A Randomized, Placebo-Controlled Study of Anti-SARS-CoV-2 S Protein 
Monoclonal Antibodies in Ambulatory Patients with COVID-19 .............................44 
2. 
STUDY OBJECTIVES ..............................................................................................44 
2.1. 
Primary Objectives .....................................................................................................44 
2.2. 
Secondary Objectives .................................................................................................45 
2.3. 
Exploratory Objectives ...............................................................................................46 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................47 
3.1. 
Hypotheses ..................................................................................................................47 
3.2. 
Rationale .....................................................................................................................48 
3.2.1. 
Rationale for Study Design .........................................................................................48 
3.2.1.1. 
Phase 1 Sentinel Safety Group ...................................................................................48 
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3.2.1.2. 
Adaptive Master Protocol Design ...............................................................................49 
3.2.1.3. 
Rationale for Phase 1 and Phase 2 Objectives ............................................................49 
3.2.1.4. 
Stratification According to Risk of Hospitalization (Phase 2) ...................................51 
3.2.1.5. 
Rationale for Phase 3 Adaptations ..............................................................................51 
3.2.1.6. 
Assessment of Long COVID ......................................................................................56 
3.2.2. 
Rationale for Dose Selection ......................................................................................57 
3.2.2.1. 
Phase 1 and Phase 2 Dose Selection ...........................................................................57 
3.2.2.2. 
Phase 3 Dose Selection ...............................................................................................58 
3.3. 
Risk-Benefit ................................................................................................................59 
3.3.1. 
Summary of Efficacy and Safety Profile in Clinical Trials ........................................59 
3.3.2. 
Summary of Risks.......................................................................................................60 
4. 
ENDPOINTS ..............................................................................................................63 
4.1. 
Primary Endpoints ......................................................................................................63 
4.2. 
Secondary Endpoints ..................................................................................................64 
4.3. 
Exploratory Endpoints ................................................................................................68 
5. 
STUDY VARIABLES................................................................................................70 
5.1. 
Demographic and Baseline Characteristics ................................................................70 
5.2. 
Efficacy Variables ......................................................................................................70 
5.3. 
Safety Variables ..........................................................................................................70 
5.4. 
Pharmacokinetic Variables .........................................................................................70 
5.5. 
Immunogenicity Variables ..........................................................................................70 
5.6. 
Pharmacodynamic and Other Biomarker Variables ...................................................70 
6. 
STUDY DESIGN .......................................................................................................71 
6.1. 
Study Description and Duration .................................................................................71 
6.1.1. 
Phase 1 ........................................................................................................................71 
6.1.2. 
Phase 2 ........................................................................................................................72 
6.1.3. 
Phase 3 ........................................................................................................................72 
6.1.3.1. 
Enrollment of Phase 3 Participants Prior to Phase 3 Adaptations ..............................74 
6.1.3.2. 
Evaluation of Long COVID in Phase 3 ......................................................................74 
6.1.3.3. 
Sharing of Data Across Studies ..................................................................................74 
6.1.4. 
Study Design Figures ..................................................................................................75 
6.1.5. 
Study Stopping Rules .................................................................................................79 
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6.1.5.1. 
Individual Patient Stopping Rules ..............................................................................79 
6.1.5.2. 
Study Stopping Criteria ..............................................................................................79 
6.1.6. 
End of Study Definition ..............................................................................................79 
6.2. 
Study Committees .......................................................................................................79 
6.2.1. 
Independent Data Monitoring Committee ..................................................................79 
6.2.2. 
Sponsor Review Committee .......................................................................................80 
6.3. 
Planned Interim Analysis ............................................................................................80 
6.4. 
Periodic Data Reviews ................................................................................................80 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............81 
7.1. 
Number of Patients Planned .......................................................................................81 
7.2. 
Study Population .........................................................................................................81 
7.2.1. 
Inclusion Criteria ........................................................................................................81 
7.2.2. 
Exclusion Criteria .......................................................................................................82 
7.3. 
Premature Withdrawal from the Study .......................................................................83 
7.4. 
Replacement of Patients .............................................................................................83 
8. 
STUDY TREATMENTS............................................................................................84 
8.1. 
Investigational and Reference Treatments ..................................................................84 
8.2. 
Background Treatment ...............................................................................................84 
8.3. 
Rescue Treatment(s) ...................................................................................................84 
8.4. 
Dose Modification and Study Treatment Discontinuation Rules ...............................84 
8.4.1. 
Dose Modification ......................................................................................................84 
8.4.2. 
Study Drug Discontinuation .......................................................................................84 
8.5. 
Management of Acute Reactions ................................................................................84 
8.5.1. 
Infusion-Related Reactions and Hypersensitivity Reactions ......................................84 
8.5.1.1. 
Interruption of the Intravenous Infusion .....................................................................84 
8.5.1.2. 
Termination of the Intravenous Infusion ....................................................................85 
8.6. 
Method of Treatment Assignment ..............................................................................85 
8.7. 
Blinding ......................................................................................................................88 
8.8. 
Emergency Unblinding ...............................................................................................89 
8.9. 
Treatment Logistics and Accountability .....................................................................89 
8.9.1. 
Packaging, Labeling, and Storage ..............................................................................89 
8.9.2. 
Supply and Disposition of Treatments .......................................................................90 
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8.9.3. 
Treatment Accountability ...........................................................................................90 
8.9.4. 
Treatment Compliance ................................................................................................90 
8.10. 
Concomitant Medications ...........................................................................................90 
8.10.1. 
Prohibited and Permitted Medications ........................................................................90 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................91 
9.1. 
Schedule of Events .....................................................................................................91 
9.1.1. 
Footnotes for the Schedule of Events Tables ...........................................................104 
9.1.2. 
Early Termination from the Study ............................................................................107 
9.1.3. 
Unscheduled Visits ...................................................................................................107 
9.2. 
Study Procedures ......................................................................................................107 
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit ...................................107 
9.2.1.1. 
Informed Consent .....................................................................................................107 
9.2.1.2. 
Diagnostic Test for SARS-CoV-2 ............................................................................107 
9.2.1.3. 
Demographics ...........................................................................................................107 
9.2.1.4. 
Medical History ........................................................................................................107 
9.2.1.5. 
Weight and Height ....................................................................................................108 
9.2.2. 
Treatment ..................................................................................................................108 
9.2.3. 
Efficacy Procedures ..................................................................................................108 
9.2.3.1. 
Nasopharyngeal Swab Collection .............................................................................108 
9.2.3.2. 
COVID-19-Related Medically-Attended Visit Details ............................................108 
9.2.4. 
Safety Procedures .....................................................................................................109 
9.2.4.1. 
Vital Signs ................................................................................................................109 
9.2.4.2. 
Adverse Event Monitoring .......................................................................................109 
9.2.4.3. 
Record Targeted Concomitant Medications and Concomitant Procedures ..............109 
9.2.5. 
Post-Day 29 Follow-Up ............................................................................................110 
9.2.6. 
Pregnancy Test for Women of Childbearing Potential .............................................110 
9.2.7. 
Laboratory Testing ....................................................................................................111 
9.2.8. 
Drug Concentration Measurements and Samples .....................................................111 
9.2.9. 
Immunogenicity Measurements and Samples ..........................................................112 
9.2.10. 
Exploratory Pharmacodynamic/Biomarker Analyses ...............................................112 
9.2.10.1. 
Neutrophil–Lymphocyte Ratio .................................................................................112 
9.2.10.2. 
Serum and Plasma Biomarkers .................................................................................112 
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9.2.10.3. 
Virology ....................................................................................................................113 
9.2.10.4. 
Serological Immunoassays for Anti-SARS-CoV-2 Antibodies ...............................113 
9.2.10.5. 
Serum and Plasma for Exploratory Research ...........................................................113 
9.2.10.6. 
Complement ..............................................................................................................114 
9.2.10.7. 
Cytokines ..................................................................................................................114 
9.2.10.8. 
Serum and Plasma for Cardiac Biomarkers ..............................................................114 
9.2.11. 
Monitoring for SARS-CoV-2 Reinfection ................................................................114 
9.2.12. 
Recording New Medical Diagnoses or Conditions ..................................................114 
9.2.13. 
Immunoprofiling Sub-Study (Optional) ...................................................................115 
9.2.14. 
Pharmacogenomics Sub-Study (Optional) ...............................................................115 
9.2.15. 
Exploratory Patient-Reported Symptoms .................................................................116 
9.2.16. 
Assessment of Long COVID ....................................................................................117 
9.2.16.1. 
Patient-Reported Evaluation of Long COVID .........................................................118 
9.2.16.2. 
Nasopharyngeal Swab Sample and Blood Sample Collections (Long COVID 
Assessment) ..............................................................................................................120 
10. 
SAFETY EVALUATION AND REPORTING .......................................................122 
10.1. 
Recording and Reporting Adverse Events ................................................................122 
10.1.1. 
General Guidelines ...................................................................................................122 
10.1.2. 
Reporting Procedure .................................................................................................123 
10.1.3. 
Events that Require Expedited Reporting to Sponsor ..............................................123 
10.1.4. 
Other Adverse Events of Special Interest That Do Not Require Expedited 
Reporting to Sponsor ................................................................................................124 
10.2. 
Definitions ................................................................................................................124 
10.2.1. 
Adverse Event ...........................................................................................................124 
10.2.2. 
Serious Adverse Event ..............................................................................................124 
10.2.3. 
Adverse Events of Special Interest ...........................................................................125 
10.2.4. 
Infusion-Related Reactions and Hypersensitivity Reactions ....................................125 
10.2.5. 
Severity .....................................................................................................................125 
10.2.6. 
Causality ...................................................................................................................126 
10.3. 
Safety Monitoring .....................................................................................................127 
10.4. 
Notifying Health Authorities, Institutional Review Board, Ethics Committee, 
and Investigators .......................................................................................................127 
11. 
STATISTICAL PLAN..............................................................................................128 
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11.1. 
Statistical Hypothesis ................................................................................................128 
11.2. 
Justification of Sample Size......................................................................................129 
11.3. 
Analysis Sets .............................................................................................................131 
11.3.1. 
Efficacy Analysis Sets ..............................................................................................131 
11.3.2. 
Safety Analysis Set ...................................................................................................132 
11.3.3. 
Pharmacokinetic Analysis Set ..................................................................................133 
11.3.4. 
Immunogenicity Analysis Sets .................................................................................133 
11.4. 
Statistical Methods ....................................................................................................133 
11.4.1. 
Patient Disposition ....................................................................................................133 
11.4.2. 
Demography and Baseline Characteristics ...............................................................134 
11.4.3. 
Efficacy Analyses .....................................................................................................134 
11.4.3.1. 
Primary Efficacy Analysis ........................................................................................134 
11.4.3.2. 
Secondary Efficacy Analysis ....................................................................................135 
11.4.3.3. 
Exploratory Analysis ................................................................................................137 
11.4.4. 
Control of Multiplicity ..............................................................................................138 
11.4.5. 
Safety Analysis .........................................................................................................141 
11.4.5.1. 
Adverse Events .........................................................................................................141 
11.4.5.2. 
Other Safety ..............................................................................................................142 
11.4.5.3. 
Treatment Exposure ..................................................................................................143 
11.4.5.4. 
Treatment Compliance ..............................................................................................143 
11.4.6. 
Pharmacokinetics ......................................................................................................143 
11.4.6.1. 
Analysis of Drug Concentration Data .......................................................................143 
11.4.7. 
Pharmacokinetics and Pharmacokinetics/Pharmacodynamics Analyses ..................143 
11.4.8. 
Analysis of Immunogenicity Data ............................................................................143 
11.5. 
Interim Analysis ........................................................................................................144 
11.6. 
Statistical Considerations Surrounding the Premature Termination of a Study .......144 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................145 
12.1. 
Data Management and Electronic Systems ..............................................................145 
12.1.1. 
Data Management .....................................................................................................145 
12.1.2. 
Electronic Systems ....................................................................................................145 
12.2. 
Study Monitoring ......................................................................................................145 
12.2.1. 
Monitoring of Study Sites .........................................................................................145 
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12.2.2. 
Source Document Requirements ..............................................................................146 
12.2.3. 
Case Report Form Requirements ..............................................................................146 
12.3. 
Audits and Inspections ..............................................................................................146 
12.4. 
Study Documentation ...............................................................................................147 
12.4.1. 
Certification of Accuracy of Data .............................................................................147 
12.4.2. 
Retention of Records ................................................................................................147 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ........................................148 
13.1. 
Good Clinical Practice Statement .............................................................................148 
13.2. 
Informed Consent .....................................................................................................148 
13.3. 
Patient Confidentiality and Data Protection .............................................................149 
13.4. 
Institutional Review Board/Ethics Committee .........................................................149 
13.5. 
Clinical Study Data Transparency ............................................................................150 
14. 
PROTOCOL AMENDMENTS ................................................................................150 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ..........................................................................................................................150 
15.1. 
Premature Termination of the Study .........................................................................150 
15.2. 
Closeout of a Site ......................................................................................................150 
16. 
CONFIDENTIALITY ..............................................................................................151 
17. 
FINANCING AND INSURANCE ...........................................................................151 
18. 
PUBLICATION POLICY ........................................................................................151 
19. 
REFERENCES .........................................................................................................152 
20. 
INVESTIGATOR’S AGREEMENT ........................................................................159 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS ...................................................160 
 
LIST OF TABLES 
Table 1: 
Summary of Main Phase 3 Adaptations .....................................................................51 
Table 2: 
REGN10933+REGN10987 IV Doses for Each Weight Group, Phase 3 
Cohort 2 (Ages 0 to <18 Years) ..................................................................................87 
Table 3: 
Schedule of Events: Phase 1 .......................................................................................92 
Table 4: 
Schedule of Events: Phase 2 (and Phase 3 Prior to Protocol Amendment 6) .............94 
Table 5: 
Schedule of Events: Phase 3 (Cohort 1 Patients) ........................................................96 
Table 6: 
Schedule of Events: Phase 3, Assessment of Long COVID (Cohort 1 
Patients) ......................................................................................................................98 
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Table 7: 
Schedule of Events: Phase 3 (Cohort 3 ≥18 Years) ....................................................99 
Table 8: 
Schedule of Events: Phase 3 (Cohort 2 Patients; Cohort 3 Patients <18 
Years) ........................................................................................................................101 
Table 9: 
Symptoms Evaluated in the Symptom Evolution of COVID-19 (SE-C19) 
Instrument .................................................................................................................116 
Table 10: Symptoms Evaluated in the Symptom Evolution of Long COVID-19 (SE-
LC19) Instrument ......................................................................................................119 
Table 11: NCI-CTCAE Severity Grading System for Adverse Events (v5.0) .........................126 
Table 12: Estimated Sample Sizes at Each Analysis Time Point for Phase 3 Patients 
with ≥1 Risk Factor for Severe COVID-19 ..............................................................130 
Table 13: Statistical Testing Hierarchy, Primary Phase 2 Analysis .........................................138 
Table 14: Statistical Testing Hierarchy, Phase 3 Cohort 1 Analysis ........................................139 
Table 15: Example Alpha Spending Function for Analysis of Primary Endpoint ...................141 
 
LIST OF FIGURES 
Figure 1: 
Phase 1 Sentinel Safety Group ...................................................................................48 
Figure 2: 
Study Flow Diagram, Phase 1 ....................................................................................75 
Figure 3: 
Study Flow Diagram, Phase 2 (and Phase 3 Prior to Amendment 6) .........................75 
Figure 4: 
Study Flow Diagram, Phase 3 (Cohort 1) ...................................................................76 
Figure 5: 
Study Flow Diagram, Phase 3 (Cohort 2 Patients; Cohort 3 Patients 
<18 Years) Prior to Amendment 10 US .....................................................................76 
Figure 6: 
Study Flow Diagram, Phase 3 (Cohort 3 Patients ≥18 Years) Prior to 
Amendment 10 US .....................................................................................................77 
Figure 7: 
Study Flow Diagram, Phase 3 (Cohort 2 Patients; Cohort 3 Patients 
<18 Years) Amendment 10 US and Later ..................................................................77 
 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Master Protocol Assessing the Safety, Tolerability, and Efficacy of Anti-Spike (S) SARS-CoV-2 
Monoclonal Antibodies for the Treatment of Ambulatory Patients with COVID-19 
Site 
Locations 
The study will be conducted in approximately 120 sites in the United States and other countries. 
Principal 
Investigator 
Anita Kohli, MD 
Note: The phase 1 and phase 2 portions of the study have been completed. Therefore, this synopsis provides 
information pertaining to phase 3 only. Refer to the main text for information regarding phase 1 and phase 2. 
Objectives 
 
Primary  
Cohort 1 (≥18 Years Old, Not Pregnant at Randomization) 
• To evaluate the clinical efficacy of REGN10933+REGN10987 compared to placebo as measured 
by COVID-19-related hospitalizations or all-cause death. 
Cohort 2 (<18 Years Old, Not Pregnant at Randomization) 
• To evaluate the safety and tolerability of REGN10933+REGN10987 compared to placebo 
• To further characterize the concentrations of REGN10933 and REGN10987 over time 
Cohort 3 (Pregnant at Randomization) 
• To evaluate the safety and tolerability of REGN10933+REGN10987  
Secondary  Cohort 1 
• To evaluate the impact of REGN10933+REGN10987 on the resolution of self-reported COVID-
19 symptoms compared to placebo 
• To evaluate the clinical efficacy of REGN10933+REGN10987 compared to placebo using various 
measures of COVID-19-related medically-attended visits, including COVID-19-related 
hospitalizations, emergency room visits, or all-cause death 
• To describe the virologic effects of REGN10933+REGN10987 compared to placebo 
• To evaluate the safety and tolerability of REGN10933+REGN10987 compared to placebo 
• To further characterize the concentrations of REGN10933 and REGN10987 in serum over time  
• To assess the immunogenicity of REGN10933 and REGN10987 
Cohort 2 
• To evaluate the clinical efficacy of REGN10933+REGN10987 compared to placebo using various 
measures of COVID-19-related medically-attended visits, including COVID-19-related 
hospitalizations or all-cause death  
• To describe the virologic effects of REGN10933+REGN10987 compared to placebo 
• To assess the immunogenicity of REGN10933 and REGN10987 
Cohort 3 
• To characterize the concentrations of REGN10933 and REGN10987 in serum over time  
• To assess the immunogenicity of REGN10933 and REGN10987 
Study 
Design 
This is an adaptive, phase 1/2/3, randomized, double-blinded, placebo-controlled master protocol to 
evaluate the efficacy, safety, and tolerability of REGN10933+REGN10987 combination therapy in 
ambulatory patients (ie, outpatients) with COVID-19.  
In phase 3, eligible patients in cohort 1 and cohort 2 were initially randomized 1:1:1 to a single dose 
of placebo or one of two dose levels of REGN10933+REGN10987. In cohort 1, 
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REGN10933+REGN10987 dose levels consisted of 1200 mg and 2400 mg. In cohort 2, body-weight 
equivalents of these two dose levels were used. Patients in cohort 3 were initially randomized 1:1 to 
one of two dose levels of REGN10933+REGN10987 (ie, no randomization to placebo), at 1200 mg 
and 2400 mg or body-weight equivalents as applicable.  
Note that as of 25 February 2021 (per IDMC recommendation and subsequently formalized in protocol 
amendment 8), patients are no longer randomized to placebo (Section 8.5.1). On 14 May 2021, 
enrollment in cohort 1 was closed. As of protocol amendment 10 US, the 2400 mg dose level was 
dropped in cohort 2 and cohort 3, such that cohort 2 and cohort 3 patients are only assigned to the 1200 
mg dose level (or body-weight equivalent for those under 18 years of age). 
On the day of dosing, patients will have NP swabs taken for SARS-CoV-2 RT-qPCR testing and blood 
drawn for safety, drug concentration, immunogenicity, and exploratory analyses. After infusion, 
patients will be monitored for at least 1 hour and released from the study site, if medically appropriate. 
Patients <12 years of age will be monitored for at least 2 hours after infusion, with more frequent vital 
sign assessments. 
Targeted safety information and COVID-19-related medically-attended visit details will be collected 
on an ongoing basis; minimally, patients (or their caregivers) will be queried during weekly phone 
visits through the first 29 days of the study. For patients <12 years of age, a phone call will be made 
within 6 to 8 hours after completing the infusion to collect targeted safety information; these patients 
(or their caregivers) should be instructed to contact the site within 24 hours post-infusion if they 
experience any side effects. Patients (or their caregivers) will also be asked to notify study personnel 
as soon as possible about any unplanned medically-attended visits that occur during the study.  
Patients enrolled in cohort 1 will have NP swabs and blood samples collected approximately every 
week through day 29 and will provide self-reported information about COVID-19 symptoms through 
electronic surveys (both daily and weekly). A subset of patients in cohort 1 will be enrolled in a PK 
sub-study. Patients in cohort 1 may also be enrolled in an optional immunoprofiling sub-study 
assessing the potential impact of REGN10933+REGN10987 on the endogenous immune response to 
SARS-CoV-2. 
Patients enrolled in cohort 2 will also have NP swabs and blood samples collected approximately every 
week through day 29, with an NP swab additionally collected on day 3. To reduce overall patient 
burden of blood sampling in this younger cohort, the frequency of blood sample collection and the total 
amount of blood collected per visit will vary according to body weight. In addition, patients in this 
cohort will be randomly assigned to one of four staggered PK-ADA sampling schedules. This will be 
done according to a central randomization scheme using an interactive web response system (IWRS). 
As part of protocol amendment 9 US, an additional series of assessments and sample collections will 
be performed in cohort 1 to better understand the biology of long COVID and the potential impact of 
prior REGN10933+REGN10987 treatment (during the acute phase of SARS-CoV-2 infection) on the 
development of long COVID symptoms. These analyses will be exploratory in nature. 
Patients in phase 3 cohort 1 will follow the prior phase 3 Schedule of Events until day 90. They will 
then follow the long COVID Schedule of Events until day 169. Patients who consent to protocol 
amendment after day 90 will enter the long COVID Schedule of Events on the corresponding day on 
which they provide consent. 
Patients in cohort 1 will complete a series of health-related questionnaires, including the SE-LC19 
developed by the Sponsor. These self-report questionnaires will be conducted on a daily basis in the 
week leading up to the day 120 visit, and in the week leading up to the day 169 visit. On day 120 and 
day 169, patients will complete several additional questionnaires, will have an NP swab sample 
collected for analysis of SARS-CoV-2 virology, and will have blood samples collected for research 
purposes related to long COVID. Also on day 120 and day 169, any new medical condition diagnosed 
after randomization will be captured as an adverse event of special interest (AESI), but will not require 
expedited reporting to the Sponsor.  
In addition to these procedures, previously described assessments (separate from the long COVID 
portion of the study) will be performed at day 120 and day 169 safety assessments, and (for those who 
were enrolled in the PK sub-study) an additional blood draw will be collected at day 120 for analysis 
of drug concentration and immunogenicity. These assessments are separate from the long COVID 
portion of the study. 
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Study  
Duration 
In phase 3, the duration of the study is 170 days for each patient.  
End of 
Study 
Definition 
The end of study is defined as the date when the last living patient completes the last study visit, 
withdraws from the study, or is lost to follow-up (ie, the study patient can no longer be contacted by 
the investigator). 
Population 
 
Sample Size Up to approximately 8500 patients will be required for phase 3 cohort 1. For cohort 2, up to 
approximately 180 patients will be required. No enrollment targets are planned for cohort 3. 
Target 
Population 
This study will enroll non-hospitalized patients who have a positive diagnostic test for SARS-CoV-2.  
In phase 3, patients must meet the following criteria to be eligible for inclusion in the study. Other 
inclusion criteria also apply and are described in the main text: 
• Meets 1 of the following 3 criteria: 
a. Cohort 1: ≥18 years of age and not pregnant at randomization  
b. Cohort 2: <18 years of age and not pregnant at randomization 
c. Cohort 3: Pregnant at randomization 
Note: Cohort 2 and cohort 3 will only be enrolled where permitted by local requirements. 
Enrollment in cohort 1 was closed on 14 May 2021. 
• Has SARS-CoV-2-positive diagnostic test from a sample collected ≤72 hours prior to 
randomization, using a validated SARS-CoV-2 antigen, RT-PCR, or other molecular diagnostic 
assay and an appropriate sample such as nasopharyngeal [NP], nasal, oropharyngeal [OP], or 
saliva 
Note: Historical record of positive result is acceptable, as long as the sample was collected ≤72 
hours prior to randomization. 
• Has symptoms consistent with COVID-19, as determined by the investigator, with onset ≤7 days 
before randomization 
• Cohort 1 and Cohort 2 only: has ≥1 risk factor for severe COVID-19 
Risk factors are defined as follows: 
a. Age ≥50 years (cohort 1 only) 
b. Obesity, defined as: 
BMI ≥30 kg/m2 (cohort 1 only) 
BMI (kg/m2) ≥95th percentile for age and sex based on CDC growth charts (cohort 2 ≥2 years 
only) 
c. Cardiovascular disease, including hypertension 
d. Chronic lung disease, including asthma 
e. Type 1 or type 2 diabetes mellitus 
f. Chronic kidney disease, including those on dialysis 
g. Chronic liver disease 
h. [Risk factor removed] 
i. Immunosuppressed, based on investigator’s assessment  
Examples include cancer treatment, bone marrow or organ transplantation, immune 
deficiencies, HIV (if poorly controlled or evidence of AIDS), sickle cell anemia, thalassemia, 
and prolonged use of immune-weakening medications 
j. Any underlying genetic condition, neurologic condition, metabolic condition, or congenital 
heart disease deemed by the investigator to be a risk factor for severe COVID-19 (cohort 2 
only) 
A patient who meets any of the following criteria will be excluded from the study. Other exclusion 
criteria also apply and are described in the main text: 
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• Was admitted to a hospital for COVID-19 prior to randomization, or is hospitalized (inpatient) for 
any reason at randomization 
• Has participated, or is participating, in a clinical research study evaluating COVID-19 
convalescent plasma, mAbs against SARS-CoV-2 (eg, bamlanivimab), or intravenous 
immunoglobulin (IVIG) within 3 months or within 5 half-lives of the investigational product 
(whichever is longer) prior to the screening visit 
• Prior, current, or planned future use of any of the following treatments: COVID-19 convalescent 
plasma, mAbs against SARS-CoV-2 (eg, bamlanivimab), IVIG (any indication), systemic 
corticosteroids (any indication), or COVID-19 treatments (authorized, approved, or 
investigational) 
Note: Prior use is defined as the past 30 days or within 5 half-lives of the investigational product 
(whichever is longer) from screening 
• Prior use (prior to randomization), current use (at randomization), or planned use (within 90 days 
of study drug administration or per current CDC recommendations, as applicable) of any 
authorized or approved vaccine for COVID-19 
• Has participated, is participating, or plans to participate in a clinical research study evaluating any 
authorized, approved, or investigational vaccine for COVID-19 
• Has a known positive SARS-CoV-2 serologic test 
• Has a positive SARS-CoV-2 antigen or molecular diagnostic test from a sample collected >72 
hours prior to randomization  
Treatments: 
Study Drug 
Cohort 1 Patients  
Closed to enrollment as of 14 May 2021 
Cohort 3 Patients ≥18 Years 
• Co-administered REGN10933+REGN10987 combination therapy, 1200 mg (600 mg each of 
REGN10933 and REGN10987) IV single dose  
Cohort 2 and Cohort 3 Patients <18 Years 
REGN10933+REGN10987 1200 mg will be adjusted according to body weight, as defined as below. 
All doses, consisting of 1:1 REGN10933 and REGN10987, will be given as IV single dose: 
• ≥40 kg: 1200 mg 
• ≥20 kg to <40 kg: 450 mg 
• ≥10 kg to <20 kg: 224 mg 
• ≥5 kg to <10 kg: 120 mg 
• ≥2.5 kg to <5 kg: 60 mg 
• <2.5 kg: 30 mg 
Endpoints 
 
Primary 
Cohort 1 
• Proportion of patients with ≥1 COVID-19-related hospitalization or all-cause death through day 
29 
Cohort 2  
• Proportion of patients with treatment-emergent serious adverse events through day 29 
• Proportion of patients with infusion-related reactions (grade ≥2) through day 4 
• Proportion of patients with hypersensitivity reactions (grade ≥2) through day 29 
• Concentrations of REGN10933 and REGN10987 in serum over time  
Cohort 3 
• Proportion of patients with treatment-emergent serious adverse events through day 29 
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• Proportion of patients with infusion-related reactions (grade ≥2) through day 4 
• Proportion of patients with hypersensitivity reactions (grade ≥2) through day 29 
Secondary 
Cohort 1  
Key secondary endpoints (other secondary endpoints are provided in the main text) 
• Proportion of patients with ≥1 COVID-19-related hospitalization or all-cause death from day 4 
through day 29 
• Time to COVID-19 symptoms resolution 
Cohort 2 and Cohort 3 
There are no key secondary endpoints in cohort 2 and cohort 3. All secondary endpoints are descriptive; 
refer to the main text. 
Procedures 
and 
Assessments 
Procedures and assessments will include the following: 
Efficacy 
• COVID-19-related medically-attended visit details 
• NP swabs for SARS-CoV-2 RT-qPCR 
Safety 
• Treatment-emergent SAEs, treatment-emergent AESIs (grade ≥2 IRRs, grade ≥2 hypersensitivity 
reactions, and any TEAE that led to a medically-attended visit), and treatment-emergent grade ≥3 
AEs (in cohort 2 only) 
• Blood collection for safety labs 
• Vital signs and concomitant medications 
• Vital status  
• Pregnancy status, pregnancy outcome (women of childbearing potential only) 
Statistical 
Plan 
This section summarizes the statistical plan for primary and key secondary analyses of phase 3 cohort 
1. For analysis of cohort 2 and cohort 3, refer to the main text. Note that cohort 2 and cohort 3 may 
continue to enroll after enrollment of cohort 1 has been completed. 
Statistical 
Hypothesis 
The statistical hypotheses for the primary endpoint of phase 3 cohort 1 are as follows: 
• H0: The risk of a patient having ≥1 COVID-19-related hospitalization or all-cause death through 
day 29 for REGN10933+REGN10987 2400 mg group is the same as that for placebo 
• H1: The risk of a patient having ≥1 COVID-19-related hospitalization or all-cause death through 
day 29 for REGN10933+REGN10987 2400 mg group is not the same as that for placebo 
Justification 
of Sample 
Size 
The sample size of phase 3 cohort 1 is based on having sufficient power to analyze the primary endpoint 
in the modified full analysis set (mFAS). 
Based on data from the phase 2 analysis involving the first 799 symptomatic patients enrolled, as well 
as blinded phase 3 data, the Sponsor assumes that 83% of randomized patients will have a positive 
SARS-CoV-2 RT-qPCR test at baseline (and can therefore be included in the mFAS). The Sponsor 
also assumes an event rate of 3.4% for COVID-19-related hospitalization or all-cause death among 
patients on placebo in the mFAS. 
The final primary efficacy analysis for the 2400 mg dose group versus placebo comparison will be 
performed based on patients randomized on or before 17 January 2021, which includes approximately 
1503 randomized patients with COVID-19 risk factors per group in the 2400 mg dose group and the 
placebo group (1248 per group in the mFAS). With this sample size, the study will have approximately 
76% power to detect a significant treatment effect in the proportion of patients with ≥1 COVID-19-
related hospitalization or all-cause death in mFAS at a 2-sided α of 0.05, assuming 3.4% of patients in 
the placebo group and 1.7% of patients in the 2400 mg group have an event (ie, a 50% reduction with 
REGN10933+REGN10987 treatment). If there is a greater treatment difference, such as a 60% 
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reduction, the study will have at least 90% power to detect a significant treatment effect in the 
proportion of patients with ≥1 COVID-19-related hospitalization or all-cause death. 
The final efficacy analysis of the 1200 mg dose group versus placebo comparison will be performed 
in approximately 1352 patients with COVID-19 risk factors per dose group (approximately 1122 per 
dose group estimated in the mFAS), representing the cohort of patients enrolled starting in Protocol 
Amendment 6 (ie, when the 1200 mg dose was introduced) through February 24, 2021, the last date 
that enrollment into the placebo group was allowed. This analysis will only include patients who were 
concurrently randomized to either the 1200 mg dose group or the placebo group. The study will have 
approximately 72% power to detect a significant treatment effect in the proportion of patients with ≥1 
COVID-19-related hospitalization or all-cause death in the mFAS at a 2-sided α of 0.05 assuming 3.4% 
of patients in the placebo group and 1.7% of patient in the 1200 mg group have an event (ie, a 50% 
reduction). If there is a greater treatment difference, such as a 60% reduction, the study will have 
approximately 88% power to detect a significant treatment effect in the proportion of patients with ≥1 
COVID-19-related hospitalization or all-cause death. 
From 25 February 2021 onward, the Sponsor plans to randomize up to 1500 patients 1:1 to either the 
1200 mg dose group or the 2400 mg dose group, in addition to the patients already enrolled under 
protocol amendment 6 and protocol amendment 7, to have adequate precision to estimate the difference 
in the proportion of patients with a COVID-19-related hospitalization or death between the 2 dose 
groups. For example, assuming an event rate of 1.7% in each group, with a total of approximately 2100 
concurrently randomized patients per arm (1744 per arm in mFAS) in 1200 mg and 2400 mg dose 
groups, a 2-sided 95% confidence interval for the difference will extend approximately 1% from the 
observed difference. Blinded sample size re-estimation may be performed based on the pooled 
observed event rates. 
Statistical 
Analysis 
Efficacy Analysis Sets (Cohort 1) 
Only patients with COVID-19 symptoms will be included in phase 3. All symptomatic patients from 
the 800th randomized symptomatic patient will be included in phase 3. For phase 3 cohort 1, the full 
analysis set (FAS) includes all randomized symptomatic patients and is based on the treatment 
allocated (as randomized). The FAS includes patients with and without risk factors for severe 
COVID-19. 
In phase 3, the mFAS includes all randomized patients with a positive SARS-CoV-2 central lab-
determined RT-qPCR test from nasopharyngeal (NP) swab samples at randomization, and with at least 
one risk factor for severe COVID-19 at baseline. If pre-dose virologic results from the qualitative test 
are missing, then results from post-dose sample may be used to determine the qualitative PCR status 
at baseline, as long as the sample was collected within 2 hours after starting the study drug infusion. 
The mFAS is based on the treatment allocated (as randomized). The seronegative mFAS is defined as 
all randomized patients with documented seronegative status at baseline in the mFAS.  
For the analyses of the 1200 mg group comparing to placebo, only patients concurrently randomized 
(ie, after protocol amendment 6 is implemented) will be included in the above analysis sets. 
Primary Efficacy Analysis (Cohort 1) 
The primary efficacy endpoint for phase 3 cohort 1 is the proportion of patients with ≥1 COVID-19-
related hospitalization or all-cause death through day 29, which will be compared between each dose 
group and placebo using the stratified Cochran-Mantel-Haenszel (CMH) test with country as a 
stratification factor. P-values from the stratified CMH test and 95% confidence intervals for the risk 
ratio and relative risk reduction (1-risk ratio) using Farrington-Manning method will be presented. 
Exact method for p-values and confidence intervals will be used if the expected frequencies in all cells 
are not at least 5. The primary analysis will be performed based on mFAS. As key secondary analyses, 
the same analyses will be performed for patients with high baseline viral load (>106 copies/mL) and 
for seronegative mFAS, and for proportion of patients with a COVID-19-related hospitalization or all-
cause death from day 4 through day 29 in the mFAS. The comparison of 1200 mg dose group to placebo 
will include only the subset of placebo patients concurrently randomized with 1200 mg dose group. 
Sensitivity and supportive analyses will be described in the SAP. 
Key Secondary Efficacy Analysis (Cohort 1) 
Time to COVID-19 symptoms resolution will be analyzed using the stratified log-rank test with 
randomization strata as stratification factor. The analyses will be performed in the mFAS. Estimates 
of median times and associated 95% confidence intervals using the Kaplan-Meier method will be 
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reported. The hazard ratio and 95% CI for time to COVID-19 symptoms resolution of COVID-19 
symptoms endpoint will be estimated by the Cox regression model with terms for treatment group and 
randomization strata. The p-value from the stratified log-rank test will be reported. Patients who do not 
experience resolution of symptoms will be censored at the last observation time point. Patients who 
died or had COVID-19-related hospitalization prior to day 29 will be censored at day 29. Patients with 
a baseline raw score ≤3 will be censored at day 0. Patients with missing baseline assessment will not 
be included in the analysis. Subgroup analyses may be performed among patients with more than one 
risk factor, with high baseline viral load, or who are seronegative at baseline. 
COVID-19 symptoms included in the analysis are as follows: Body aches such as muscle pain or joint 
pain, Chest pain, Chills, Cough, Diarrhea, Dizziness, Fatigue, Feverish, Headache, Loss of appetite, 
Loss of taste/smell, Nausea, pressure/tight chest, Red or watery eyes, Runny nose, Shortness of 
breath/difficulty breathing, Sore throat, Sputum/Phlegm, and Stomachache. 
Time to COVID-19 symptoms resolution will be defined as time from randomization to the first day 
during which the subject scored ‘no symptom’ (score of 0) on all of the above symptoms except Cough, 
Fatigue, and Headache, which can be ‘mild/moderate symptom’ (score of 1) or ‘no symptom’ (score 
of 0). 
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1. 
INTRODUCTION 
1.1. 
Emergence of SARS-CoV-2 and COVID-19 
Coronaviruses are a family of enveloped, single-stranded RNA viruses. In recent decades, two 
highly pathogenic strains of coronavirus were identified in humans: severe acute respiratory 
syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus 
(MERS-CoV). These viruses were found to cause severe, and sometimes fatal, respiratory illness 
(Cui, 2019) (Fehr, 2015). 
In December 2019, pneumonia of unknown cause was identified in clusters of patients in Wuhan 
City, China. A novel enveloped RNA betacoronavirus – severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) – was identified in these patients, and the disease caused by SARS-
CoV-2 infection was later designated coronavirus disease 2019 (COVID-19) by the World Health 
Organization (WHO, 2020) (Zhu, 2020). Millions of SARS-CoV-2 infections have been confirmed 
worldwide, and the rapidly-spreading, worldwide outbreak has prompted the WHO to declare 
COVID-19 a pandemic and public health emergency of international concern. 
1.2. 
Clinical Outcomes in Hospitalized Patients with COVID-19 
Patients with COVID-19 are at risk for developing a variety of respiratory conditions, ranging 
from relatively mild symptoms to respiratory failure and death (Wu, 2020). Among hospitalized 
patients, intensive care and/or supplemental oxygen intervention (eg, mechanical ventilation) is 
often required, and reported fatality rates are high.  
In a report from the Chinese Center for Disease Control and Prevention that included 44,500 
confirmed infections, nearly 20% of patients presented with advanced respiratory symptoms (14% 
with dyspnea, hypoxia, and >50% lung involvement on imaging; 5% with respiratory failure, 
shock, or multiorgan failure) (Wu, 2020). Another analysis of patients with COVID-19 in China 
found that, among 1,099 hospitalized patients, 5% had been admitted to an intensive care unit 
(ICU), 2.3% required invasive mechanical ventilation, and 1.4% died. Among patients with 
advanced disease on admission (defined as pneumonia, hypoxemia, and tachypnea), these negative 
outcomes rose to 19%, 14.5%, and 8.1%, respectively (Guan, 2020). A report of 2634 hospitalized 
patients with COVID-19 in the United States identified similar clinical outcomes: 14.2% were 
admitted to an ICU, 12.2% required invasive mechanical ventilation, and 21% died (Guan, 2020). 
Other reports have found that approximately 20% to 30% of hospitalized patients with COVID-19 
and pneumonia require intensive care for respiratory support (Richardson, 2020). 
1.3. 
Ambulatory Care as a Potential COVID-19 Treatment Setting 
Although severe COVID-19 can occur across all age groups, accumulating data have identified 
several factors that can place patients at risk of more serious illness and potentially lead to 
hospitalization, emergency room visits, or other medically-attended visits. These include age, 
pregnancy, as well as variety of comorbidities such as obesity and cardiovascular disease 
(Chen, 2020b). An anti-viral therapeutic that could be administered to ambulatory patients (ie, 
outpatients) has the potential to significantly reduce COVID-19-related medically-attended visits, 
particularly among those with 1 or more baseline risk factors Currently, there is a great need for 
therapies capable of reducing viral load and slowing or preventing COVID-19 disease progression. 
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1.4. 
Long-Term Outcomes in Patients with COVID-19  
Although much has been learned about acute SARS-CoV-2 infection and the resulting COVID-19 
disease course, the long-term sequelae of SARS-CoV-2 infection and COVID-19 remain poorly 
understood. Long COVID is characterized by persistent symptoms, occurring beyond 4 weeks 
from the initial SARS-CoV-2 infection, that are not explained by an alternative diagnosis 
(Nalbandian, 2021) (CDC, 2021) (NICE, 2021). Initial assessments of long COVID indicate that 
approximately 10% to 35% of patients who recover from acute SARS-CoV-2 infection may 
experience persistent symptoms suggestive of long COVID (Tenforde, 2020) (Greenhalgh, 2020). 
To date, it is unclear whether and how the treatment of acute SARS-CoV-2 infection may impact 
the subsequent development of long COVID symptomatology. 
1.5. 
The Role of Spike (S) Protein in SARS-CoV-2 Pathogenesis 
Coronaviruses consist of an RNA genome packaged in nucleocapsid (N) protein surrounded by an 
outer envelope. The envelope is comprised of membrane (M) protein and envelope (E) protein, 
which are involved in virus assembly, and spike (S) protein, which mediates entry into host cells. 
S proteins form large trimeric projections, providing the hallmark crown-like appearance of 
coronaviruses. S protein trimers bind to a host receptor and, after priming by cellular proteases, 
mediate host–virus membrane fusion (Huang, 2020). The S protein appears to be central to viral 
infectivity by SARS-CoV-2. SARS-CoV-2 S protein binds the host receptor angiotensin-
converting enzyme 2 (ACE2) with high affinity, and in cell assays and animal models can utilize 
ACE2 as a functional receptor for host cell entry (Hoffmann, 2020) (Ou, 2020) (Walls, 2020). 
Blockade of host cell entry through the use of neutralizing antibodies against S protein is a viable 
mechanistic strategy shown to reduce viral infectivity of SARS-CoV and MERS-CoV 
(Jiang, 2020). In light of the likely pivotal role of S protein in the pathogenesis of SARS-CoV-2 
(Datta, 2020), a number of efforts are underway to develop antibodies and vaccines that target the 
S protein of this novel coronavirus.  
1.6. 
REGN10933+REGN10987: Human Monoclonal Antibodies that 
Target SARS-CoV-2 S Protein 
Regeneron Pharmaceuticals, Inc. (Regeneron) has developed monoclonal antibodies (mAbs) 
directed against the RBD of the SARS-CoV-2 S protein. Casirivimab (REGN10933) and 
imdevimab (REGN10987) are human, IgG1 mAbs that bind simultaneously to the RBD and block 
interaction with ACE2. As co-administered combination therapy, casirivimab and imdevimab, also 
referred to by the proprietary name conditionally accepted by the FDA (REGEN-COV™) and by 
the EMA (RONPAPREVE®), is being evaluated for the treatment and prevention of SARS-CoV-
2 infection and retains neutralization potency against circulating SARS-CoV-2 variants of concern 
(UK B.1.1.7 [alpha], South Africa B.1.351 [beta], California B.1.429 [epsilon], India B.1.617.2 
[delta], and Brazil P.1 [gamma]) and protects against the selection of resistant variants in vitro 
(Copin, 2021) (REGEN-COV™ (casirivimab with imdevimab) [HCP Fact Sheet], 2021). 
In phase 3 clinical trials, the combination of casirivimab and imdevimab was shown to be effective 
and well-tolerated in the treatment of outpatient and hospitalized adults with COVID-19, and in 
the prevention of SARS-CoV-2 infection in adults and adolescents (Horby, 2021) (O’Brien, 
2021a) (O’Brien, 2021b) (Weinreich, 2021b) (see Section 3.3 for additional information). 
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Casirivimab and imdevimab (1200 mg; 600 mg of each mAb) is currently authorized under 
Emergency Use Authorization (EUA) for the treatment of outpatients 12 years and older who are 
at high risk for developing severe COVID-19 (FDA, 2020).  
1.7. 
A Randomized, Placebo-Controlled Study of Anti-SARS-CoV-2 
S Protein Monoclonal Antibodies in Ambulatory Patients with 
COVID-19  
Several therapeutic and preventative agents are under investigation for the treatment or prevention 
of COVID-19. While a number of these agents have received approvals or conditional 
authorizations (FDA, 2021) (EMA, 2021), there remains a significant unmet medical need for 
COVID-19 treatments. Multiple COVID-19 therapies will be required, both to address the medical 
requirements of distinct patient populations and to bolster treatment supplies as caseloads continue 
to rise worldwide. The availability of multiple treatment options, and the continued collection of 
data on conditionally authorized treatments, are both critically important in the setting of a global 
pandemic.  
This is an adaptive, phase 1/2/3 master protocol to further evaluate the efficacy and safety of co-
administered REGN10933+REGN10987 in ambulatory patients (ie, outpatients) with COVID-19.  
For more information regarding the rationale for the study design and dose selection, refer to 
Section 3.2. Additional background information on the study drugs and the overall development 
program can be found in the Investigator’s Brochure. 
2. 
STUDY OBJECTIVES  
2.1. 
Primary Objectives 
Phase 1 
The primary objectives of phase 1 are: 
• To evaluate the safety and tolerability of REGN10933+REGN10987 compared to 
placebo 
• To evaluate the virologic efficacy of REGN10933+REGN10987 compared to placebo 
in reducing viral load of SARS-CoV-2 
Phase 2 
The 
primary 
objective 
of 
phase 
2 
is 
to 
evaluate 
the 
virologic 
efficacy 
of 
REGN10933+REGN10987 compared to placebo in reducing viral load of SARS-CoV-2. 
Phase 3 
Cohort 1 (≥18 Years Old, Not Pregnant at Randomization)* 
The primary objective is to evaluate the clinical efficacy of REGN10933+REGN10987 compared 
to placebo as measured by COVID-19-related hospitalizations or all-cause death. 
Cohort 2 (<18 Years Old, Not Pregnant at Randomization)* 
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The primary objectives are: 
• To evaluate the safety and tolerability of REGN10933+REGN10987 compared to 
placebo 
• To further characterize the concentrations of REGN10933 and REGN10987 in serum 
over time  
Cohort 3 (Pregnant at Randomization)* 
The primary objective is to evaluate the safety and tolerability of REGN10933+REGN10987.  
*Refer to Section 7.2.1 for study cohort definitions. 
2.2. 
Secondary Objectives 
Phase 1 
The secondary objectives of phase 1 are: 
• To evaluate additional indicators of virologic efficacy of REGN10933+REGN10987 
compared to placebo 
• To estimate the clinical efficacy of REGN10933+REGN10987 compared to placebo 
• To compare quantitative reverse transcription polymerase chain reaction (RT-qPCR) 
results acquired with different sample types (nasopharyngeal [NP], nasal, and saliva) 
• To characterize the PK profiles of REGN10933 and REGN10987 in serum  
• To assess the immunogenicity of REGN10933 and REGN10987 
Phase 2 
The secondary objectives of phase 2 are: 
• To evaluate additional indicators of virologic efficacy of REGN10933+REGN10987 
compared to placebo 
• To evaluate the clinical efficacy of REGN10933+REGN10987 compared to placebo 
• To evaluate the safety and tolerability of REGN10933+REGN10987 compared to 
placebo 
• To characterize the concentrations of REGN10933 and REGN10987 in serum over 
time  
• To assess the immunogenicity of REGN10933 and REGN10987 
Phase 3 
The secondary objectives of phase 3 are: 
Cohort 1* 
• To evaluate the impact of REGN10933+REGN10987 on the resolution of self-reported 
COVID-19 symptoms compared to placebo 
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• To evaluate the clinical efficacy of REGN10933+REGN10987 compared to placebo 
using various measures of COVID-19-related medically-attended visits, including 
COVID-19-related hospitalizations, emergency room visits, or all-cause death 
• To describe the virologic effects of REGN10933+REGN10987 compared to placebo 
• To evaluate the safety and tolerability of REGN10933+REGN10987 compared to 
placebo 
• To further characterize the concentrations of REGN10933 and REGN10987 in serum 
over time  
• To assess the immunogenicity of REGN10933 and REGN10987 
Cohort 2* 
• To evaluate the clinical efficacy of REGN10933+REGN10987 compared to placebo 
using various measures of COVID-19-related medically-attended visits, including 
COVID-19-related hospitalizations or all-cause death  
• To describe the virologic effects of REGN10933+REGN10987 compared to placebo 
• To assess the immunogenicity of REGN10933 and REGN10987 
Cohort 3* 
• To characterize the concentrations of REGN10933 and REGN10987 in serum over 
time 
• To assess the immunogenicity of REGN10933 and REGN10987 
*Refer to Section 7.2.1 for study cohort definitions. 
2.3. 
Exploratory Objectives 
The exploratory objectives (phase 1, phase 2, and phase 3) are: 
• To evaluate viral variants at baseline and post-treatment 
• To explore the potential association of baseline humoral immune response to SARS-
CoV-2 on response to REGN10933+REGN10987  
• To evaluate the effects of REGN10933+REGN10987 compared to placebo on 
generation of a humoral immune response to SARS-CoV-2 (as measured by anti-
SARS-CoV-2 N protein) 
• To explore the effects of REGN10933+REGN10987 on measures of SARS-CoV-2 
infectivity as assessed in experimental laboratory assays 
• To explore biomarkers predictive of REGN10933+REGN10987 safety, efficacy, 
and/or disease progression and COVID-19 clinical outcomes 
• To explore the underlying mechanisms of action and biology of 
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• To explore relationships between REGN10933+REGN10987 exposure and selected 
efficacy endpoints, safety endpoints, and/or biomarkers 
• To evaluate the impact on self-reported symptoms of REGN10933+REGN10987 
compared to placebo 
Additional exploratory objective for phase 1 only: 
• To evaluate additional indicators of clinical efficacy of REGN10933+REGN10987 
compared to placebo 
Additional exploratory objective for phase 3 only: 
• To assess the clinical efficacy of different dose levels of REGN10933+REGN10987, 
as measured by COVID-19-related hospitalizations or all-cause death 
• To describe the relationship between virologic effects of REGN10933+REGN10987 
and risk of COVID-19-related medically-attended visit or all-cause death 
• To evaluate the effects of REGN10933+REGN10987 compared to placebo on the 
generation of endogenous humoral and/or cellular immune responses to SARS-CoV-2 
(optional sub-study) (cohort 1) 
• To evaluate the impact of REGN10933+REGN10987 on the resolution of self-reported 
COVID-19 symptoms compared to placebo (cohort 2 age ≥12 years)  
• To describe the clinical outcomes of patients treated with REGN10933+REGN10987 
using various measures of COVID-19-related medically-attended visits, including 
COVID-19-related hospitalizations or all-cause death (cohort 3) 
• To evaluate the impact of REGN10933+REGN10987 treatment, given during acute 
SARS-CoV-2 infection, on long COVID symptoms (cohort 1 only) 
3. 
HYPOTHESIS AND RATIONALE 
3.1. 
Hypotheses 
Phase 1 
Treatment of ambulatory patients with COVID-19 with REGN10933+REGN10987 will be 
tolerated and will reduce viral load. 
Phase 2 
Treatment of ambulatory patients with SARS-CoV-2 infection with REGN10933+REGN10987 
will reduce viral load. 
Phase 3 
Treatment of ambulatory patients (≥18 years) with COVID-19 with REGN10933+REGN10987 
will improve clinical outcomes. 
Treatment of ambulatory patients (<18 years) with COVID-19 with REGN10933+REGN10987 
will be well tolerated. 
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Information concerning statistical hypotheses can be found in Section 11.1. 
3.2. 
Rationale  
3.2.1. 
Rationale for Study Design 
This randomized, double-blinded, placebo-controlled, adaptive phase 1/2/3 master protocol will 
assess the safety, tolerability, and efficacy of REGN10933+REGN10987 in ambulatory patients 
with COVID-19 (including, in phase 2, those with asymptomatic SARS-CoV-2 infection). The 
multicenter conduct of this study will enable generalizable evidence of the safety, tolerability, and 
efficacy of these investigational mAbs for COVID-19.  
3.2.1.1. 
Phase 1 Sentinel Safety Group 
This master protocol will include a first-in-human (FIH) phase 1 study to evaluate safety and 
tolerability. Driven by the medical urgency of the COVID-19 pandemic, the process described 
below is designed to maximize efficient enrollment of eligible patients while optimizing safety of 
FIH exposure with limited preclinical data. 
Phase 1 will include a sentinel safety group (Figure 1), where the initial safety data up to day 3 
will be reviewed by an independent data monitoring committee (IDMC). 
Figure 1: 
Phase 1 Sentinel Safety Group  
 
Patients in this sentinel safety group can be derived from either of 2 concurrent FIH studies, where 
the safety and tolerability of REGN10933+REGN10987 will be evaluated: 
• R10933-10987-COV-2066, in hospitalized adult patients with COVID-19 
• R10933-10987-COV-2067, in ambulatory adult patients with COVID-19  
For IDMC review, patients will be pooled together from the phase 1 portions of either of the 
2 studies. Once safety data have been collected on day 3 for approximately 30 patients (from one 
or both of the studies combined), the IDMC will review the data.  
Note that phase 1 enrollment will pause during the IDMC review.  
Initiation of phase 2 enrollment is contingent upon IDMC review of phase 1 data from the sentinel 
safety group. Study stopping criteria are outlined in Section 6.1.5.2.  
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After the IDMC reviews and provides a positive recommendation for the phase 1 sentinel safety 
group, 
enrollment 
of 
studies 
assessing 
REGN10933+REGN10987 
(including 
REGN10933+REGN10987 treatment arms in phase 2 of this study and R10933-10987-COV-
2066) may begin.  
Once phase 2 of this study is active, phase 1 will continue to enroll to completion. However, 
phase 2 enrollment does not require the completion of phase 1 enrollment. 
Review of Sentinel Safety Group (information added to protocol in amendment 5) 
A 
blinded 
Sponsor 
analysis 
of 
the 
sentinel 
safety 
group 
data 
showed 
that 
REGN10933+REGN10987 was well tolerated in hospitalized or ambulatory adult (≥18 years) 
patients with COVID-19, with no hypersensitivity reactions or infusion-related reactions reported. 
Vital signs and laboratory assessments did not identify any safety signals. IDMC review 
recommended to continue enrollment in the studies after unblinded data review. For more details, 
refer to the Investigator’s Brochure. 
3.2.1.2. 
Adaptive Master Protocol Design 
The study utilizes an adaptive master protocol design. The adaptive design has been selected to 
maximize the efficiency of identifying early signs of efficacy, increase the efficiency of studying 
multiple therapeutic combinations, and avoid the use of ineffective dose levels in patients with 
COVID-19.  
Due to the novel nature of the COVID-19 pandemic, efficacy endpoints are not well established, 
and the standard-of-care is expected to evolve over time. The adaptive design of this study allows 
for the assessment of virologic and clinical efficacy endpoints in phase 2, which are then 
seamlessly confirmed in the phase 3 portion of the study, as well as evaluating the benefit and risk 
of the different treatment arms.  
This master protocol will allow for treatment arm(s) to be dropped if there is a clinically 
meaningful imbalance between treatment arms in the incidence of SAEs or the incidence of AESIs, 
or if there is a meaningful imbalance between treatment arms regarding efficacy endpoints. 
The design will allow for the addition of new treatment arms at different dose levels of 
REGN10933+REGN10987, the addition of treatment arms with other anti-SARS-CoV-2 S protein 
mAbs as they become available for clinical testing (umbrella design), refinement of disease 
characteristics of eligible study populations (basket design), as well as other adaptations, including 
determination of phase 3 primary endpoints and phase 3 sample size estimation.  
3.2.1.3. 
Rationale for Phase 1 and Phase 2 Objectives 
Safety and Tolerability 
The primary objective of phase 1 is safety and tolerability, evaluated by targeted collection of 
treatment-emergent serious adverse events (SAEs) throughout the study and treatment-emergent 
adverse events of special interest (AESIs) through day 29. In addition, grade 3 and grade 4 
treatment-emergent adverse events (TEAEs) will be recorded in phase 1 to inform safety 
assessments in later phases. 
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Many patients who are ambulatory and experiencing relatively early stages of COVID-19 may 
nevertheless present with complicated disease presentation at baseline or could quickly and 
unexpectedly deteriorate and progress to have a complicated disease presentation. As such, their 
TEAE profile could be complex and dynamic. Accurately collecting such a large volume of TEAEs 
could impose unnecessary burden on an already over-strained healthcare system, and frequent 
exposure to infected patients could increase the risk of infection to the study staff. 
Evaluating treatment-emergent SAEs and treatment-emergent AESIs (grade ≥2 hypersensitivity 
reactions and grade ≥2 infusion-related reactions), as well as targeted treatment-emergent grade 3 
or 4 TEAEs in phase 1, will provide the most relevant safety information to adequately evaluate 
the safety and tolerability of REGN10933+REGN10987. This subset of treatment-emergent grade 
3 or 4 TEAEs, treatment-emergent SAEs and treatment-emergent AESIs encompasses the key 
safety concern that would be expected for mAbs against exogenous targets and help evaluate 
unexpected SAEs. Regeneron plans to collect data on non-serious TEAEs (as well as serious 
TEAEs) in a parallel-conducted prophylaxis study (R10933-10987-COV-2069) and a repeated 
dose study in adult volunteers (R10933-10987-HV-2093) with REGN10933+REGN10987, where 
the study population will not have a complicated disease presentation and there is a significantly 
lower risk of overburdening the healthcare delivery system. 
Virologic Efficacy 
The primary mechanism of action of REGN10933+REGN10987 is blockade of the S protein RBD 
interaction with ACE2, leading to decreased infection of host cells. Blocking viral entry would 
result in reductions in SARS-CoV-2 RNA replication and corresponding viral load in affected 
tissues. In phase 1 and phase 2, the primary virologic endpoint will therefore evaluate, as proof of 
mechanism, the ability of REGN10933+REGN10987 to reduce viral load in the upper respiratory 
tract. Day 22 (21 days after dosing) was chosen as the cutoff date for this analysis, based on 
accumulating evidence that this time period approaches the lower limit of detection in samples 
collected from the upper respiratory tract in patients spontaneously recovering from COVID-19 
(He, 2020). In phase 2, virologic efficacy will also be evaluated in asymptomatic patients with 
laboratory-confirmed SARS-CoV-2 infection. The 21-day assessment period is similarly 
appropriate for this cohort, based on evidence that peak viral load occurs just before or soon after 
the onset of COVID-19 symptoms (Cao, 2020) (Wang, 2020c). 
Prior to unblinding for analysis of interim phase 1/2 data and analysis of phase 2 data, the cutoff 
date of the primary virologic endpoint was pre-specified in the statistical analysis plan (SAP) as 
day 7 rather than day 22. This was done as the result of the phase 1/2 analysis, which showed that 
the majority of viral clearance had occurred prior to day 7. For more information, refer to 
Section 3.2.1.5 and (Weinreich, 2020).  
Clinical Efficacy 
Clinical efficacy will also be evaluated. Patients enrolled in this study will be in the early phase of 
their infection (Section 7.2.1), and are therefore expected to be presymptomatic or have milder, 
less advanced disease compared with individuals diagnosed at later stages of COVID-19. By 
directly targeting host entry by SARS-CoV-2, REGN10933+REGN10987 may impact the early 
stages of the disease course, preventing symptom onset, mitigating early disease progression, and 
reducing the likelihood that patients will experience the more advanced symptoms associated with 
hospitalization and/or other urgent medical visits. Phase 2 will therefore assess the proportion of 
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patients requiring COVID-19-related medically-attended visits (defined in Section 9.2.3.2) 
subsequent to their initial disease diagnosis and released home.  
3.2.1.4. 
Stratification According to Risk of Hospitalization (Phase 2) 
In phase 2, randomization will be stratified based on risk factors for hospitalization due to COVID-
19 (refer to Section 8.5.1 for complete definition of phase 2 risks factors; also note that other 
stratification factors will be used as described in Section 8.5.1).  
Although more advanced COVID-19 illness can occur in individuals of all ages, it primarily occurs 
in older adults or those with underlying medical conditions, including cardiovascular disease, 
diabetes mellitus, hypertension, chronic lung disease, obesity (body mass index [BMI] ≥30 kg/m2), 
cancer, and chronic kidney disease (CDC, 2020b) (Lighter, 2020) (Wu, 2020) (Zhou, 2020).  
Hospitalization rates for COVID-19 increase with age, with one study reporting a 1% 
hospitalization rate for those 20 to 29 years, 4% rate for those 50 to 59 years, and 18% for those 
>80 years of age (Liu, 2020). Moreover, the majority of those hospitalized or in ICUs are older 
adults. Among 4,226 COVID-19 cases reported in the United States during February and 
March 2020, for example, 45% of hospitalizations and 53% of ICU admissions for COVID-19 
were among adults ≥65 years of age (CDC, 2020c). 
In addition to older patients, younger patients with underlying medical conditions may be at higher 
risk for hospitalization due to COVID-19. Among 7,162 patients reported in the United States with 
COVID-19 who had data available on their underlying health conditions, for example, patients 
with underlying conditions were hospitalized at higher rates compared to those without underlying 
conditions (27.3% to 29.8% compared to 7.2% to 7.8%). The most common underlying conditions 
in the study were diabetes mellitus, cardiovascular disease and chronic lung disease (CDC, 2020b). 
Obesity is prevalent condition that may also be a risk factor for hospitalization with COVID-19, 
with one study reporting that young obese patients (BMI ≥30 kg/m2) were more likely to be 
hospitalized or admitted to an ICU compared to young patients who were not obese 
(Lighter, 2020). In the United States, nearly 40% of adults are obese and may be at higher risk of 
hospitalization due to COVID-19 (CDC, 2017).  
3.2.1.5. 
Rationale for Phase 3 Adaptations 
A summary of the most substantial phase 3 adaptations is provided in Table 1. These adaptations 
are being implemented based on available data from phase 1 and phase 2, which are summarized 
in the sub-sections below (and, for dose selection, in Section 3.2.2.2) and in the Investigator’s 
Brochure. Modifications to these phase 3 adaptations were subsequently made in response to 
health authority feedback and are captured in the table below.  
Table 1: 
Summary of Main Phase 3 Adaptations 
Study 
Component 
Adaptation1 
Patient 
Eligibility 
• Patients from 0 to <18 years will be enrolled as a separate cohort (cohort 2), 
where permitted by local requirements. Patients ≥18 years old will be enrolled 
in cohort 1 
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• Patients who are pregnant or breastfeeding can enroll in the study. Patients 
who are pregnant at randomization will be enrolled in cohort 3, where 
permitted by local requirements 
• Patients in cohort 1 and cohort 2 must have ≥1 risk factor for severe COVID-
19 
• Patients with a known positive SARS-CoV-2 serology test will be excluded  
• Patients with a positive SARS-CoV-2 antigen test or molecular diagnostic test 
from a sample collected >72 hours prior to randomization will be excluded 
• Patients with active infection with influenza or other non-SARS-CoV-2 
respiratory pathogen, confirmed by a diagnostic test, will be excluded 
Treatment 
Arms 
• For cohort 1, the treatment arms will be REGN10933+REGN10987 2400 mg 
IV, REGN10933+REGN10987 1200 mg IV, and placebo. Note that as of 25 
February 2021 (per IDMC recommendation), patients in this cohort will no 
longer be randomized to placebo. 
• For cohort 2, the treatment arms will be weight-tiered dosing that matches 
REGN10933+REGN10987 2400 mg IV, REGN10933+REGN10987 1200 mg 
IV, and placebo IV. Note that as of 25 Feb 2021, patients in this cohort will no 
longer be randomized to placebo.  
• For cohort 3, the treatment arms will be REGN10933+REGN10987 2400 mg 
IV and REGN10933+REGN10987 1200 mg IV. No placebo arm will be used. 
Weight-tiered dosing will be used for patients <18 years of age.  
Objectives 
/Endpoints 
• For cohort 1, primary endpoint will be the proportion of patients with ≥1 
COVID-19-related hospitalization or all-cause death. The key pre-specified 
secondary endpoints include time to COVID-19 symptoms resolution. A 
hierarchical testing strategy will be used to control for multiplicity.  
• For cohort 2 and cohort 3, the primary endpoints will be safety/tolerability  
• For cohort 2, secondary endpoint analyses will be descriptive 
• Virologic analyses for all cohorts will be secondary and descriptive 
• Cohort 1 will enroll up to 300 patients in an optional sub-study to assess, as an 
exploratory objective, the potential impact of REGN10933+REGN10987 on 
the endogenous immune response 
Sample Size 
• Enrollment in phase 3 cohort 1 is anticipated to be up to approximately 
8500 patients  
• Cohort 2 will enroll up to approximately 180 patients; there will be a 
minimum enrollment of 20 patients <10 kg (10 per treatment group) and 20 
patients between ≥10 kg and <40 kg (10 per treatment group)  
• No minimum or maximum enrollment is planned for cohort 3  
• Cohort 2 and cohort 3 may continue to enroll after enrollment of cohort 1 has 
been completed  
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1 Phase 3 adaptations were initially implemented in protocol amendment 6. Modifications to the 
phase 3 adaptations were subsequently implemented in response to health authority feedback 
(protocol amendment 7) and prior to phase 3 statistical analyses (protocol amendment 8). Refer 
to the amendment history table for more detailed information. 
Virologic Efficacy  
An interim analysis of pooled phase 1/2 data (n=275) was conducted to assess preliminary 
virologic and clinical efficacy of REGN10933+REGN10987. Among patients who were SARS-
CoV-2 seronegative at baseline, those who received REGN10933+REGN10987 had a greater 
reduction in viral load through day 7 compared with those who received placebo, as measured by 
time-weighted average (TWA) change from baseline. For example, seronegative patients receiving 
either REGN10933+REGN10987 2400 mg or 8000 mg (combined analysis) had a TWA viral load 
change of -1.94 log10 copies/ml, versus -1.37 log10 copies/ml in the placebo arm (difference 
between combined dose group and placebo, -0.56 log10 copies/mL; nominal p=0.0165). Post-hoc 
analysis of virologic outcomes by baseline viral load found that patients with the highest viral load 
at baseline had the largest treatment benefit.  
A subsequent analysis of the remaining patients in phase 2 (n=524) formally corroborated the 
virologic efficacy findings observed in the phase 1/2 analysis in a prespecified and statistically 
rigorous manner. There was a statistically significant reduction in the TWA change from baseline 
in viral load (log10 copies/mL) from day 1 through day 7 in patients treated with either dose of 
REGN10933+REGN10987 or the combined dose group (-1.66 log10 copies/ml) compared to 
placebo (-1.30 log10 copies/ml) (difference between combined dose group and placebo, -0.36 log10 
copies/mL; p=0.0003). Statistically significant reductions were observed in the overall population 
that were SARS-CoV-2 RT-qPCR positive at baseline. and were more pronounced in those with 
high baseline viral load (>107 copies/mL or >106 copies/mL) or those who were seronegative at 
baseline. Descriptively, the greater reduction in viral load with REGN10933+REGN10987 
treatment compared to placebo could be observed as early as 2 days post-treatment (the first time 
point assessed) and was maintained at each subsequent time point through day 11, when the mean 
viral load in each of the REGN10933+REGN10987 treatment groups fell below the lower limit of 
quantification (<2.87 log10 copies/mL).  
By contrast, patients who were seropositive at baseline had mean baseline viral loads 
approximately 3-log lower than patients who were seronegative at baseline, and the change from 
baseline in viral load through day 7 for seropositive patients treated with either dose of 
REGN10933+REGN10987 was similar to the reduction in patients treated with placebo. These 
results suggest that the true benefit of a potent antiviral might be concentrated in the higher risk 
groups (eg, seronegative at baseline and higher baseline viral load).  
Clinical Efficacy  
The above virologic data collectively provide definitive evidence that REGN10933+REGN10987 
markedly enhances SARS-CoV-2 viral clearance. Moreover, data from a pooled phase 1/2 analysis 
indicate that the viral load reduction translated into clinical benefit by significantly reducing 
COVID-19-related MAVs, defined as hospitalizations, ER visits, urgent care visits, or physician 
office or telemedicine visits for COVID-19. Specifically, a prespecified and multiplicity-
controlled analysis of pooled phase 1/2 data in symptomatic patients who were SARS-CoV-2 RT-
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qPCR positive at baseline (n=799; mFAS=665) showed a statistically significant reduction in 
MAVs in the REGN10933+REGN10987 treated groups compared to placebo (2.8% combined 
dose groups vs 6.5% placebo; p=0.0240). Most of the MAVs occurred in patients who were higher 
risk, defined as seronegative at baseline, had higher baseline viral load, or had at least 1 
pre-existing risk factor for severe COVID-19 (eg, age >50 years old, obesity, co-morbid 
conditions). In exploratory analyses, treatment with REGN10933+REGN10987 showed the 
greatest benefit in these high-risk groups, with reductions in the proportion of patients with MAVs 
compared to placebo of 62% (3.2% combined treatment versus 8.5% placebo) for those with 
baseline viral loads >104 copies/mL, 65% (3.4% combined treatment versus 9.7% placebo) for 
those who were seronegative at baseline, and 72% (2.6% combined treatment versus 9.2% 
placebo) for those who had at least 1 risk factor for severe COVID-19. Treatment with 
REGN10933+REGN10987 did not reduce MAVs for those who were seropositive at baseline 
(2.9% combined treatment versus 1.9% placebo) or for those who were without pre-existing risk 
factors for severe disease (2% combined treatment versus 1.9% placebo), suggesting that MAVs 
in these groups are less modifiable with treatment.  
Considering the clinical benefits observed in phase 2, phase 3 will focus on confirming the clinical 
benefit of REGN10933+REGN10987 in reducing the risk of having a COVID-19-related 
hospitalization or all-cause death for high-risk patients, thereby demonstrating the clinical benefit 
of reducing viral burden. Virologic secondary analyses will be conducted during phase 3, but these 
will be descriptive in nature.  
Note: A primary efficacy analysis of the phase 3 portion found that treatment with 
REGN10933+REGN10987 was well-tolerated and significantly reduced COVID-19-related 
hospitalization or all-cause death, rapidly resolved symptoms, and reduced viral load 
(Weinreich, 2021b). Refer to Section 3.3.1 for more details. 
Requirement of ≥1 Risk Factor for Severe COVID-19 
The placebo-treated patients in the phase 1/2 portion of the study provided key insights into the 
natural history of COVID-19. Patients who were seronegative at baseline or who had at least 1 risk 
factor for severe COVID-19 had higher baseline viral loads compared to those who were 
seropositive or those who did not have pre-existing risk factors for severe disease. These patients 
took longer to reduce viral load and accounted for the majority of patients with MAVs. As 
described above, it was also these high-risk patients that had the greatest benefit with 
REGN10933+REGN10987 
treatment 
in 
reducing 
MAVs. 
Treatment 
with 
REGN10933+REGN10987 did not appear to reduce MAVs in patients who were seropositive at 
baseline or in patients without risk factors for severe disease, suggesting the true benefit of 
treatment is in patients who have not yet mounted a sufficient immune response or have baseline 
risk factors for severe disease. Based on these very important learnings from the available data and 
considering that risk factors can readily be assessed by the treating provider without additional 
testing, adult patients enrolled in phase 3 subsequent to amendment 6 will be required to have at 
least one risk factor for severe COVID-19.  
Risk factors for COVID-19 that will be applied to the study populations in phase 3 are defined in 
Section 7.2.1. These risk factors encompass the CDC definition of “at increased risk” and “might 
be at an increased risk” patients for severe COVID-19. Modifications to this list of risk factors 
have been made for phase 3. Pregnant women are included because pregnancy is considered a risk 
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factor based on accumulating evidence that women who are pregnant are at increased risk for 
severe COVID-19 (Ellington, 2020) (Knight, 2020). Additional examples of immunosuppressed 
patients have also been added to more fully capture those noted to be at risk according to the CDC’s 
definition. 
In addition to the above risk factors, other modifications to eligibility criteria have been made in 
phase 3 to ensure further that at-risk patients are included. Although serological testing for negative 
serostatus will not be required for study entry, patients who have a known history SARS-CoV-2 
infection prior to this study (demonstrated by a positive SARS-CoV-2 serology, antigen, molecular 
diagnostic test or other diagnostic assay other than the one used for eligibility into this study) will 
be excluded. Similarly, patients who report or have a known history of COVID-19 any time prior 
to the current episode of COVID-19 will be excluded.  
Inclusion of Patients Under 18 Years of Age 
Patients age 0 to <18 years with symptomatic COVID-19 and at least 1 risk factor for severe 
COVID-19 (defined in Section 7.2.1) will be included in the phase 3 portion of the study as a 
separate 
cohort 
to 
assess 
the 
safety, 
PK, 
immunogenicity, 
and 
efficacy 
of 
REGN10933+REGN10987.  
Most children with COVID-19 seem to experience mild disease that can be managed 
symptomatically in the outpatient setting. However, children with risk factors including underlying 
medical conditions such as obesity, diabetes, chronic lung disease, or immunosuppression might 
be at increased risk for severe COVID-19 (Kim, 2020) (Shekerdemian, 2020). Surveillance data 
reported to CDC through May 2020 indicated that the COVID-19-related hospitalization rate 
among children 0 to 9 years and 10 to 19 years old with underlying health conditions was 
approximately 6 times greater compared to children in the same age group with no reported 
underlying conditions (0 to 9 years, 22.3% versus 3.7%; 10 to 19 years, 14.9% versus 2.3%, 
respectively), and was similar to the hospitalization rate reported in adults, especially younger 
adults (eg, 20 to 29 years old), with and without underlying health conditions (17.5% versus 2.7%) 
(Stokes, 2020). Additionally, according to COVID-NET, a population-based surveillance for 
laboratory-confirmed COVID-19–associated hospitalizations in 99 counties in 14 states in the US, 
pediatric patients <12 years accounted for 58.2% of all hospitalized children and adolescents age 
12 to 17 years accounted for 42% of all hospitalized children reported to COVID-NET between 
1 Mar 2020 to 25 Jul 2020 (Kim, 2020). 
Based on the phase 2 data described above, high-risk pediatric patients with COVID-19 could 
benefit from the anti-viral activity of REGN10933+REGN10987 and the potential clinical benefit 
of reducing COVID-19-related MAVs.  
Since the rates of MAVs in pediatric patients with COVID-19 are unknown, these patients will be 
enrolled as a separate cohort and will not contribute to the primary efficacy endpoint. Instead, the 
primary objective for cohort 2 will be safety, with MAVs as a descriptive secondary objective.  
REGN10933+REGN10987 mAbs are directed against an exogenous antigen, administration of 
REGN10933+REGN10987 and thus is not anticipated to affect endogenous pathways. Therefore, 
the safety profile in children is expected to be similar to that observed in adults. Safety data is 
reviewed in a continuous manner by the sponsor (blinded data) and by the IDMC (unblinded data). 
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Inclusion of Pregnant Women 
Pregnant women are reported to be at an increased risk for severe COVID-19. Surveillance data 
reported to the CDC from January to June 2020 reported that pregnant women with COVID-19 
were more likely to be hospitalized compared to nonpregnant women (31.5% versus 5.8%, 
respectively) (Ellington, 2020). Data reported to CDC through September 2020 showed that 
compared with nonpregnant women, pregnant women were more frequently admitted to an ICU 
(10.5 versus 3.9 per 1,000 cases; adjusted risk ratio = 3.0; 95% CI = 2.6–3.4), received invasive 
ventilation (2.9 versus 1.1 per 1,000 cases; adjusted risk ratio = 2.9; 95% CI = 2.2–3.8) and 
received ECMO (0.7 versus 0.3 per 1,000 cases; adjusted risk ratio = 2.4; 95% CI = 1.5–4.0) 
(Zambrano, 2020). Partly based on these data, the CDC considers pregnancy among the risk factors 
that places patients “at increased risk” for severe COVID-19. These outcome data suggest pregnant 
women could benefit from the anti-viral activity of REGN10933+REGN10987 and potential 
clinical benefit of reducing COVID-19-related MAVs. As such, pregnant women will be included 
in the phase 3 portion of the trial. These patients will be included as a separate double-blinded 
cohort, randomized only to different dose levels of REGN10933+REGN10987 (see Section 8.5.1 
for details). The absence of a placebo arm will help to ensure that adequate descriptive safety 
information is collected for study drug in a population whose enrollment is anticipated to be 
relatively small and thus preclude hypothesis-driven analysis.  
As an added safety measure in phase 3, for newborn infants of patients who were treated in the 
study and were pregnant at randomization or became pregnant at any time in the study, the 
incidence and outcome of any SARS-CoV-2 infection in these infants will be collected during 
follow-up phone calls. This collection is in addition to standard collection of pregnancy outcome 
information (Section 10.1.3). 
Addition of Optional Immunoprofiling Sub-Study 
An optional sub-study will be conducted at specified sites in phase 3 cohort 1 (and cohort 3 patients 
≥18 years old) to explore the cellular and humoral immune response to SARS-CoV-2 infection. 
The intent of the sub-study is to explore the potential impact of treatment on the endogenous 
immune 
response 
to 
infection, 
as 
this 
is 
considered 
a 
theoretical 
risk 
for 
REGN10933+REGN10987 (Section 3.2.2.2). Refer to Section 9.2.13 for more information about 
this sub-study. 
Phase 3 Sample Size Adjustment 
In light of the modifications to the phase 3 primary endpoint, adjustments to the phase 3 sample 
size were necessary to ensure adequate power to evaluate the primary endpoint. Refer to 
Section 11.2 for more information on sample size justification. 
3.2.1.6. Assessment of Long COVID  
Long COVID encompasses a wide variety of heterogeneous neurological, neuropsychiatric, 
autonomic, and systemic symptoms, including fatigue, cognitive difficulties, mood dysregulation, 
dyspnea, coughing, palpitations, chest pain, fever, and joint or muscle pain) and can be debilitating 
(Alwan, 2020) (del Rio, 2020). However, the clusters of symptoms reported by patients post-
COVID-19 are not unique or specific to long COVID, and for most of the symptoms there are no 
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validated biomarkers for diagnosis of long COVID, with identification of long COVID largely 
constrained in medical practice to diagnostic exclusion (Burke, 2021).  
To address knowledge gaps in the etiology and symptomatology of long COVID, additional 
assessments will be conducted in patients in cohort 1. These assessments will evaluate patient-
reported symptoms and related outcomes, to develop a better understanding of the nature of long 
COVID and to assess whether prior treatment with REGN10933+REGN10987 during acute 
SARS-CoV-2 infection may impact subsequent symptoms and quality-of-life outcomes. In 
addition, blood samples will be collected for biomarker analysis and immunoprofiling, to gain a 
better understanding of the underlying biology of long COVID and the impact of prior treatment 
in the acute stage of disease. Nasopharyngeal (NP) swab samples will be collected to assess for 
the presence of SARS-CoV-2 during this later stage of analysis. 
Patient-Reported Symptoms. To better understand the patient experience of long COVID, 
patients will answer questions about their symptoms and how these symptoms impact their 
functioning and quality of life (Section 9.2.16.1). The analysis will largely focus on pre-defined 
groupings of symptoms identified across guidelines from the Centers for Disease Control (CDC), 
National Health Service (NHS), and the World Health Organization (WHO) (CDC, 2021) 
(NHS, 2021) (WHO, 2021). Symptoms will be analyzed according to whether they are considered 
lingering symptoms and identified across all three guidelines (category A), identified across all 
three guidelines (category B), or identified across at least two guidelines (category C) (Section 4.3 
and Table 10  
In addition to these areas of focus, a variety of concepts important to patients beyond symptoms 
will be evaluated, including functioning, impact on daily lives, and overall quality of life, in order 
to generate a broad depiction of long COVID in the study population. 
Blood sample collection. While the underlying biology of long COVID is unclear, potential 
mechanisms contributing to the pathophysiology of post-acute COVID-19 disease include virus-
specific pathophysiologic changes, immunologic aberrations and inflammatory damage in 
response to acute infection, and expected sequelae of post-critical illness (Nalbandian, 2021) 
(Talla, 2021). Based on these data, as well as reports of biomarkers and signatures observed in 
patients with long COVID (Nalbandian, 2021), an agnostic multiplex proteomic and 
transcriptomic profiling focused on the disease mechanism will be performed to gather additional 
insights in the sequelae of long COVID. The specific aims of this analysis are described in 
Section 9.2.16.2.  
3.2.2. 
Rationale for Dose Selection  
3.2.2.1. 
Phase 1 and Phase 2 Dose Selection 
Phase 1 and phase 2 will assess a single IV dose of REGN10933+REGN10987 as combination 
therapy administered in a 1:1 ratio. The 1:1 ratio for REGN10933+REGN10987 is thought to be 
appropriate as these are non-competing mAbs targeting non-overlapping epitopes of the RBD of 
the S protein of SARS-CoV-2, with similar in vitro binding and neutralization properties (for more 
information, refer to the Investigator’s Brochure). These study phases will evaluate the co-
administered REGN10933+REGN10987 as combination therapy at an initial dose level of 
2400 mg (1200 mg per mAb), which is expected to be an efficacious dose (see below). The study 
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phases will also evaluate REGN10933+REGN10987 at a higher dose, 8000 mg (4000 mg per 
mAb), in the event that a higher dose is required for efficacy. 
Cellular entry of coronaviruses depends on binding of the S protein to a specific cellular receptor 
and subsequent S protein priming by cellular proteases. ACE2 is the receptor for cellular entry of 
SARS-CoV-2 and its gene expression has been reported in the lungs, particularly in type-2 alveolar 
epithelial cells and bronchial airway epithelium (Xu, 2020). The strategy taken for dose selection 
in this study was to identify a target concentration in lung epithelial lining fluid (ELF) that 
approximates the effective concentration of 99% viral neutralization (EC99)* observed against live 
virus SARS-CoV-2 and to then identify a dose that will meet or exceed this concentration in lung 
ELF. The EC99 against SARS-CoV-2 is 0.14 µg/mL (REGN10933), 0.78 µg/mL (REGN10987), 
and 0.01 µg/mL (REGN10989). 
An average lung ELF-to-serum mean Cmax ratio of ~0.15 has been reported for other exogenous 
IgG1 mAbs for the treatment of Staphylococcus aureus lung infections (Magyarics, 2019). It is 
assumed that the lung ELF-to-serum Cmax ratio is 0.15 for REGN10933, REGN10987, and 
REGN10989. Dividing the target lung ELF concentration by this ratio, the associated serum 
concentration for these targets is therefore estimated to be ~at least 5 µg/mL for the combination 
of REGN10987+REGN10933, and ~0.1 µg/mL for REGN10989. 
Taking into account uncertainties regarding mAb penetration into lung ELF, prediction of human 
PK, and effects of disease on PK, 20 µg/mL was selected as a target concentration in serum for the 
initial dose of REGN10933+REGN10987 combination therapy. The goal for the initial 
REGN10933+REGN10987 combination dose is for ≥95% of patients to exceed the target serum 
concentration for 28 days after dosing, for each mAb. Based on healthy subject human PK data for 
six Regeneron mAbs directed against an exogenous target (N=6 to 12 subjects per mAb), a single 
IV combination dose of 1200 mg per mAb is predicted to result in ≥95% of patients exceeding the 
target serum concentration for 28 days after dosing, for each mAb. 
*Please note that the EC values discussed here are identical to the inhibitory concentration (IC) values discussed in 
the Investigator's Brochure(s). 
3.2.2.2. 
Phase 3 Dose Selection 
Adult Patients 
Note: A subset of patients in phase 3 were enrolled prior to the phase 3 adaptations implemented 
in protocol amendment 6 and received study drug doses selected for phase 1 and 2.  
Phase 3 will assess 2 dose levels of REGN10933+REGN10987, 1200 mg and 2400 mg, 
administered in a 1:1 ratio (600 mg and 1200 mg per mAb, respectively). The 1:1 ratio for 
REGN10933+REGN10987 is thought to be appropriate as these are noncompeting mAbs targeting 
non-overlapping epitopes of the RBD of the S protein of SARS-CoV-2, with similar in vitro 
binding and neutralization properties (for more information, refer to the Investigator’s Brochure). 
In the most recent analysis of phase 1 and 2 results in study R10933-10987-COV-2067, the 2400 
mg and 8000 mg doses of REGN10933+REGN10987 demonstrated similar virologic and clinical 
efficacy as assessed by medically attended visits (MAVs), and both doses had similar and 
acceptable safety profiles. Given the similarities between the 2400 mg and 8000 mg doses, the 
2400 mg dose will be studied in this phase 3 study as the highest dose, along with a lower dose of 
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1200 mg. Based on the observed linear PK for both mAbs, the 1200 mg dose is expected to provide 
50% of the REGN10933 and REGN10987 exposures of the 2400 mg dose. 
Subsequently, the 2400 mg dose arm was removed in protocol amendment 10 US based on a 
consistent efficacy and safety profile between the 2400 mg and 1200 mg doses, indicating the 
absence of a dose response. As cohort 1 enrollment had been closed on 14 May 2021, this change 
only impacts cohort 2 and cohort 3. 
Pediatric Patients  
Initial dose selection in the pediatric population (<18 years of age) utilized a body weight-tiered 
flat dose approach for both the higher and lower doses. For each weight-tiered dose targeting the 
higher dose in adults (2400 mg), the goal is to select doses that are predicted by population PK 
modeling to ensure that the lower fifth percentile of concentration in serum 28 days after dosing 
(C28) is similar to, or greater than, the observed lower fifth percentile of C28 in adults for the 
2400 mg dose. An additional consideration is to ensure that predicted Cmax and AUC0-28 for each 
weight-tiered dose do not exceed values previously achieved in adults. Both REGN10933 and 
REGN10987 have demonstrated linear PK, and as such, the same 50% reduction employed in 
selecting the lower adult dose in phase 3 (2400 mg to 1200 mg) was applied to each of the pediatric 
body weight-tiered flat doses targeting the 1200 mg adult dose (Table 2). 
To facilitate the predicted exposures in pediatric patients a 2-compartment population PK model 
with linear clearance developed for adults was used to simulate concentrations in serum over time 
for various doses in each pediatric weight group using allometrically scaled estimates of clearance 
and volume of distribution [gestational-age corrected allometrically scaled estimates were used for 
subjects <10 kg] (Robbie, 2012). For the pediatric doses in each weight group for the equivalent 
adult 2400 mg dose shown in Table 2, the predicted fifth percentile of C28 for all pediatric weight 
groups was greater than the observed fifth percentile of C28 for the adult 2400 mg dose; the 
predicted 50th percentile of C28 for all pediatric weight groups ranged from 1.0 to 1.3x and 1.3 to 
1.6x the observed 50th percentile of C28 for REGN10933 and REGN10987 for the adult 2400 mg 
dose, respectively. The predicted 95th percentiles of Cmax and AUC0-28 for each pediatric dose 
equivalent of the 2400 mg adult dose were below the observed 50th percentiles of Cmax and 
observed mean AUC0-28 values for both REGN10933 and REGN10987 for adults at 8000 mg, a 
dose shown to have an acceptable safety and tolerability profile. 
3.3. 
Risk-Benefit 
The anticipated risks and benefits of REGN10933+REGN10987 (casirivimab+imdevimab) are 
informed by pre-clinical and clinical data, including data from phase 3 trials.  
For additional information concerning clinical and pre-clinical data, refer to the Investigator’s 
Brochure. 
3.3.1. 
Summary of Efficacy and Safety Profile in Clinical Trials 
Clinical trial data are summarized below. Overall, REGN10933+REGN10987 have demonstrated 
efficacy as an anti-viral agent for the treatment and prevention of COVID-19, across a variety of 
populations, and is generally well-tolerated with an acceptable safety profile.  
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Clinical Benefit of REGN10933+REGN10987 in Clinical Trials for the Treatment of 
COVID-19. In COV-2067, the phase 3 outpatient treatment trial, a single intravenous dose of 
REGN10933+REGN10987 was shown (relative to placebo) to reduce COVID-19-related 
hospitalizations or all-cause death by 71.3% (2400 mg dose) and 70.4% (1200 mg dose), reduce 
symptom duration by 4 days (2400 mg and 1200 mg), and reduce viral load over the first 7 days. 
Serious adverse events occurred more frequently in the placebo group (4.0%) than in either 
treatment group (2400 mg, 1.1%; 1200 mg, 1.3%), and grade ≥2 infusion-related reactions were 
infrequent (<0.3% in all groups) (Weinreich, 2021b). Similar virologic efficacy and a similar 
safety profile were observed in the phase 1/2 portion of this trial, which evaluated 
REGN10933+REGN10987 at 8000 mg and 2400 mg IV doses (Weinreich, 2021a). 
Clinical Benefit of REGN10933+REGN10987 in Clinical Trials for the Prevention of 
COVID-19. In COV-2069, the phase 3 prevention trial in those at high risk of infection by a 
household contact, a single subcutaneous dose of REGN10933+REGN10987 (1200 mg) reduced 
(relative to placebo) symptomatic SARS-CoV-2 infection by 81.4%, and reduced overall SARS-
CoV-2 infection by 66.4%. Serious adverse events occurred at similar frequencies in the treatment 
group (1%) and placebo group (1%). Injection-site reactions were more common in the treatment 
group (4%) compared to the placebo group (2%), but no injection-site reactions in the study were 
grade 3 or above. The majority of injection site reactions occurred within one day and resolved 
within two days (O’Brien, 2021b).  
Among a sub-group of individuals in COV-2069 who were identified as SARS-CoV-2 positive 
but asymptomatic during screening, a single subcutaneous dose of casirivimab and imdevimab 
(1200 mg) reduced (relative to placebo) progression to symptomatic disease by 31.5%, and 
reduced the duration of symptoms in those that developed symptomatic infections. Injection-site 
reactions were more common in the treatment group (4%) compared to the placebo group (1%), 
but no injection-site reactions in the study were grade 3 or above (O’Brien, 2021a).  
In COV-2069, efficacy results were similar in adolescents (age 12 to <18) as observed in adults: 
0% of subjects in the 1200 mg SC treatment group experienced symptomatic infection, compared 
with 9.3% of subjects in the placebo group. Safety data in adolescent subjects were also similar to 
that observed in adults. Injection site reactions were more common in the treatment group (5.9%) 
compared to the placebo group (1.6%), but none were grade 3 or above in any group.  
In COV-2093, the adult volunteer study evaluating multiple doses of subcutaneous administration 
of REGN10933+REGN10987 (monthly dosing over 6 months), exploratory efficacy results 
showed benefit with chronic treatment for preventing COVID-19. This efficacy was balanced by 
an acceptable safety profile, where injection site reactions were more common in the treatment 
group (34.6%) compared with the placebo group (15.8%), but none were grade 3 or above in any 
group and all injection site reactions either self-limiting or manageable with over-the-counter 
medications. 
3.3.2. 
Summary of Risks 
Important Identified Risks. As with other protein therapeutics, hypersensitivity reactions, 
including acute infusion-related reactions (intravenous [IV] administration) or injection site 
reactions (subcutaneous [SC] administration), may develop immediately or within a few hours to 
days after study drug administration. Hypersensitivity reactions, including anaphylaxis, infusion-
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related reactions or injection site reactions, have been observed in patients who received 
REGN10933+REGN10987 during ongoing clinical trials. 
Important Potential Risks. The important potential risks of REGN10933+REGN10987 are the 
clinical consequences of immunogenicity and embryo-fetal toxicity. 
Protein therapeutics carry the potential risk of an immunogenic response in the form of ADA and 
NAb development following administration, with possible consequences on safety and efficacy. 
Therefore, blood samples for immunogenicity assessment will be collected during the studies.  
Reproductive and developmental toxicology studies have not been conducted; therefore, the 
effects of REGN10933, REGN10987, and REGN10933+REGN10987 combination therapy on the 
fetus and reproductive organs in males and females are unknown. Human immunoglobulin G1 
(IgG1) antibodies are known to cross the placental barrier and are present in breast milk; therefore, 
the REGN10933+REGN10987 combination therapy have the potential to be transferred from the 
mother to the developing fetus or a breastfed child. Given the high affinity and specificity of 
REGN10933 and REGN10987, off-target pharmacological effects are not anticipated in either the 
mother or the fetus, and no off-target binding of REGN10933 or REGN10987 was observed in 
any of the human or monkey tissues evaluated ex vivo in tissue cross-reactivity studies. However, 
it is unknown whether the potential transfer of the combination of REGN10933+REGN10987 
therapy provides any treatment benefit or risk to the developing fetus or a breastfed child. 
There is currently limited clinical experience in the use of REGN10933, REGN10987, and 
REGN10933+REGN10987 combination therapy in female patients who are pregnant or 
breastfeeding. The combination of REGN10933+REGN10987 therapy should be used during 
pregnancy or breastfeeding only if the potential benefit justifies the potential risk for the mother 
and the fetus or breastfed child considering all associated health factors. If a female patient is 
pregnant or were to become pregnant while receiving REGN10933+REGN10987 combination, 
the pregnancy should be followed until outcome and any safety issue observed get reported.  
Other 
Theoretical 
Considerations. 
Theoretical 
risks 
of 
administration 
of 
the 
REGN10933+REGN10987 combination include interference with the patient’s endogenous 
immune response to either SARS-CoV-2 infection or vaccination against COVID-19. In this study, 
risk mitigation includes exclusion criteria for certain vaccination scenarios (refer to Section 7.2.2). 
A reference to current CDC guidance is provided (Section 8.10.1) to aid investigators on 
appropriate management of COVID-19 vaccination. 
Antibody-dependent enhancement (ADE) has been observed for some therapeutics targeting 
exogenous viral proteins. For antibody therapies, ADE is thought to occur when binding of 
antibody to the target viral protein enhances Fc gamma receptor (FcγR)-mediated host cell entry 
of the virus (Iwasaki, 2020). This could potentially lead to worsening of disease and, in the case 
of SARS, acute lung injury (Liu, 2019). REGN10933 and REGN10987 retain the Fc region, as 
this may play a role in protecting against viral infection (Yasui, 2014), there is no strong evidence 
of ADE in other coronavirus models (Kam, 2007) (Liu, 2019) (Luo, 2018). To date, Fc-containing 
mAbs developed by the Sponsor for Ebola virus and MERS-CoV have demonstrated specificity to 
their exogenous targets with no significant unexpected safety findings in preclinical or clinical 
studies. All patients will have follow-up assessments by phone during the drug elimination period. 
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Pediatric Population. Emerging data suggest that the pediatric population is equally vulnerable 
to SARS-COV-2 infection, and may contribute significantly to viral transmission (Wang, 2016) 
(Weingartl, 2004). Moreover, neonatal transmission of SARS CoV-2 has also been reported, 
suggesting that the youngest of the pediatric population can also be at risk of infection 
(Lewis, 2020) (Szablewski, 2020). If infected, the burden of severe disease in pediatric patients 
that become symptomatic and develop COVID-19 seem to be greater in those with underlying 
medical conditions. REGN10933+REGN10987 was safe and well-tolerated in the adult population 
and no new safety signals were identified in the adolescent population (>12 years). As it is an 
exogenous target, the safety of REGN10933+REGN10987 is not anticipated to be different from 
that observed in the adult patients. Additionally, nonclinical toxicology studies have not shown 
any safety findings including no tissue cross-reactivity to human fetal tissues. These data therefore 
favor assessing the safety and efficacy of REGN10933+REGN10987 in pediatric patients (for 
more information on dose rationale for these patients, refer to Section 3.2.1.6). 
Summary. Overall, the anticipated benefit of REGN10933+REGN10987 combination therapy in 
treatment of infection with SARS-CoV-2 virus, along with the risk minimization measures in 
place, support continued clinical development of the product. 
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4. 
ENDPOINTS 
4.1. 
Primary Endpoints 
The definition of a COVID-19-related medically-attended visit is provided in Section 9.2.3.2. Note 
that a patient with multiple COVID-19 related MAVs will be counted as having one event. 
Phase 1 
The primary endpoints for phase 1 are:  
• Proportion of patients with treatment-emergent serious adverse events (SAEs) 
through day 29 
• Proportion of patients with infusion-related reactions (grade ≥2) through day 4 
• Proportion of patients with hypersensitivity reactions (grade ≥2) through day 29 
• Time-weighted average change from baseline in viral load (log10 copies/mL) from day 
1 to day 7, as measured by RT-qPCR in NP swab samples. 
Note: Time-weighted average of change from baseline viral load from day 1 to day 7 
will be calculated for each patient using the trapezoidal rule as the area under the 
curve for change from baseline at each time point divided by the time interval for the 
observation period. 
Phase 2 
The primary endpoint for phase 2 is time-weighted average change from baseline in viral load 
(log10 copies/mL) from day 1 to day 7, as measured by RT-qPCR in NP swab samples. 
Phase 3 
Cohort 1 
The primary endpoint for phase 3 is proportion of patients with ≥1 COVID-19-related 
hospitalization or all-cause death through day 29. 
Cohort 2  
The primary endpoints for phase 3 are: 
• Proportion of patients with treatment-emergent serious adverse events through day 29 
• Proportion of patients with infusion-related reactions (grade ≥2) through day 4 
• Proportion of patients with hypersensitivity reactions (grade ≥2) through day 29 
• Concentrations of REGN10933 and REGN10987 in serum over time 
Cohort 3 
The primary endpoints for phase 3 are: 
• Proportion of patients with treatment-emergent serious adverse events through day 29 
• Proportion of patients with infusion-related reactions (grade ≥2) through day 4 
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• Proportion of patients with hypersensitivity reactions (grade ≥2) through day 29 
4.2. 
Secondary Endpoints 
The definition of a COVID-19-related medically-attended visit is provided in Section 9.2.3.2. Note 
that a patient with multiple COVID-19 related MAVs will be counted as having one event. 
Phase 1 
Virologic  
• Time-weighted average change from baseline in viral load (log10 copies/mL) from day 
1 to day 22, as measured by RT-qPCR in saliva samples 
• Time-weighted average change from baseline in viral load (log10 copies/mL) from day 
1 to day 22, as measured by RT-qPCR in nasal swab samples 
• Time to negative RT-qPCR in all tested samples with no subsequent positive RT-qPCR 
in any tested samples (nasopharyngeal swabs, nasal swabs, saliva)  
• Change from baseline in viral load at each visit through day 29, as measured by RT-
qPCR in nasopharyngeal swabs 
• Change from baseline in viral load at each visit through day 29, as measured by RT-
qPCR in saliva samples 
• Change from baseline in viral load at each visit through day 29, as measured by RT-
qPCR in nasal swabs 
• Correlation and concordance of RT-qPCR results across different sample types (NP, 
nasal, and saliva)  
• Time-weighted average change from baseline in viral load (log10 copies/mL) from day 
1 to post-baseline study days (eg, day 5, 7, 15, and 29) 
Clinical  
• Proportion of patients with ≥1 COVID-19-related medically-attended visit through 
day 29 
• Proportion of patients with ≥2 COVID-19-related medically-attended visits through 
day 29 
• Total number of COVID-19-related medically-attended visits through day 29 
• Proportion of patients admitted to a hospital due to COVID-19 by day 29 
• Proportion of patients with ≥1 outpatient or telemedicine visit due to COVID-19 by 
day 29 
PK/ADA 
• Concentrations of REGN10933 and REGN10987 in serum and corresponding 
pharmacokinetics parameters 
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• Immunogenicity, as measured by anti-drug antibodies to REGN10933 and 
REGN10987  
Phase 2 
The secondary endpoints for phase 2 are: 
Virologic 
• Time to negative RT-qPCR in nasopharyngeal swabs with no subsequent positive RT-
qPCR  
• Change from baseline in viral load at each visit, as measured by RT-qPCR in 
nasopharyngeal samples 
• Time-weighted average change from baseline in viral load (log10 copies/mL) from day 
1 to post-baseline study days  
• Proportion of patients with high viral load (>104 copies/mL, >105 copies/mL, >106 
copies/mL, >107 copies/mL) at each visit 
• Proportion of patients with viral loads below the limit of detection at each visit 
• Proportion of patients with viral loads below the lower limit of quantitation at each visit 
Clinical 
• Proportion of patients with ≥1 COVID-19-related medically-attended visit through 
day 29 
• Proportion of patients with ≥2 COVID-19-related medically-attended visits through 
day 29 
• Total number of COVID-19-related medically-attended visits through day 29 
• Proportion of patients admitted to a hospital due to COVID-19 by day 29 
• Proportion of patients admitted to an intensive care unit due to COVID-19 by day 29 
• Proportion of patients with ≥1 outpatient or telemedicine visit due to COVID-19 by 
day 29 
• Proportion of patients requiring mechanical ventilation due to COVID-19 by day 29 
• Days of hospitalization due to COVID-19 
• Proportion of patients with all-cause mortality by day 29 
• Time to first onset of symptoms consistent with COVID-19 (asymptomatic cohort 
only) 
• Duration of symptoms consistent with COVID-19 
Safety 
• Proportion of patients with treatment-emergent serious adverse events through day 29 
• Proportion of patients with infusion-related reactions (grade ≥2) through day 4 
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• Proportion of patients with hypersensitivity reactions (grade ≥2) through day 29 
 
PK/ADA 
• Concentrations of REGN10933 and REGN10987 in serum  
• Immunogenicity, as measured by anti-drug antibodies and neutralizing antibodies to 
REGN10933 and REGN10987  
Phase 3 
Cohort 1  
The key secondary endpoints for phase 3 are: 
• Proportion of patients with ≥1 COVID-19-related hospitalization or all-cause death 
from day 4 through day 29 
• Time to COVID-19 symptoms resolution. 
Note: COVID-19 symptoms resolution is defined in Section 11.4.3.2. 
The other secondary endpoints for phase 3 are: 
Clinical 
• Proportion of patients with ≥1 COVID-19-related hospitalization, emergency room 
visit, or all-cause death through day 29 
• Proportion of patients with ≥1 COVID-19-related medically-attended visit or all-cause 
death through day 29 
• Proportion of patients with ≥1 COVID-19-related medically-attended visit by type of 
visit 
(hospitalization, 
emergency 
room, 
urgent 
care, 
and/or 
physician’s 
office/telemedicine) through day 29 
• Proportion of patients with ≥2 COVID-19-related medically-attended visits through 
day 29 
• Cumulative incidence of patients with ≥1 COVID-19-related hospitalization or all-
cause death through day 29 
• Cumulative incidence of patients with ≥1 COVID-19-related hospitalization, 
emergency room visit, or all-cause death through day 29 
• Cumulative incidence of patients with ≥1 COVID-19-related medically-attended visit 
or all-cause death through day 29 
• Days of hospitalization due to COVID-19 
• Proportion of patients admitted to an intensive care unit due to COVID-19 by day 29 
• Proportion of patients requiring supplemental oxygen due to COVID-19 by day 29 
• Proportion of patients requiring mechanical ventilation due to COVID-19 by day 29 
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• Total number of COVID-19-related medically-attended visits through day 29  
• Time to all-cause death 
• All-cause death by day 29, day 120, and day 169 
Virologic 
• Time-weighted average change from baseline in viral load (log10 copies/mL) from day 
1 to day 7, as measured by RT-qPCR in nasopharyngeal swab samples (patients 
enrolled prior to protocol amendment 6 only)  
• Change from baseline in viral load at each visit, as measured by RT-qPCR in 
nasopharyngeal swab samples 
Safety 
• Proportion of patients with treatment-emergent serious adverse events through day 29  
• Proportion of patients with infusion-related reactions (grade ≥2) through day 4  
• Proportion of patients with hypersensitivity reactions (grade ≥2) through day 29  
PK/ADA 
• Concentrations of REGN10933 and REGN10987 in serum  
• Immunogenicity, as measured by anti-drug antibodies and neutralizing antibodies to 
REGN10933 and REGN10987  
Cohort 2 
The secondary endpoints for phase 3 are: 
Clinical 
• Proportion of patients with ≥1 COVID-19-related hospitalization or all-cause death 
through day 29 
• Proportion of patients with ≥1 COVID-19-related hospitalization or all-cause death 
from day 4 through day 29 
• Proportion of patients with ≥1 COVID-19-related hospitalization, emergency room 
visit, or all-cause death through day 29 
• Proportion of patients with ≥1 COVID-19-related medically-attended visit or all-cause 
death through day 29 
• Proportion of patients with ≥1 COVID-19-related medically-attended visit by type of 
visit(s) (hospitalization, emergency room, urgent care, and/or physician’s 
office/telemedicine) through day 29 
• Proportion of patients with ≥2 COVID-19-related medically-attended visits through 
day 29 
• Cumulative incidence of patients with ≥1 COVID-19-related hospitalization or all-
cause death through day 29 
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• Cumulative incidence of patients with ≥1 COVID-19-related hospitalization, 
emergency room visit, or all-cause death through day 29 
• Cumulative incidence of patients with ≥1 COVID-19-related medically-attended visit 
or all-cause death through day 29 
• Days of hospitalization due to COVID-19 
• Proportion of patients admitted to an intensive care unit due to COVID-19 by day 29 
• Proportion of patients requiring supplemental oxygen due to COVID-19 by day 29 
• Proportion of patients requiring mechanical ventilation due to COVID-19 by day 29 
• Total number of COVID-19-related medically-attended visits through day 29 
• Time to all-cause death 
• All-cause death by day 29, day 120, and day 169 
Virologic 
• Time-weighted average change from baseline in viral load (log10 copies/mL) from 
day 1 to day 7, as measured by RT-qPCR in nasopharyngeal swab samples  
• Change from baseline in viral load at each visit, as measured by RT-qPCR in 
nasopharyngeal swab samples 
ADA 
• Immunogenicity, as measured by anti-drug antibodies and neutralizing antibodies to 
REGN10933 and REGN10987 
Cohort 3 
The secondary endpoints for phase 3 are: 
PK/ADA 
• Concentrations of REGN10933 and REGN10987 in serum over time 
• Immunogenicity, as measured by anti-drug antibodies and neutralizing antibodies to 
REGN10933 and REGN10987  
4.3. 
Exploratory Endpoints 
The exploratory endpoints for phase 1 and phase 2: 
• Change and percentage change in neutrophil-lymphocyte ratio (NLR) at each visit 
through day 29 
• Change and percentage change in D-dimer at each visit through day 29 
• Change and percentage change in ferritin at each visit through day 29 
• Change and percentage change in C-reactive protein (CRP) at each visit through day 29 
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• Change and percentage change in lactate dehydrogenase (LDH) at each visit through 
day 29  
• Change in SE-C19 item scores over time  
• Change in PGIS score over time 
• PGIC score at day 29 
Additional exploratory endpoints for phase 1 only: 
• Proportion of patients admitted to an intensive care unit due to COVID-19 by day 29 
• Proportion of patients requiring mechanical ventilation due to COVID-19 by day 29 
Phase 3 
The exploratory endpoints for phase 3 are: 
• Viral 
load over time in 
patients 
with 
and without COVID-19-related 
medically-attended visits 
• Change in WPAI+CIQ over time 
• Change in EQ-5D-5L over time 
• Time to COVID-19 symptoms resolution (cohort 2 ages ≥12 years) 
Note: COVID-19 symptoms resolution is defined in Section 11.4.3.2. 
The exploratory long COVID endpoints for phase 3 (cohort 1 only) are listed below.  
• Proportion of patients with ≥1 symptom from SE-LC19 Category A by day 169  
• Proportion of patients with ≥1 symptom from SE-LC19 Category B by day 169  
• Proportion of patients with ≥1 symptom from SE-LC19 Category C by day 169  
• Proportion of patients with ≥2 symptoms from SE-LC19 Category A by day 169  
• Proportion of patients with ≥2 symptoms from SE-LC19 Category B by day 169  
• Proportion of patients with ≥2 symptoms from SE-LC19 Category C by day 169 
Note: SE-LC19 symptom categories are provided in Table 10. 
• Change from baseline in viral load through day 29, and at day 120 and day 169, as 
measured by RT-qPCR in nasopharyngeal swab samples 
• Proportion of patients with positive SARS-CoV-2 test results after randomization 
through day 169 
Additional analyses related to psychometric validation of the SE-LC19 as well as potential 
biomarkers predicting long COVID will be outlined in separate SAP(s). 
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5. 
STUDY VARIABLES  
This section outlines variables to be measured in the study. For description and rationale of 
corresponding study procedures, refer to Section 9.2. For a full listing of variables, refer to the 
corresponding statistical analysis plans. 
5.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, weight, height, etc), 
disease characteristics, medical history, risk factors for severe COVID-19, and medication history 
for each patient. 
5.2. 
Efficacy Variables 
Efficacy variables include viral load (log10 copies/mL), number of patients with a COVID-19-
related medically-attended visit, number of patients admitted to a hospital, ICU, or outpatient 
telemedicine visit, and number of patients requiring mechanical ventilation.  
5.3. 
Safety Variables 
Safety variables include incidence of targeted TEAEs as described in Section 10.1.1.  
5.4. 
Pharmacokinetic Variables 
For phase 1, the PK variables are the concentration of REGN10933 and REGN10987 in serum and 
time and select PK parameters. For phase 2 and phase 3, the variables are the concentration of 
REGN10933 and REGN10987 in serum and time. Samples will be collected at the visits specified 
in the relevant schedule of events. 
5.5. 
Immunogenicity Variables 
The immunogenicity variables are ADA status, titer, NAb positivity (yes/no), and time point/visit. 
Samples will be collected at the visits specified in the relevant schedule of events.  
5.6. 
Pharmacodynamic and Other Biomarker Variables 
Exploratory endpoint variables may include, but not be limited to, parameters reported in complete 
blood counts with differential, levels of D-dimer, ferritin, CRP, LDH, cardiac biomarkers, per-
symptom SE-C19 score, PGIS score, PGIC score, and other parameters related to long COVID 
questionnaires.  
These results may be reported outside of the clinical study report (CSR). 
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6. 
STUDY DESIGN  
6.1. 
Study Description and Duration 
This is an adaptive, phase 1/2/3, randomized, double-blinded, placebo-controlled master protocol 
to evaluate the efficacy, safety, and tolerability of REGN10933+REGN10987 combination therapy 
in ambulatory patients (ie, outpatients) with COVID-19, including (in phase 2) asymptomatic 
patients with SARS-CoV-2 infection. The study will be conducted in approximately 120 sites, in 
the US and other countries. To be eligible, patients must have laboratory-confirmed SARS-CoV-
2 but must not have been previously hospitalized for COVID-19 or currently hospitalized for any 
reason. In phase 1, only patients with COVID-19 symptoms will be enrolled. In phase 2, 
symptomatic patients and asymptomatic patients will be enrolled into separate cohorts. In phase 3, 
symptomatic patients who are ≥18 years old and <18 years old, and not pregnant at randomization, 
will be enrolled in two separate cohorts. Patients who are pregnant at randomization, regardless of 
age, will be enrolled in a third cohort (refer to Section 7.2 for study inclusion and exclusion 
criteria). 
The schedules of events can be found in Section 9.1. Study design figures are provided in 
Section 6.1.4. Additional information on study procedures can be found in Section 9.2. 
6.1.1. 
Phase 1 
Note: As of protocol amendment 6, phase 1 has been completed and is closed. 
On day 1, eligible patients will be randomized to a single intravenous (IV) administration of 
REGN10933+REGN10987 (2400 mg), REGN10933+REGN10987 (8000 mg), or placebo. 
Patients will also have NP swab, nasal swab, and saliva samples taken and have blood drawn for 
safety, PK, ADA, and exploratory analyses.  
Patients in the phase 1 sentinel safety group (Section 3.2.1.1) will be sequestered for the first 
48 hours after dosing, during which time they will be closely monitored for TEAEs (grade 3 or 4), 
treatment-emergent SAEs, and treatment-emergent AESIs (Section 10). This sequester period is 
mandatory. These patients will then have the option to leave their sequester on day 3 (if medically 
appropriate) after completing day 3 assessments. Alternatively, patients may choose to remain 
sequestered for any additional period of time up to day 7. After completing assessments on day 7, 
all patients who are still sequestered will be sent home, if medically appropriate. 
Patients who are not in the sentinel safety group will not have a mandatory sequestering period. 
However, they will have the option to be sequestered for any period of time up to day 7. After 
completing assessments on day 7, all patients who are still sequestered will be sent home, if 
medically appropriate. 
Since patients will be sequestered and/or home for the duration of the study, assessments and 
sample collections may occur through a variety of in-person and remote methods. This may include 
(but is not limited to) visits at the study site or place of infusion, visits at the place of sequester, 
home-based visits (defined as visits by home health staff, at mobile units, and/or testing centers), 
or by phone/telemedicine. Throughout the study, biological samples will be obtained by study 
personnel only at study locations where appropriate personal protective equipment (PPE) can be 
used. 
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NP swabs, nasal swabs, and saliva samples will be collected every other day for the first 2 weeks 
and then approximately twice weekly thereafter. Patients will also have blood drawn during a 
subset of these visits.  
Information regarding SAEs, AESIs, and medically-attended related due to COVID-19 will be 
recorded during weekly telemedicine and/or phone visits, and patients will be asked to notify study 
personnel as soon as possible about any medically-attended visits. Throughout the study, patients 
will also provide daily self-reported information about COVID-19 symptoms through an electronic 
survey. 
The study will end on day 29, when patients will have final assessments including NP swab, nasal 
swab, and saliva sample collections and blood draws for PK, ADA, and exploratory analyses. 
6.1.2. 
Phase 2 
Note: As of protocol amendment 6, phase 2 has been completed and is closed. 
Phase 2 will initiate following IDMC clearance of a pooled phase 1 sentinel safety group across 2 
studies (R10933-10987-COV-2066 and R10933-10987-COV-2067), and after initiation will enroll 
concurrently with phase 1. Once phase 2 is active, phase 1 will continue to enroll to completion, 
but phase 2 enrollment does not require the completion of phase 1 enrollment (for complete 
description and rationale for this process, refer to Section 3.2.1).  
On day 1, eligible patients will be randomized 1:1:1 to a single dose of REGN10933+REGN10987 
(2400 mg), REGN10933+REGN10987 (8000 mg), or placebo. Patients will also have NP swabs 
taken and blood drawn for safety, PK, ADA, and exploratory analyses.  
Patients will not be sequestered during phase 2. After infusion of study drug, patients will be 
observed for 2 hours and, if no SAEs or AESIs are observed, will be sent home (if medically 
appropriate).  
Since patients will be at home, subsequent assessments and sample collections will potentially 
occur through a variety of in-person and remote methods as described in phase 1. NP swabs will 
be collected every other day for the first 2 weeks and then approximately twice weekly thereafter. 
Blood samples will also be collected periodically. 
Information regarding treatment-emergent SAEs, treatment-emergent AESIs, and medically-
attended visits related to COVID-19 will be recorded during weekly telemedicine and/or phone 
visits, and patients will be asked to notify study personnel as soon as possible about any medically-
attended visits. Throughout the study, patients will also provide daily self-reported information 
about COVID-19 symptoms through an electronic survey. 
On day 29, patients will have final assessments including NP swab collection and blood draws for 
PK, ADA, and exploratory analysis.  
All patients in phase 2, regardless of cohort, will follow the same schedule of events.  
6.1.3. 
Phase 3  
In phase 3, eligible patients in cohort 1 and cohort 2 were initially randomized 1:1:1 to a single 
dose of placebo or one of two dose levels of REGN10933+REGN10987. In cohort 1, 
REGN10933+REGN10987 dose levels consisted of 1200 mg and 2400 mg. In cohort 2, body-
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weight equivalents of these two dose levels were used. Patients in cohort 3 were initially 
randomized 1:1 to one of two dose levels of REGN10933+REGN10987 (ie, no randomization to 
placebo), at 1200 mg and 2400 mg or body-weight equivalents as applicable.  
Note that as of 25 February 2021 (per IDMC recommendation and subsequently formalized in 
protocol amendment 8), patients are no longer randomized to placebo (Section 8.5.1). On 14 May 
2021, enrollment in cohort 1 was closed. As of protocol amendment 10 US, the 2400 mg dose 
level was dropped in Cohort 2 and Cohort 3, such that Cohort 2 and Cohort 3 patients are only 
assigned to the 1200 mg dose level (or body-weight equivalent for those under 18 years of age). 
On the day of dosing, patients will have NP swabs taken for SARS-CoV-2 RT-qPCR testing and 
blood drawn for safety, drug concentration, immunogenicity, and exploratory analyses. After 
infusion, patients will be monitored for at least 1 hour and released from the study site, if medically 
appropriate. Patients <12 years of age will be monitored for at least 2 hours after infusion, with 
more frequent vital sign assessments (refer to schedules of events for more information). 
Targeted safety information (Section 10.1.1) and COVID-19-related medically-attended visit 
details (Section 9.2.3.2) will be collected on an ongoing basis; minimally, patients (or their 
caregivers) will be queried during weekly phone visits through the first 29 days of the study. For 
patients <12 years of age, a phone call will be made within 6 to 8 hours after completing the 
infusion to collect targeted safety information; these patients (or their caregivers) should be 
instructed to contact the site within 24 hours post-infusion if they experience any side effects. 
Patients (or their caregivers) will also be asked to notify study personnel as soon as possible about 
any unplanned medically-attended visits that occur during the study.  
Assessments and sample collections may potentially occur through a variety of in-person and 
remote methods. This may include (but is not limited to) visits at the study site or place of infusion, 
home-based visits (defined as visits by home health staff, at mobile units, and/or testing centers), 
or by phone/telemedicine. Throughout the study, biological samples will be obtained by study 
personnel only at study locations where appropriate PPE can be used. 
Patients enrolled in cohort 1 will follow the schedule events in Table 5. These patients will have 
NP swabs and blood samples collected approximately every week through day 29 and will provide 
self-reported information about COVID-19 symptoms through electronic surveys (both daily and 
weekly). A subset of patients in cohort 1 will be enrolled in a PK sub-study (Section 9.2.8). Patients 
in cohort 1 may also be enrolled in an optional immunoprofiling sub-study (Section 9.2.13) 
assessing the potential impact of REGN10933+REGN10987 on the endogenous immune response 
to SARS-CoV-2. 
Patients enrolled in cohort 2 will follow the schedule events in Table 8. These patients will also 
have NP swabs and blood samples collected approximately every week through day 29, with an 
NP swab additionally collected on day 3. To reduce overall patient burden of blood sampling in 
this younger cohort, the frequency of blood sample collection and the total amount of blood 
collected per visit will vary according to body weight. In addition, patients in this cohort will be 
randomly assigned to one of four staggered PK-ADA sampling schedules. This will be done 
according to a central randomization scheme using an interactive web response system (IWRS). 
Patients enrolled in cohort 3 who are ≥18 years of age will follow the schedule of events in Table 7; 
those <18 will follow the schedule of events in Table 8 . 
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After the final in-person visit, all cohorts will have 2 follow-up phone calls to collect safety 
information, including (when applicable) additional information regarding pregnancy outcome 
(Section 9.2.5).  
6.1.3.1. 
Enrollment of Phase 3 Participants Prior to Phase 3 Adaptations 
Note that a subset of patients in phase 3 were enrolled prior to the phase 3 adaptations implemented 
in protocol amendment 6. Patients enrolled prior to protocol amendment 6 followed the schedule 
of events in Table 4, which included a more intensive regimen of NP swab sample collection. 
These patients will be re-consented and will follow the phase 3 schedule of events in Table 5 
beginning at the point at which they re-consent. Data from these patients may be subject to 
modified and/or additional analyses, contingent upon sample collection frequency, eligibility with 
inclusion/exclusion criteria adaptation, and other parameters. Additional information will be 
provided in the statistical analysis plan.  
6.1.3.2. 
Evaluation of Long COVID in Phase 3 
As part of protocol amendment 9 US, an additional series of assessments and sample collections 
will be performed in cohort 1 to better understand the biology of long COVID and the potential 
impact of prior REGN10933+REGN10987 treatment (during the acute phase of SARS-CoV-2 
infection) on the development of long COVID symptoms. These analyses will be exploratory in 
nature (Section 11.4.3.3). 
Patients in phase 3 cohort 1 will follow the prior phase 3 Schedule of Events (Table 5) until day 
90. They will then follow the long COVID Schedule of Events (Table 6) until day 169. Patients 
who reconsent after day 90 will enter the long COVID Schedule of Events on the corresponding 
day on which they provide consent. 
Patients in cohort 1 will complete a series of health-related questionnaires, including the SE-LC19 
developed by the Sponsor. These self-report questionnaires will be conducted on a daily basis in 
the week leading up to the day 120 visit, and in the week leading up to the day 169 visit (Table 6 
and Figure 4). On day 120 and day 169, patients will complete several additional questionnaires, 
will have an NP swab sample collected for analysis of SARS-CoV-2 virology, and will have blood 
samples collected for research purposes related to long COVID.  
In addition to these procedures, previously described assessments (separate from the long COVID 
portion of the study) will be performed at day 120 and day 169 safety assessments, and (for those 
who were enrolled in the PK sub-study) an additional blood draw will be collected at day 120 for 
analysis of drug concentration and immunogenicity. These assessments are separate from the long 
COVID portion of the study. 
Additional information concerning the procedures to be performed is provided in Section 9.2.16. 
Rationale for the study is provided in Section 3.2.1.6 .  
6.1.3.3. 
Sharing of Data Across Studies 
For patients in this study who are also index cases of household contacts in the R10933-10987-
COV-2069 prophylaxis study, data may be used from R10933-10987-COV-2067 as part of 
R10933-10987-COV-2069 analyses. The data may include treatment arm allocation, virologic and 
serologic data and treatment outcomes. This will facilitate, in R10933-10987-COV-2069, 
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assessing the potential impact of REGN10933+REGN10987 treatment of index cases on infection 
rates in household contacts. 
6.1.4. 
Study Design Figures 
Figure 2: 
Study Flow Diagram, Phase 1 
 
 
Figure 3: 
Study Flow Diagram, Phase 2 (and Phase 3 Prior to Amendment 6) 
 
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Figure 4: 
Study Flow Diagram, Phase 3 (Cohort 1) 
 
 
Figure 5: 
Study Flow Diagram, Phase 3 (Cohort 2 Patients; Cohort 3 Patients 
<18 Years) Prior to Amendment 10 US 
 
 
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Figure 6: 
Study Flow Diagram, Phase 3 (Cohort 3 Patients ≥18 Years) Prior to 
Amendment 10 US 
 
 
 
 
Figure 7: 
Study Flow Diagram, Phase 3 (Cohort 2 Patients; Cohort 3 Patients 
<18 Years) Amendment 10 US and Later 
 
 
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Figure 8: 
Study Flow Diagram, Phase 3 (Cohort 3 Patients ≥18 Years) Amendment 10 
US and Later 
 
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6.1.5. 
Study Stopping Rules 
6.1.5.1. 
Individual Patient Stopping Rules 
For an individual patient, the infusion rate can be slowed, interrupted, or stopped if there is a 
suspected drug-related event during the infusion suggestive of severe hypersensitivity or an 
infusion-related reaction, as per investigator discretion if it is deemed to be in the patient’s best 
interest (see Section 8.5). As this is a single dose study, there are no other study drug 
discontinuation rules. 
Patient stopping rules from the study include withdrawal of consent.  
6.1.5.2. 
Study Stopping Criteria 
The Sponsor may decide to stop or make adaptations to the study based upon the recommendations 
by an IDMC recommendations and/or review of the totality of evidence (see Section 6.2.1). 
A treatment arm may be dropped if there is a clinically meaningful imbalance between treatment 
arms in both of the following criteria:  
• Incidence of treatment-emergent SAEs evaluated as related to study treatment  
and 
• A risk-benefit imbalance based upon any key efficacy and safety endpoint of the study 
such that one dosing arm appears to be doing substantially better than another without 
requiring any specific statistical level of precision 
6.1.6. 
End of Study Definition 
The end of study is defined as the date when the last living patient completes the last study visit, 
withdraws from the study, or is lost to follow-up (ie, the study patient can no longer be contacted 
by the investigator).  
6.2. 
Study Committees  
6.2.1. 
Independent Data Monitoring Committee 
An IDMC will actively review data throughout the study to monitor patient safety and efficacy 
data. The IDMC can make recommendations about early study closure or changes to the study 
conduct. The operation of the IDMC is governed by a charter describing further details, such as 
procedures (including but not limited to periodic safety monitoring) and requirements for reporting 
its observations to the Sponsor. 
An IDMC will review pooled safety data through day 3 in the sentinel safety group as described 
in Section 3.2.1. In addition, the IDMC will conduct periodic data reviews, for instance, after all 
patients are enrolled into phase 1. Additional periodic reviews will be conducted during phase 2 
and 3 of this study as detailed in the IDMC charter. These data reviews will include all available 
efficacy and safety data, including deaths, from all enrolled study participants up to the data cut 
point for the analysis. The IDMC will meet regularly throughout the course of the study to review 
safety data and make recommendations on study conduct. 
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6.2.2. 
Sponsor Review Committee 
Periodic data reviews may be performed by selected unblinded senior Sponsor physicians and a 
statistician with no direct involvement in the study. Reviews will assess the totality of evidence 
and may be used to determine study adaptations (see Section 3.2.1.2). 
6.3. 
Planned Interim Analysis  
A description of the statistical methods to be employed is provided in Section 11.5, and blinding 
implications are discussed in Section 8.7. 
Initial Phase 1/2 
An interim descriptive analysis of first 275 symptomatic randomized patients was planned.  
Phase 3 
An interim analysis may be performed in phase 3. Refer to Section 11.4.4 and Section 11.5 for 
details regarding this analysis.  
6.4. 
Periodic Data Reviews 
Periodic reviews may be performed during phase 1 and phase 2 by selected unblinded senior 
Sponsor physicians and a statistician with no direct involvement in the study. Reviews will assess 
the totality of evidence and in phase 2 may be used to determine study adaptations (eg, whether to 
drop a dose arm).  
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7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
7.1. 
Number of Patients Planned 
Phase 1 will continue to enroll until approximately 100 patients are randomized. Phase 2 will 
continue to enroll until approximately 1300 patients are randomized.  
It is estimated that up to approximately 8500 patients will be required for phase 3 cohort 1. For 
cohort 2, it is estimated that up to approximately 180 patients will be required. This will include 
minimum enrollment according to weight categories (refer to Section 8.6). 
For information on the initial timing of enrollment for phase 1 and phase 2, refer to Section 3.2.1. 
For treatment allocation and randomization, refer to Section 8.6. Additional information on sample 
size can be found in Section 11.2. 
7.2. 
Study Population  
This study will enroll non-hospitalized patients who have a positive diagnostic test for SARS-
CoV-2. 
7.2.1. 
Inclusion Criteria  
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Meets 1 of the following 3 criteria: 
a. Cohort 1: ≥18 years of age and not pregnant at randomization  
b. Cohort 2: <18 years of age and not pregnant at randomization 
c. Cohort 3: Pregnant at randomization 
Note: Cohort 2 and cohort 3 will only be enrolled where permitted by local 
requirements. Enrollment in cohort 1 was closed on 14 May 2021. 
2. Has SARS-CoV-2-positive diagnostic test from a sample collected ≤72 hours prior to 
randomization, using a validated SARS-CoV-2 antigen, RT-PCR, or other molecular 
diagnostic assay and an appropriate sample such as nasopharyngeal [NP], nasal, 
oropharyngeal [OP], or saliva 
Note: Historical record of positive result is acceptable, as long as the sample was collected 
≤72 hours prior to randomization. 
3. [Criterion removed] 
4. Has symptoms consistent with COVID-19, as determined by the investigator, with onset 
≤7 days before randomization  
5. Maintains O2 saturation ≥93% on room air 
6. Is willing and able to provide informed consent as below:  
a. If at or above country’s legal age of adulthood, signed by study patient or legally 
authorized representative  
b. If below country’s legal age of adulthood, signed by parent(s) or legal guardian(s).  
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Age-appropriate assent will be collected from the study patient according to local 
regulatory (competent authority/ethics) guidelines 
7. Is willing and able to comply with study procedures  
8. Is able to understand and complete study-related questionnaires (patients aged ≥12 years 
only) 
9. Cohort 1 and Cohort 2 only: has ≥1 risk factor for severe COVID-19 
Risk factors are defined as follows: 
a. Age ≥50 years (cohort 1 only) 
b. Obesity, defined as: 
BMI ≥30 kg/m2 (cohort 1 only) 
BMI (kg/m2) ≥95th percentile for age and sex based on CDC growth charts (cohort 2 
≥2 years only) 
c. Cardiovascular disease, including hypertension 
d. Chronic lung disease, including asthma 
e. Type 1 or type 2 diabetes mellitus 
f. Chronic kidney disease, including those on dialysis 
g. Chronic liver disease 
h. [Risk factor removed] 
i. Immunosuppressed, based on investigator’s assessment  
Examples include cancer treatment, bone marrow or organ transplantation, immune 
deficiencies, HIV (if poorly controlled or evidence of AIDS), sickle cell anemia, 
thalassemia, and prolonged use of immune-weakening medications 
j. Any underlying genetic condition, neurologic condition, metabolic condition, or 
congenital heart disease deemed by the investigator to be a risk factor for severe 
COVID-19 (cohort 2 only) 
7.2.2. 
Exclusion Criteria  
A patient who meets any of the following criteria will be excluded from the study: 
1. Was admitted to a hospital for COVID-19 prior to randomization, or is hospitalized 
(inpatient) for any reason at randomization 
2. Has participated, or is participating, in a clinical research study evaluating COVID-19 
convalescent plasma, mAbs against SARS-CoV-2 (eg, bamlanivimab), or intravenous 
immunoglobulin (IVIG) within 3 months or within 5 half-lives of the investigational 
product (whichever is longer) prior to the screening visit 
3. Prior, current, or planned future use of any of the following treatments: COVID-19 
convalescent plasma, mAbs against SARS-CoV-2 (eg, bamlanivimab), IVIG (any 
indication), systemic corticosteroids (any indication), or COVID-19 treatments 
(authorized, approved, or investigational) 
Note: Prior use is defined as the past 30 days or within 5 half-lives of the investigational 
product (whichever is longer) from screening  
4. [Criterion consolidated with criterion #3] 
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5. [Criterion removed] 
6. Has known allergy or hypersensitivity to components of study drug 
7. Has been discharged, or is planned to be discharged, to a quarantine center  
8. [Criterion removed] 
9. [Criterion removed] 
10. Has a known positive SARS-CoV-2 serologic test  
11. Has a positive SARS-CoV-2 antigen or molecular diagnostic test from a sample collected 
>72 hours prior to randomization  
12. Has known active infection with influenza or other non-SARS-CoV-2 respiratory 
pathogen, confirmed by a diagnostic test 
13. Prior use (prior to randomization), current use (at randomization), or planned use (within 
90 days of study drug administration or per current CDC recommendations, as applicable) 
of any authorized or approved vaccine for COVID-19 
14. Has participated, is participating, or plans to participate in a clinical research study 
evaluating any authorized, approved, or investigational vaccine for COVID-19 
15. Is a member of the clinical site study team or their immediate family member 
7.3. 
Premature Withdrawal from the Study  
A patient has the right to withdraw from the study at any time, for any reason, and without 
repercussion. 
The investigator and/or Sponsor have the right to withdraw a patient from the study if it is no 
longer in the interest of the patient to continue in the study, or if the patient’s continuation in the 
study places the scientific outcome of the study at risk (eg, if a patient does not or cannot follow 
study procedures). An excessive rate of withdrawals would render the study uninterpretable; 
therefore, unnecessary withdrawal of patients should be avoided. 
Patient who are withdrawn prematurely from the study will be asked to complete an early 
termination visit and follow up contact, as described in Section 1. 
7.4. 
Replacement of Patients 
In phase 1, patients who have missing or negative baseline virologic sample(s) or are missing ≥1 
follow-up virologic sample(s) may be replaced. Patients prematurely discontinued from the study 
will not be replaced.  
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8. 
STUDY TREATMENTS  
8.1. 
Investigational and Reference Treatments 
Instructions on dose preparation are provided in the pharmacy manual. See Section 8.6 for dose 
levels and method of treatment allocation for each phase of the study.  
• Co-administered REGN10933+REGN10987 combination therapy 
• Placebo IV single dose 
8.2. 
Background Treatment 
No background treatment will be allowed. Patients may self-administer non-prescribed 
medications (eg, antipyretics). 
8.3. 
Rescue Treatment(s) 
Patients can receive rescue therapy for COVID-19 per local standard-of-care. Rescue treatment(s) 
will not be provided as part of the study. 
8.4. 
Dose Modification and Study Treatment Discontinuation Rules 
8.4.1. 
Dose Modification 
This is a single dose study; dose modification is not allowed. 
8.4.2. 
Study Drug Discontinuation 
This is a single dose study; study drug discontinuation is not applicable.  
8.5. 
Management of Acute Reactions  
8.5.1. 
Infusion-Related Reactions and Hypersensitivity Reactions 
Emergency equipment and medication for the treatment of infusion reactions must be available for 
immediate use if required for treatment. All grade ≥2 infusion-related reactions and grade ≥2 
hypersensitivity reactions (using the CTCAE severity scale specified in Section 10.2.5) must be 
reported as AESIs (see Section 10.2.3).  
8.5.1.1. 
Interruption of the Intravenous Infusion 
The infusion should be interrupted if any of the following AEs are observed: 
• Sustained/severe cough 
• Rigors/chills 
• Rash, pruritus (itching) 
• Urticaria (hives, welts, wheals) 
• Diaphoresis (sweating) 
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• Hypotension 
• Dyspnea (shortness of breath) 
• Vomiting 
• Flushing 
The reaction(s) should be treated symptomatically, and the infusion may be restarted at 50% of the 
original rate. 
If investigators feel there is a medical need for treatment or discontinuation of the infusion other 
than described above, they should use clinical judgment to provide the appropriate response 
according to typical clinical practice. 
8.5.1.2. 
Termination of the Intravenous Infusion 
The infusion should be terminated and not restarted if any of the following AEs occur: 
• Anaphylaxis* 
• Laryngeal/pharyngeal edema 
• Severe bronchospasm 
• Chest pain 
• Seizure 
• Severe hypotension 
• Other neurological symptoms (confusion, loss of consciousness, paresthesia, paralysis, 
etc) 
• Any other symptom or sign that, in the opinion of the investigator, warrants termination 
of the IV infusion 
*Consider anaphylaxis if the following is observed (Sampson, 2006): acute onset of an illness 
(minutes to several hours) with involvement of the skin, mucosal tissue, or both (eg, generalized 
hives, pruritus or ﬂushing, swollen lips-tongue-uvula) and at least one of the following: 
• Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow, hypoxemia) 
• Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia 
[collapse], syncope, incontinence) 
8.6. 
Method of Treatment Assignment  
Patients will be randomized according to a central randomization scheme using an interactive web 
response system (IWRS).  
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Phase 1 
Patients will be randomized in a 1:1:1 allocation ratio to one of the following:  
• Co-administered REGN10933+REGN10987 combination therapy, 2400 mg (1200 mg 
each of REGN10933 and REGN10987) IV single dose  
• Co-administered REGN10933+REGN10987 combination therapy, 8000 mg (4000 mg 
each of REGN10933 and REGN10987) IV single dose  
• Placebo IV single dose 
In phase 1, randomization will not be stratified.  
Phase 2 (and Phase 3 Prior to Protocol Amendment 6) 
Patients will be randomized in a 1:1:1 allocation ratio to one of the treatments listed below:  
• Co-administered REGN10933+REGN10987 combination therapy, 2400 mg (1200 mg 
each of REGN10933 and REGN10987) IV single dose  
• Co-administered REGN10933+REGN10987 combination therapy, 8000 mg (4000 mg 
each of REGN10933 and REGN10987) IV single dose  
• Placebo IV single dose 
In phase 2, randomization will be stratified by: 
• Presence/absence of COVID-19 symptoms (ie, symptomatic versus asymptomatic 
cohort) 
• Country 
• Risk factors for hospitalization due to COVID-19 (no risk factors for hospitalization 
due to COVID 19 versus ≥1 risk factor for hospitalization due to COVID-19) 
The following are considered risk factors for the purposes of stratification (for rationale, refer to 
Section 3.2.1.5): 
• Age >50 years 
• Obesity, defined as BMI >30 
• Cardiovascular disease, including hypertension 
• Chronic lung disease, including asthma 
• Chronic metabolic disease, including diabetes 
• Chronic kidney disease, including those on dialysis 
• Chronic liver disease 
• Immunosuppressed, based on investigator’s assessment (examples include: cancer 
treatment, bone marrow or organ transplantation, immune deficiencies, poorly-
controlled HIV or AIDS, and prolonged use of immune-weakening medications) 
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Phase 3 
Cohort 1 (Prior to 25 February 2021) 
Patients in cohort 1 who are enrolled into phase 3 under protocol amendment 6 or 7 will be 
randomized in a 1:1:1 allocation ratio to one of the treatments listed below:  
• Co-administered REGN10933+REGN10987 combination therapy, 1200 mg (600 mg 
each of REGN10933 and REGN10987) IV single dose  
• Co-administered REGN10933+REGN10987 combination therapy, 2400 mg (1200 mg 
each of REGN10933 and REGN10987) IV single dose  
• Placebo IV single dose 
In phase 3 cohort 1, Randomization will be stratified by country. 
Cohort 1 (25 February 2021 and Later)* 
Patients in cohort 1 who are enrolled into phase 3 under protocol amendment 8 or later will be 
randomized in a 1:1 allocation ratio to one of the treatments listed below:  
• Co-administered REGN10933+REGN10987 combination therapy, 1200 mg (600 mg 
each of REGN10933 and REGN10987) IV single dose  
• Co-administered REGN10933+REGN10987 combination therapy, 2400 mg (1200 mg 
each of REGN10933 and REGN10987) IV single dose  
In phase 3 cohort 1, randomization will be stratified by country. 
Cohort 2 (Prior to 25 February 2021) 
Patients in cohort 2 will be randomized in a 1:1:1 allocation ratio to co-administered 
REGN10933+REGN10987 combination therapy, IV single dose at 1200 mg (or body weight 
equivalent), 2400 mg (or body weight equivalent), or placebo. The REGN10933+REGN10987 
dose level will be adjusted according to body weight as defined in Table 2. 
In phase 3 cohort 2, randomization will be stratified by country. 
 
Table 2: 
REGN10933+REGN10987 IV Doses for Each Weight Group, Phase 3 Cohort 
2 (Ages 0 to <18 Years) 
Body Weight 
Group 
Dose Equivalent for 
REGN10933+REGN10987 1200 
mg IV Dose (600 mg per mAb) 
Dose Equivalent for 
REGN10933+REGN10987 2400 mg 
IV Dose (1200 mg per mAb) 
≥40 kg 
1200 mg (600 mg per mAb) 
2400 mg (1200 mg per mAb) 
≥20 kg to <40 kg 
450 mg (225 mg per mAb) 
900 mg (450 mg per mAb) 
≥10 kg to <20 kg 
224 mg (112 mg per mAb) 
450 mg (225 mg per mAb) 
≥5 kg to <10 kg 
120 mg (60 mg per mAb) 
240 mg (120 mg per mAb) 
≥2.5 kg to <5 kg 
60 mg (30 mg per mAb) 
120 mg (60 mg per mAb) 
<2.5 kg 
30 mg (15 mg per mAb) 
60 mg (30 mg per mAb) 
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Cohort 2 (25 February 2021 and Later)* 
Patients in cohort 2 will be randomized in a 1:1 allocation ratio to co-administered 
REGN10933+REGN10987 combination therapy, IV single dose at 1200 mg (or body weight 
equivalent) or 2400 mg (or body weight equivalent). The REGN10933+REGN10987 treatment 
arms will be adjusted according to body weight as defined in Table 2. 
In phase 3 cohort 2, randomization will be stratified by country. 
Cohort 3* 
Patients in cohort 3 will be randomized in a 1:1 allocation ratio to co-administered 
REGN10933+REGN10987 combination therapy IV single dose (no placebo). Patients in cohort 3 
who are ≥18 years of age will follow the REGN10933+REGN10987 dose levels described for 
cohort 1 (1200 mg and 2400 mg). Patients in cohort 3 who are <18 years of age will follow the 
adjusted REGN10933+REGN10987 dose levels described in Table 2. 
In phase 3 cohort 3, randomization will not be stratified. 
*Cohort 1, Cohort 2, and Cohort 3 (Protocol Amendment 10 US and Later) 
As 
of 
protocol 
amendment 
10 
US, 
all 
newly-enrolled 
patients 
will 
receive 
REGN10933+REGN10987 combination therapy at the 1200 mg IV dose. Patients who are 
<18 years of age will follow the body-weight adjusted equivalent of REGN10933+REGN10987 
1200 mg dose level described in Table 2. 
8.7. 
Blinding  
Note: As of protocol amendment 10 US, the study consists of a single arm and blinding is no longer 
applicable. Treatment assignment to patients enrolled under protocol amendment 10 US and later 
will be open-label. The information in this section applies only to patients enrolled prior to 
protocol amendment 10 US. 
A pharmacist or qualified personnel at the site, not otherwise associated with the conduct of the 
study, will reconstitute the drug for IV administration. The drug infusion solution must be provided 
in identical form for active and placebo treatments, so that they remain indistinguishable to both 
study personnel and patients.  
Study patients, the principal investigators, and study site personnel (with the exception of the 
unblinded pharmacist at each site) will remain blinded to all randomization assignments 
throughout the study. The Regeneron medical/study director, study monitor, and any other 
Regeneron and contract research organization (CRO) personnel who are in regular contact with 
the study site will remain blinded to all patient randomization assignments in all phases of the 
study.  
Selected individuals from the Sponsor not involved in the conduct of the study may have access 
to unblinded phase 1 or phase 2 data as needed for safety review or other data review (see 
Section 6.2.2). The team performing the interim data reviews will be separate from the ongoing 
study team. No study personnel involved in the day-to-day conduct of the study will have access 
to any unblinded data before the database is locked for this study.  
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Anti-drug antibody, drug concentration, and biomarker results will not be communicated to the 
sites, and the Sponsor’s blinded operational team will not have access to results associated with 
patient identification until after the database is locked. 
8.8. 
Emergency Unblinding  
Note: As of protocol amendment 10 US, the study consists of a single arm and blinding is no longer 
applicable. The information in this section applies only to patients enrolled prior to protocol 
amendment 10 US. 
Unblinding of treatment assignment for a patient may be necessary due to a medical emergency or 
any other significant medical event and when a treatment decision is contingent on knowing the 
patient's treatment assignment. 
If unblinding is required: 
• Only the investigator will make the decision to unblind the treatment assignment 
• Only the affected patients will be unblinded 
• Unblinding is performed using the IWRS, which will notify the Sponsor. The 
designated study pharmacist(s)/designee at the study site will provide the treatment 
assignment to the investigator. If the study pharmacist(s)/designee is not available, the 
investigator for the site will unblind the patient.  
• If the IWRS is unavailable, the investigator will ask the unblinded study 
pharmacist(s)/designee to perform manual unblinding. All manual unblinding 
procedure will be adequately documented, including the reason why the IWRS was not 
used. 
• The investigator will notify Regeneron and/or designee as soon as possible after 
unblinding the patient 
Treatment assignment is not to be provided to site personnel, other than the unblinded study 
pharmacist (when applicable), at any time during the conduct of the study, except in the case of a 
true emergency and when a treatment decision is contingent on knowing the patient's treatment 
assignment. In the event that there is no study pharmacist, the individual at the site fulfilling that 
role will be the only unblinded member of the site personnel. 
8.9. 
Treatment Logistics and Accountability 
8.9.1. 
Packaging, Labeling, and Storage  
Note: As of protocol amendment 10 US, the study consists of a single arm and blinding is no longer 
applicable. The information in this section related to blinding applies only to patients enrolled 
prior to protocol amendment 10 US. 
A medication numbering system will be used to label unblinded investigational study drug. Lists 
linking medication numbers with product lot numbers will be maintained by the groups (or 
companies) responsible for study drug packaging. In order to maintain the blind, these lists will 
not be accessible to individuals involved in study conduct. 
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The unblinded pharmacist will prepare the unblinded investigational product and dispense it in a 
blinded manner to the blinded study staff for administration to the patient. 
Study drug will be stored at the site at a temperature of 2ºC to 8ºC. Storage instructions will be 
provided in the pharmacy manual. 
8.9.2. 
Supply and Disposition of Treatments  
Study drug will be shipped at a temperature of 2ºC to 8ºC to the investigator or designee at regular 
intervals or as needed during the study. At specified time points during the study (eg, interim site 
monitoring visits), at the site close-out visit, and following drug reconciliation and documentation 
by the site monitor, all opened and unopened study drug will be destroyed at the site with approval 
by the Sponsor or returned to the Sponsor or designee. 
8.9.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all opened and unopened study drug. These records 
should contain the dates, quantity, and study medication: 
• Dispensed to each patient 
• Returned from each patient (if applicable), and 
• Disposed of at the site or returned to the Sponsor or designee. 
All accountability records must be made available for inspection by the Sponsor and regulatory 
agency inspectors; photocopies must be provided to the Sponsor at the conclusion of the study. 
8.9.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the Sponsor 
and regulatory agency inspectors. 
8.10. 
Concomitant Medications 
Any treatment or procedure administered from the first dose of study drug to the final study visit 
will be considered a concomitant medication or procedure. This includes medications and 
procedures that were started before the study and are ongoing during the study.  
For more information on recording of concomitant medications and procedures, refer to 
Section 9.2.4.3. 
8.10.1. 
Prohibited and Permitted Medications 
Patients are not permitted to receive any medication specified in the exclusion criteria for study 
enrollment (Section 7.2.2) unless medically indicated. Patients may otherwise continue their 
normal regimen of medications and procedures. 
Based on CDC guidance and investigator discretion, deferring the use of any authorized or 
approved COVID-19 vaccine for at least 90 days after dosing may be considered to reduce 
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potential interference of the study drug with vaccine-induced immune responses. For more 
information, refer to the current CDC guidance (CDC, 2020a). 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
9.1. 
Schedule of Events 
 
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Table 3: 
Schedule of Events: Phase 1 
Day 
Screening/Baseline Visit1 
Mandatory 
/ Optional 
Sequester2 
Optional 
Sequester2 
Follow Up 
EOS 
-1 to 1 
2 
3 
4 5 6 7 
83 
9 
11 
13 
153 
18 
223 
25 
29 
Screen Pre-
Dose Dose Post-
Dose 
Visit Number 
1 
2 
3 
4 5 6 7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Window (Days) 
 
 
 
 
 
 
 
 
 
 
 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±3 
 
Screening/Baseline Only 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PGx sub-study consent (optional)4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Molecular diagnostic test for SARS-CoV-25 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history (including COVID-19 illness) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight and height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Study drug administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy 
Medically-attended COVID-19 visit details 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
Saliva sample for SARS-CoV-2 RT-qPCR 
 
X 
 
 
 
X 
 X  X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Nasal swab for SARS-CoV-2 RT-qPCR 
 
X 
 
 
 
X 
 X  X 
 
X 
X 
X 
X 
X 
X 
X 
X 
NP swab for SARS-CoV-2 RT-qPCR 
 
X 
 
 
 
X 
 X  X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Safety 
Vital signs 
 
X6 
X6 
X6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment-emergent grade ≥2 IRRs7 
 
 
← continuous monitoring →  
 
 
 
 
 
 
 
 
 
 
 
Treatment-emergent grade 3 or 4 AEs7 
 
 
← continuous monitoring → 
Treatment-emergent SAEs7 
 
 
← continuous monitoring → 
Treatment-emergent grade ≥2 hypersensitivity7 
 
 
← continuous monitoring → 
Targeted concomitant medications8 
X 
 
X 
X 
X 
X 
X X X X 
X 
 
 
 
X 
 
X 
 
X 
Pregnancy test (WOCBP)9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Central Laboratory Testing 
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Day 
Screening/Baseline Visit1 
Mandatory 
/ Optional 
Sequester2 
Optional 
Sequester2 
Follow Up 
EOS 
-1 to 1 
2 
3 
4 5 6 7 
83 
9 
11 
13 
153 
18 
223 
25 
29 
Screen Pre-
Dose Dose Post-
Dose 
Visit Number 
1 
2 
3 
4 5 6 7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Window (Days) 
 
 
 
 
 
 
 
 
 
 
 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±3 
 
Hematology (including differential) 
X10 
 
 
 
 
 
 
 X 
 
 
 
 
 
 
 
 
X 
Blood chemistry (including AST, ALT, CRP 
ferritin, LDH) 
X10 
 
 
 
 
 
 
 X 
 
 
 
 
 
 
 
 
X 
Coagulation tests (D-dimer, PT/INR, aPTT) 
X10 
 
 
 
 
 
 
 X 
 
 
 
 
 
 
 
 
X 
Central PK and Immunogenicity Testing 
Serum for PK11 
 
X12 
 
X12 
 
X 
 X  X 
 
 
 
 
X 
 
 
 
X 
Serum for ADA13 
 
X13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Central Biomarker Testing 
Serum for serology 
 
X 
 
 
 
X 
 
 
 X 
 
 
 
 
 
 
 
 
X 
Serum for cytokines 
 
X 
 
 
 
X 
 
 
 X 
 
 
 
 
 
 
 
 
X 
Plasma for complement 
 
X 
 
 
 
X 
 
 
 X 
 
 
 
 
 
 
 
 
X 
Serum for research 
 
X 
 
 
 
X 
 
 
 X 
 
 
 
 
 
 
 
 
X 
Plasma for research 
 
X 
 
 
 
X 
 
 
 X 
 
 
 
 
 
 
 
 
X 
Exploratory Patient-Reported Symptoms 
SE-C1914 
 
X 
 
X 
Daily 
 
X 
PGIS14 
 
X 
 
X 
Daily 
 
X 
PGIC14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pharmacogenomics (Optional Sub-Study) 
Blood for DNA4 
 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for RNA4 
 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADA, anti-drug antibodies; AE; adverse event; ALT, alanine transaminase; aPTT, activated partial thromboplastin time; AST, aspartate transaminase; CRP, c-reactive protein; EOS, 
end of study; INR, international normalized ratio; IRR, infusion-related reaction; LDH, lactate dehydrogenase; NP, nasopharyngeal; PGIC, Patient Global Impression of Change of 
symptoms associated with COVID-19; PGIS, Patient Global Impression of Severity of symptoms associated with COVID-19; PGx, pharmacogenomics; PK, pharmacokinetics; PT; 
prothrombin time; SAE, serious adverse event; RT-PCR, reverse transcription polymerase chain reaction; RT-qPCR, quantitative reverse transcription polymerase chain reaction; 
SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SE-C19, Symptom Evolution of COVID-19; WOCBP, women of childbearing potential.  
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Table 4: 
Schedule of Events: Phase 2 (and Phase 3 Prior to Protocol Amendment 6) 
Note: For more information on patients in phase 3 who initially enrolled prior to phase 3 adaptations, refer to Section 6.1.3. 
Day 
Screening/Baseline 
Visit1 
Follow Up 
EOS 
-1 to 1 
2 
3 
4 
5 
7 
83 
9 
11 
13 
153 
18 
223 
25 
29  
Screen Pre-
Dose Dose Post-
Dose 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
Window (Days) 
X 
 
 
 
 
 
 
 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±3 
 
Screening/Baseline Only 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PGx sub-study consent (optional)4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Antigen or molecular diagnostic test for SARS-
CoV-25 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history (including COVID-19 illness) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight and height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment  
Study drug administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy  
Medically-attended COVID-19 visit details 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
NP swab for SARS-CoV-2 RT-qPCR 
 
X 
 
 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Safety  
Vital signs 
 
X6 
 
X6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment-emergent grade ≥2 IRRs7 
 
 
← continuous monitoring → 
 
 
 
 
 
 
 
 
 
 
 
Treatment-emergent SAEs7 
 
 
← continuous monitoring → 
Treatment-emergent grade ≥2 hypersensitivity7 
 
 
← continuous monitoring → 
Targeted concomitant medications8 
X 
 
← continuous monitoring → 
Pregnancy test (WOCBP)9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Central Laboratory Testing  
Hematology (including differential) 
X10 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
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Day 
Screening/Baseline 
Visit1 
Follow Up 
EOS 
-1 to 1 
2 
3 
4 
5 
7 
83 
9 
11 
13 
153 
18 
223 
25 
29  
Screen Pre-
Dose Dose Post-
Dose 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
Window (Days) 
X 
 
 
 
 
 
 
 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±3 
 
Blood chemistry (including AST, ALT, CRP 
ferritin, LDH) 
X10 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
Coagulation tests (D-dimer, PT/INR, aPTT) 
X10 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
Central PK and Immunogenicity Testing  
Serum for PK11 
 
X12 
 
X12 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum for ADA13 
 
X13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Central Biomarker Testing  
Serum for serology 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum for cytokines and CK-MB 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
Serum for research and cardiac biomarkers 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
Plasma for research and cardiac biomarkers 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
Plasma for hsTroponin-T14 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
Exploratory Patient-reported Symptoms  
SE-C1914 
 
X 
 
 
Daily 
PGIS14 
 
X 
 
 
Daily 
PGIC14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pharmacogenomics (Optional Sub-Study) 
Blood for DNA4 
 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for RNA4 
 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADA, anti-drug antibodies; AE; adverse event; ALT, alanine transaminase; aPTT, activated partial thromboplastin time; AST, aspartate transaminase; CK-MB, creatine kinase-MB, 
CRP, c-reactive protein; EOS, end of study; INR, international normalized ratio; IRR, infusion-related reaction; LDH, lactate dehydrogenase; NP, nasopharyngeal; PGIC, Patient 
Global Impression of Change of symptoms associated with COVID-19; PGIS, Patient Global Impression of Severity of symptoms associated with COVID-19; PGx, 
pharmacogenomics; PK, pharmacokinetics; PT, prothrombin time; PT, prothrombin time; SAE, serious adverse event; RT-PCR, reverse transcription polymerase chain reaction; RT-
qPCR, quantitative reverse transcription polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SE-C19, Symptom Evolution of COVID-19; 
WOCBP, women of childbearing potential.  
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Table 5: 
Schedule of Events: Phase 3 (Cohort 1 Patients) 
Day 
Screening/Baseline Visit1 
Follow Up3 
-1 to 1 
2 
3 
4 
7 
15 
22 
29 
60 
90 
Screen Pre-
Dose Dose Post-
Dose 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Window (Days) 
 
 
 
 
 
 
 
±1 
±3 
±3 
±3 
±3 
±3 
 
Screening/Baseline Only 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PGx sub-study consent (optional)4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Immunoprofiling sub-study consent (optional)4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Antigen or molecular diagnostic test for SARS-CoV-25 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history (including COVID-19 illness, risk factors) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight and height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization (treatment assignment) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Treatment  
Study drug administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Efficacy  
 
Query for COVID-19-related medically-attended visit details 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
NP swab for SARS-CoV-2 RT-qPCR 
 
X 
 
 
 
 
 
X 
X 
 
X 
 
 
Safety  
 
Vital signs 
 
X6 
 
X6 
 
 
 
 
 
 
 
 
 
Treatment-emergent grade ≥2 IRRs7,8 
 
 
X 
X 
← cont. mon. → 
 
 
 
 
 
 
TEAEs that led to any medically-attended visit7,8 
 
 
 
X 
← continuous monitoring → 
 
 
Treatment-emergent grade ≥2 hypersensitivity7,8 
 
 
X 
X 
← continuous monitoring → 
 
 
Treatment-emergent SAEs7,8,16 
 
 
X 
X 
← continuous monitoring → 
 
Targeted concomitant medications7, 8 
X 
 
X 
X 
← continuous monitoring → 
 
Concomitant procedures7,8 
X 
 
X 
X 
← continuous monitoring → 
 
Vital status16 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (women of childbearing potential)9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy status16 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety information (newborns of study participants)16 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central Laboratory Safety Testing  
 
Hematology (including differential) 
X10 
 
 
 
 
 
X 
X 
 
X 
 
 
Blood chemistry (including AST, ALT, CRP, LDH) 
X10 
 
 
 
 
 
X 
X 
 
X 
 
 
Coagulation tests (D-dimer, PT/INR, aPTT) 
X10 
 
 
 
 
 
X 
X 
 
X 
 
 
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Day 
Screening/Baseline Visit1 
Follow Up3 
-1 to 1 
2 
3 
4 
7 
15 
22 
29 
60 
90 
Screen Pre-
Dose Dose Post-
Dose 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Window (Days) 
 
 
 
 
 
 
 
±1 
±3 
±3 
±3 
±3 
±3 
 
Central Laboratory Immunogenicity Testing (Not Enrolled in PK Sub-Study) 
 
Serum for ADA13 
X13 
 
 
 
 
 
 
 
 
X 
 
 
Central Laboratory Drug Concentration and Immunogenicity Testing (Enrolled in PK Sub-Study) 
 
Serum for drug concentration (PK)12 
X10,12 
 
 
 
 
 
 
 
 
X12 
 
 
Serum for ADA13 
X13 
 
 
 
 
 
 
 
 
X13 
 
 
Central Laboratory Biomarker Testing  
 
Serum for serology 
X10 
 
 
 
 
 
 
 
 
X 
 
 
Serum for research  
X10 
 
 
 
 
 
X 
X 
 
X 
 
 
Plasma for research  
X10 
 
 
 
 
 
X 
X 
 
X 
 
 
Exploratory Patient-reported Outcomes 
 
SE-C1914 
 
X 
 
 
Daily 
 
 
PGIS14 
 
X 
 
 
Daily 
 
 
PGIC14 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Item: return to usual health14 
 
X 
 
 
Daily 
 
 
Item: return to usual activities14 
 
X 
 
 
Daily 
 
 
EQ-5D-5L14 
 
X 
 
 
Daily 
X14 
X14 
WPAI+CIQ14 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
SARS-CoV-2 Reinfection 
Details of positive SARS-CoV-2 local test result22 
 
 
 
 
 
 
 
 
 
 
 
cont. mon.22 → 
Immunoprofiling (Optional Sub-Study) 
 
Blood for PBMCs  
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Pharmacogenomics (Optional Sub-Study) 
 
Blood for DNA4 
 
X4 
 
 
 
 
 
 
 
 
 
 
 
Blood for RNA4 
X4 
 
 
 
 
 
 
 
 
 
 
 
ADA, anti-drug antibodies; AE; adverse event; ALT, alanine transaminase; aPTT, activated partial thromboplastin time; AST, aspartate transaminase; CRP, c-reactive protein; INR, 
international normalized ratio; IRR, infusion-related reaction; LDH, lactate dehydrogenase; NP, nasopharyngeal; PBMC, peripheral blood mononuclear cells; PGx, 
pharmacogenomics; PK, pharmacokinetics; PT, prothrombin time; SAE, serious adverse event; RT-qPCR, quantitative reverse transcription polymerase chain reaction; TEAE, 
treatment-emergent adverse event. 
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Table 6: 
Schedule of Events: Phase 3, Assessment of Long COVID (Cohort 1 Patients) 
Day 
Follow Up, with Long COVID Assessments3 
EOS 
114 
115 
116 
117 
118 
119 
120 
163 164 
165 
166 
167 
168 
169 
Visit Number 
- 
- 
- 
- 
- 
- 
11 
- 
- 
- 
- 
- 
- 
12 
Window (Days) 
- 
- 
- 
- 
- 
- 
+7 or ±719 
- 
- 
- 
- 
- 
- 
+7 or ±719 
 
Questionnaires20  
SE-LC1914 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PGIS14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PGIC14 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Return to usual health14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Return to usual activities14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SF-3614 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
WPAI+CIQ14 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
EQ-5D-5L 14 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Safety 
Treatment-emergent SAEs 
← continuous monitoring8 → 
Targeted concomitant medications 
← continuous monitoring8 → 
Concomitant procedures 
← continuous monitoring8 → 
Hematology (including differential) 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Blood chemistry 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Vital status16 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Pregnancy status16 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Safety information (newborns of study participants) 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Sample Collections 
NP swab for SARS-CoV-2 RT-qPCR 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Blood for PBMCs21 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Serum for exploratory long COVID research (SARS-
CoV-2 serology, proteomics, and other research) 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Plasma for exploratory long COVID research 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Central Laboratory Drug Concentration and Immunogenicity Testing (Enrolled in PK Sub-Study; Not Related to Long COVID Analysis) 
Serum for drug concentration (PK) 
 
 
 
 
 
 
X12 
 
 
 
 
 
 
 
Serum for ADA 
 
 
 
 
 
 
X13 
 
 
 
 
 
 
 
Additional Adverse Events of Special Interest  
Details of positive SARS-CoV-2 local test result22 
continuous monitoring from the day of consent to protocol amendment 9 US22 → 
New medical diagnoses or conditions24 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Pharmacogenomics (Optional Sub-Study) 
Blood for DNA23 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
ADA, anti-drug antibodies; EOS, end of study; NP, nasopharyngeal; PBMC, peripheral blood mononuclear cells; PK, pharmacokinetics; SAE, serious adverse event; RT-qPCR, 
quantitative reverse transcription polymerase chain reaction. 
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Table 7: 
Schedule of Events: Phase 3 (Cohort 3 ≥18 Years) 
Day 
Screening/Baseline Visit1 
Follow Up3 
EOS 
-1 to 1 
2 
3 
4 
7 15 22 29 60 90 12018 
169 
Screen Pre-Dose Dose Post-Dose 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 10 
11 
12 
Window (Days) 
 
 
 
 
 
 
 
±1 ±3 ±3 ±3 ±3 ±3 ±712 
±7 
 
 
 
 
 
Screening/Baseline Only 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PGx sub-study consent (optional)4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunoprofiling sub-study consent (optional)4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Antigen or molecular diagnostic test for SARS-CoV-25 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history (including COVID-19 illness, risk factors) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight and height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization (treatment assignment) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment  
Study drug administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy  
Query for COVID-19-related medically-attended visit details 
 
 
 
 
 
 
 
X 
X X X 
 
 
 
 
NP swab for SARS-CoV-2 RT-qPCR 
 
X 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
Safety  
Vital signs 
 
X6 
 
X6 
 
 
 
 
 
 
 
 
 
 
 
Treatment-emergent grade ≥2 IRRs7,8 
 
 
X 
X 
← cont. mon. → 
 
 
 
 
 
 
 
 
TEAEs that led to any medically-attended visit7,8 
 
 
 
X 
← continuous monitoring → 
 
 
 
 
Treatment-emergent grade ≥2 hypersensitivity7,8 
 
 
X 
X 
← continuous monitoring → 
 
 
 
  
Treatment-emergent SAEs7,8,16 
 
 
X 
X 
← continuous monitoring → 
Targeted concomitant medications7, 8 
X 
 
X 
X 
← continuous monitoring → 
Concomitant procedures7,8 
X 
 
X 
X 
← continuous monitoring → 
Vital status16 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Pregnancy test (women of childbearing potential)9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy status16 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Safety information (newborns of study participants)16 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Central Laboratory Safety Testing  
Hematology (including differential) 
X10 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
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Day 
Screening/Baseline Visit1 
Follow Up3 
EOS 
-1 to 1 
2 
3 
4 
7 15 22 29 60 90 12018 
169 
Screen Pre-Dose Dose Post-Dose 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 10 
11 
12 
Window (Days) 
 
 
 
 
 
 
 
±1 ±3 ±3 ±3 ±3 ±3 ±712 
±7 
 
 
 
 
 
Blood chemistry (including AST, ALT, CRP, LDH) 
X10 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
Coagulation tests (D-dimer, PT/INR, aPTT) 
X10 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
Central Laboratory Drug Concentration and Immunogenicity Testing 
Serum for drug concentration (PK)12 
X10,12 
 
X12 
 
 
 
 
 
 X12 X12   
X12 
 
Serum for ADA13 
X13 
 
 
 
 
 
 
 
 X13 
 
 
X13 
 
Central Laboratory Biomarker Testing  
Serum for serology 
X10 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Serum for research  
X10 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
Plasma for research  
X10 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
Exploratory Patient-reported Outcomes 
SE-C1914 
 
X 
 
 
Daily 
 
 
 
 
PGIS14 
 
X 
 
 
Daily 
 
 
 
 
PGIC14 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Item: return to usual health14 
 
X 
 
 
Daily 
 
 
 
 
Item: return to usual activities14 
 
X 
 
 
Daily 
 
 
 
 
EQ-5D-5L14 
 
X 
 
 
Daily 
X14 X14 X14 
X14 
WPAI+CIQ14 
 
X 
 
 
 
 
 
X 
X X X 
 
 
 
 
Immunoprofiling (Optional Sub-Study) 
Blood for PBMCs  
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Pharmacogenomics (Optional Sub-Study) 
Blood for DNA4 
 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for RNA4 
X4 
 
 
 
 
 
 
 
  
 
 
 
 
ADA, anti-drug antibodies; AE; adverse event; ALT, alanine transaminase; aPTT, activated partial thromboplastin time; AST, aspartate transaminase; CRP, c-reactive protein; EOS, 
end of study; INR, international normalized ratio; IRR, infusion-related reaction; LDH, lactate dehydrogenase; NP, nasopharyngeal; PBMC, peripheral blood mononuclear cells; 
PGx, pharmacogenomics; PK, pharmacokinetics; PT, prothrombin time; SAE, serious adverse event; RT-qPCR, quantitative reverse transcription polymerase chain reaction; TEAE, 
treatment-emergent adverse event. 
 
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Table 8: 
Schedule of Events: Phase 3 (Cohort 2 Patients; Cohort 3 Patients <18 Years)  
Day 
Screening/Baseline Visit1 
Follow Up3 
EOS 
-1 to 1 
2 
3 
4 
7 
15 22 29 60 90 12018 169 
 
Screen Pre-Dose Dose Post-Dose 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 10 
11 
12 
Window (Days) 
 
 
 
 
 
 
 
±1 ±3 ±3 ±3 ±3 ±3 
±7 
±7 
 
 
 
 
 
Screening/Baseline Only 
 
 
 
 
Parental informed consent and informed assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Antigen or molecular diagnostic test for SARS-CoV-25 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history (including COVID-19 illness, risk factors) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight and height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization (treatment assignment) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization (PK-ADA schedule assignment)15 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment  
 
 
 
 
Study drug administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy  
 
 
 
 
Query for COVID-19-related medically-attended visit details 
 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
NP swab for SARS-CoV-2 RT-qPCR 
 
X 
 
 
 
X 
 
X 
X 
 
X 
 
 
 
 
Safety  
 
 
 
 
Vital signs (≥12 years) 
 
X6 
 
X6 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (<12 years) 
 
X6 
X6 
X6 
 
 
 
 
 
 
 
 
 
 
 
Treatment-emergent grade ≥2 IRRs7,8 
 
 
X 
X17 
← cont. mon. → 
 
 
 
 
 
 
 
 
TEAEs that led to any medically-attended visit7, 8 
 
 
 
X17 
← continuous monitoring → 
 
 
 
 
Treatment-emergent grade ≥2 hypersensitivity7, 8 
 
 
X 
X17 
← continuous monitoring → 
 
 
 
 
Treatment-emergent grade 3 or 4 AEs8  
 
 
X 
X17 
← continuous monitoring → 
 
 
 
 
Treatment-emergent SAEs7, 8,16 
 
 
X 
X17 
← continuous monitoring → 
Targeted concomitant medications7,8 
X 
 
X 
X17 
← continuous monitoring → 
Concomitant procedures7,8 
X 
 
X 
X17 
← continuous monitoring → 
Vital status16 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Pregnancy test (women of childbearing potential)9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy status16 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
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Day 
Screening/Baseline Visit1 
Follow Up3 
EOS 
-1 to 1 
2 
3 
4 
7 
15 22 29 60 90 12018 169 
 
Screen Pre-Dose Dose Post-Dose 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 10 
11 
12 
Window (Days) 
 
 
 
 
 
 
 
±1 ±3 ±3 ±3 ±3 ±3 
±7 
±7 
 
 
 
 
 
Safety information (newborns of study participants)16 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Central Laboratory Safety Testing and Central Laboratory Biomarker Testing, Body Weight ≥20 kg  
Hematology (including differential) 
X10 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
Blood chemistry (including AST, ALT, CRP, LDH) 
X10 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
Serum for serology 
X10 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Serum for exploratory research 
X10 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
Plasma for exploratory research 
X10 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
Central Laboratory Safety Testing and Central Laboratory Biomarker Testing, Body Weight ≥10 kg to <20 kg 
Hematology (including differential) 
X10 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
Blood chemistry (including AST, ALT, CRP, LDH) 
X10 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
Serum for serology 
X10 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Central Laboratory Safety Testing and Central Laboratory Biomarker Testing, Body Weight <10 kg 
Hematology (including differential) 
X10 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
Blood chemistry (including AST, ALT, CRP, LDH) 
X10 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
Serum for serology 
X10 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central Laboratory Drug Concentration and Immunogenicity Testing (All Body Weight Tiers) 
Serum for PK-ADA (Schedule A)15 
X10,12 
 
X12 
 
X12 
 
 
 
 
X12 
 X12  
 
 
Serum for PK-ADA (Schedule B)15 
X10,12 
 
X12 
 
 
 
X12 
 
 
X12 
 X12  
 
 
Serum for PK-ADA (Schedule C)15 
X10,12 
 
X12 
 
 
 
 
X12 
 
X12 
 
 
X12  
 
Serum for PK-ADA (Schedule D)15 
X10,12 
 
X12 
 
 
 
 
 
X12 X12 
 
 
X12  
 
Exploratory Patient-reported Outcomes (Age ≥12 Years Only)14 
SE-C1914 
 
X 
 
 
Daily 
 
 
 
 
PGIS14 
 
X 
 
 
Daily 
 
 
 
 
PGIC14 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Item: return to usual health14 
 
X 
 
 
Daily 
 
 
 
 
Item: return to usual activities14 
 
X 
 
 
Daily 
 
 
 
 
EQ-5D-Y14 
 
X 
 
 
Daily 
X14 X14 X14 
X14 
WPAI+CIQ14 
 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
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Day 
Screening/Baseline Visit1 
Follow Up3 
EOS 
-1 to 1 
2 
3 
4 
7 
15 22 29 60 90 12018 169 
 
Screen Pre-Dose Dose Post-Dose 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 10 
11 
12 
Window (Days) 
 
 
 
 
 
 
 
±1 ±3 ±3 ±3 ±3 ±3 
±7 
±7 
 
 
 
 
 
ADA, anti-drug antibodies; AE; adverse event; ALT, alanine transaminase; aPTT, activated partial thromboplastin time; AST, aspartate transaminase; CRP, c-reactive protein; EOS, 
end of study; INR, international normalized ratio; IRR, infusion-related reaction; LDH, lactate dehydrogenase; NP, nasopharyngeal; PGx, pharmacogenomics; PK, pharmacokinetics; 
PT, prothrombin time; SAE, serious adverse event; RT-qPCR, quantitative reverse transcription polymerase chain reaction; TEAE, treatment-emergent adverse event. 
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9.1.1. 
Footnotes for the Schedule of Events Tables 
1. Screening visit may occur on the same day as, or the day prior to, the baseline visit. 
2. [Phase 1 footnote removed] 
3. On visit days where in-person sample collections or assessments are not required, 
information may be collected by phone.  
4. Patients (cohort 1; cohort 3 ≥18 years old) must provide separate consent to collect blood 
samples as part of the optional pharmacogenomics (PGx) sub-study. Blood sample for 
RNA may be collected at day -1 or day 1 (ie, screening or pre-dose) but must be collected 
prior to randomization. Blood sample for DNA should be collected at the day -1 or day 1 
visit but may be collected at any visit. Refer to Section 9.2.14 for more information about 
the PGx sub-study. 
Patients (cohort 1; cohort 3 ≥18 years old) must provide separate consent to collect blood 
samples as part of the optional peripheral blood mononuclear cell (PBMC) sub-study. 
Blood samples for PBMCs must be collected at the visits indicated. Refer to Section 9.2.13 
for more information about this sub-study. 
5. Refer to Section 9.2.1.2 for diagnostic test requirements during screening. 
6. Vital signs, including temperature, blood pressure, heart rate, and SpO2 will be collected 
as described in Section 9.2.4.1.  
For patients in cohort 1 and patients ≥12 years in cohort 2 and cohort 3, vital signs will 
be taken once before the infusion and once after the infusion is completed. After infusion 
of study drug, these patients will be observed for at least 1 hour.  
For patients <12 years in cohort 2 and cohort 3, vital signs will be taken before infusion, 
approximately every 30 minutes during the infusion, after the infusion is completed, 
approximately 1-hour post-infusion, and approximately 2 hours post-infusion. After 
infusion of study drug, these patients will be observed for at least 2 hours. 
7. Treatment-emergent AESIs (grade ≥2 IRRs, grade ≥2 hypersensitivity, and TEAEs 
associated with any medically-attended visit) and treatment-emergent SAEs will be 
recorded until day 29. From day 30 to day 169, only treatment-emergent SAEs will be 
recorded. For patients in cohort 2 and patients <18 years in cohort 3, treatment-
emergent grade 3 or 4 AEs will also be recorded until day 29. Refer to Section 10 for more 
information on reporting and recording requirements. 
Targeted concomitant medications and concomitant procedures will also be reviewed and 
recorded. Refer to Section 9.2.4.3 for more information. 
8. Continuously-monitored events will be recorded when they occur during the corresponding 
time period marked on the schedule of events. Study visits (including phone calls) are not 
required solely to collect continuously-monitored assessments, if no other assessments are 
planned on that day.  
9. Pregnancy testing will be performed in women of childbearing potential (WOCBP) only 
and regardless of pregnancy status. A negative test is not required prior to study drug 
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administration. Serum or urine pregnancy test are both acceptable. Refer to Section 9.2.6 
for more information, including a definition of WOCBP. 
Note that a paper pregnancy report form must be completed for each patient who becomes 
pregnant or is pregnant at the signing of consent.  
10. The indicated blood samples may be collected at the either day -1 or day 1 (ie, screening 
or pre-dose), but must be collected prior to randomization. For patients in phase 3 cohort 
2, efforts should be made to collect all screening/pre-dose blood samples on the same study 
visit, when feasible. 
11. [Footnote removed] 
12. Actual dosing time and drug concentration sample collection times, as applicable, will be 
recorded. 
At the screening/baseline visit, blood for assessment of drug concentration in serum will 
be taken prior to dosing and within 60 minutes after the end of infusion (EOI). The EOI 
sample should be collected from the arm contralateral to that used for IV infusion. If not 
medically feasible, the EOI sample can be drawn from the same arm, but not from the 
infusion catheter.  
In cohort 1 and cohort 3 (≥18 years old), patients will follow different blood sample 
collection schedules for drug concentration and immunogenicity depending on whether 
they enrolled in the PK sub-study (cohort 1), not enrolled in the PK sub-study (cohort 1), 
or are pregnant at randomization (cohort 3 patients ≥18 years old). For samples collected 
on day 120, the collection window is ±28 days. Refer to Section 9.2.8 for more information 
on the PK sub-study. 
13. The window for predose ADA sample collection is as close to administration of study drug 
as is reasonable. Actual dosing time and ADA sample collection times, as applicable, will 
be recorded.  
14. On visit days when other assessments or sample collections are required, the site will verify 
that questionnaires have been completed prior to all other assessments or collections. The 
order of questionnaire completion is provided below. On days when a questionnaire is not 
required it will be skipped, but the overall order will remain the same. Refer to Section 9.2 
for additional information regarding these questionnaires.  
Cohort 1: SE-LC19, PGIS, PGIC, return to usual health, return to usual activities, SF-36, 
WPAI+CIQ, EQ-5D-5L. 
Cohort 2 (≥12 years): SE-C19, PGIS, PGIC, return to usual health, return to usual 
activities, EQ-5D-Y, WPAI+CIQ. 
Cohort 3 (≥12 years): SE-C19, PGIS, PGIC, return to usual health, return to usual 
activities, EQ-5D-5L (or EQ-5D-Y), WPAI+CIQ.  
On days 60 and 90, the window for questionnaire assessment is ±3 days. On days 120 and 
169, the window for questionnaire assessment is ±7 days. Study visits are not required on 
days when only questionnaires are collected.  
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Note that questionnaires will only be administered to sites when regionally available, and 
will only be administered to patients who are able to complete the questionnaires in the 
language available at their site. 
15. In cohort 2 (and patients <18 years in cohort 3), each patient will be assigned at 
randomization by IWRS to a blood sample collection schedule for drug concentration and 
immunogenicity analysis. Actual dosing time and PK-ADA sample collection times will 
be recorded. To conserve blood volume, a single blood draw for drug concentration and 
immunogenicity will be obtained. In patients <12 years, immunogenicity will be analyzed 
only in pre-dose and day 29 PK-ADA samples. 
16. Patients will be followed at day 120 and day 169 for vital status, pregnancy status, targeted 
safety information, and additional safety information in newborns of study participants. 
Refer to Section 9.2.5 for more information on these follow-up assessments. 
17. For patients <12 years in cohort 2 and cohort 3, follow-up by phone will be conducted 
within 6 to 8 hours of infusion to collect the information indicated. 
18. Patients in phase 3 cohort 1 will follow the Schedule of Events in Table 5 until day 90. 
They will then follow the long COVID Schedule of Events Table 6 until day 169. 
19. For all day 120 and day 169 questionnaires, a visit window of +7 days will be applied. For 
all other day 120 and day 169 assessments and sample collections, a visit window of ±7 
days will be applied. 
20. Refer to Section 9.2.16 for additional information regarding assessments and procedures 
related to long COVID analyses. Note that in addition to the analyses planned in this study, 
exit interviews may be conducted by a third party as part of a separate study. Refer to 
Section 9.2.16; additional information, including study visits and windows for these 
interviews, will be detailed in the separate study.  
21. PBMC collections during the long COVID portion of the study are mandatory and are 
separate collections from those of the optional immunoprofiling sub-study. 
22. Patients in phase 3 cohort 1 will be asked to report any positive SARS-CoV-2 local test 
results obtained during the period indicated, starting from the day at which they consent to 
protocol amendment 9 US. Refer to Section 9.2.11 for additional information regarding 
collection and reporting. 
23. Patients who consent to the optional pharmacogenomics (PGx) sub-study should have a 
blood sample for DNA collected during any in-person study visit. Efforts should be made 
to consent patients to the PGx sub-study if they have not already consented. Patients who 
already consented to the sub-study will not be consented a second time, and patients who 
have already provided a sample for the PGx sub-study should not have a second sample 
collected. Refer to Section 9.2.14 for more information about the PGx sub-study. 
24. For phase 3 cohort 1 patients, any new medical condition(s) diagnosed after randomization 
will be recorded. Refer to Section 9.2.12 for additional information regarding collection 
and reporting. 
 
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9.1.2. 
Early Termination from the Study 
Patients who are withdrawn from the study before day 29 will be asked to allow an early 
termination visit consisting of day 29 assessments and sample collections. Patients who are 
withdrawn from the study after day 29 will be asked to allow an early termination visit consisting 
of end-of-study assessments and sample collections. 
9.1.3. 
Unscheduled Visits 
All attempts should be made to keep patients on the study schedule. Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for collection of NP swabs, 
blood, serum, or plasma, for follow-up of treatment-emergent SAEs, treatment-emergent AESIs, 
or for any other reason, as warranted. 
9.2. 
Study Procedures 
This section describes the procedures and collections that will be performed in this study. 
Procedures and collections will occur according to the schedule of events (Section 9.1). 
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit 
The following procedures will be performed for the sole purpose of determining study eligibility 
or characterizing the baseline population.  
9.2.1.1. 
Informed Consent 
Informed consent (and assent, as applicable) must be obtained according to the requirements 
described in Section 13.2. Optional informed consent/assent may be obtained for participation in 
the 
pharmacogenomics 
sub-study 
(Section 9.2.14) 
and 
immunoprofiling 
sub-study 
(Section 9.2.13). 
9.2.1.2. 
Diagnostic Test for SARS-CoV-2 
The investigator or sub-investigator will verify that the patient has tested positive for SARS-CoV-
2, either at screening or by historical record (refer to Section 7.2.1 for detailed screening 
requirements). For tests performed at screening, the local testing result, specimen type, assay type, 
and date of the test will be recorded in the eCRF.  
9.2.1.3. 
Demographics 
Refer to Section 5.1. 
9.2.1.4. 
Medical History 
Medical history will include the following:  
• COVID-19 with start date as the date of onset of first symptoms related to COVID-19 
• Risk factors for severe COVID-19/hospitalization due to COVID-19, as defined in 
Section 7.2.1  
• Whether the patient is receiving oxygen at home by nasal cannula  
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• Menopausal history 
• Pregnancy or breastfeeding status, if applicable  
9.2.1.5. 
Weight and Height 
Weight and height will be recorded at the screening/baseline visit. 
9.2.2. 
Treatment 
See Section 8.1. 
9.2.3. 
Efficacy Procedures  
9.2.3.1. 
Nasopharyngeal Swab Collection 
Nasopharyngeal (NP) swab samples will be collected from patients to determine presence or 
absence of SARS-CoV-2 virus, including at baseline, and to measure viral load. Samples will be 
used for RT-qPCR analysis. Samples collected from patients may additionally be used for 
exploratory viral RNA sequencing, plaque forming unit assays (PFU) assays and/or viral culture. 
Additional details regarding sample collection and analysis can be found in the laboratory manual. 
9.2.3.2. 
COVID-19-Related Medically-Attended Visit Details 
A COVID-19-related medically-attended visit will be defined as follows: hospitalization, 
emergency room (ER) visit, urgent care visit, physician’s office visit, or telemedicine visit, with 
the primary reason for the visit being COVID-19.  
Medically-attended visits related to COVID-19, as determined by the investigator, will be recorded 
in the eCRF. During each indicated collection visit in the Schedule of Events, all previously 
unrecorded COVID-19-related medically-attended visits and details will be recorded, beginning 
from the day of dosing up to and including the day of collection. 
Details will include at minimum: 
• Type of visit (hospitalization, ER, urgent care, physician’s office visit, telemedicine) 
• Date of visit 
• If hospitalized due to COVID-19, length of visit 
• Reason (list all COVID-19-related symptom[s] or clinical manifestation[s]) that 
prompted medically-attended visit) 
• If hospitalized due to COVID-19, whether ICU care was given 
• If hospitalized due to COVID-19, whether mechanical ventilation was required 
• Treatments given for COVID-19 (including, but not limited to supplemental oxygen, 
corticosteroids, COVID-19 convalescent plasma, remdesivir, bamlanivimab, etc) 
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9.2.4. 
Safety Procedures  
9.2.4.1. 
Vital Signs 
Vital signs will include temperature, blood pressure, heart rate (per minute), SpO2. For phase 1, 
respiratory rate (per minute) will also be assessed.  
Temperature may be measured using the following methods: axilla, oral, tympanic, or temporal. 
Body temperature should be measured using the same method each time. Temperature should be 
measured after at least 5 minutes of rest (supine or sitting). 
Blood pressure should be measured after the patient has been resting quietly for at least 5 minutes 
and may be obtained from a seated or supine position. 
SpO2 will be measured using a fingertip or similar non-invasive device following 5 minutes of rest 
(inactivity) while supine, semi-recumbent, or sitting and will only be measured in the presence of 
a good SpO2 wave form. 
9.2.4.2. 
Adverse Event Monitoring 
Targeted TEAEs (as defined in Section 10.1.1) will be recorded. 
9.2.4.3. 
Record Targeted Concomitant Medications and Concomitant Procedures 
A targeted list of the following concomitant medications will be recorded in the eCRF: 
• Putative COVID-19 treatments (eg, remdesivir, bamlanivimab, convalescent serum, 
IVIG, IL-6 receptor inhibitors [eg, sarilumab, tocilizumab], JAK inhibitors [eg, 
baricitinib], ivermectin)  
• Oxygen 
• SARS-CoV-2 vaccinations 
• Influenza vaccinations 
• Any other vaccinations 
• Antipyretics (eg, aspirin, acetaminophen, ibuprofen) 
• Anticoagulants (eg, enoxaparin, warfarin, rivaroxaban)  
• Immunosuppressants (eg, cyclosporine A, corticosteroids) 
• Interferon beta  
• Theophylline 
• Antiepileptics (eg, carbamazepine, divalproex, phenytoin) 
• Antiarrhythmics (eg, digoxin, disopyramide, procainamide) 
• Antivirals, antibacterials, and antifungals 
• Antiparasitics (chloroquine or hydroxychloroquine) 
• Angiotensin receptor blockers (eg, losartan, valsartan) 
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• Angiotensin converting enzyme inhibitors (eg, benazepril, lisinopril) 
• Any medication used to treat an adverse event 
In addition, any concomitant procedures used to treat an adverse event will be recorded in the 
eCRF. 
For more information on concomitant medications and procedures, refer to Section 8.10. 
9.2.5. 
Post-Day 29 Follow-Up 
In phase 3, patients (and/or their parent or legal guardian) will be contacted for the post-day 29 
safety assessments described below at the time points listed in the respective schedules of events. 
These assessments will include vital status, pregnancy status, and targeted safety information. If 
no in-person procedures (eg, sample collections) are required, visit may occur remotely. Phone or 
telemedicine are the preferred methods of remote contact, but other modes of communication (eg, 
email) are acceptable if a patient cannot be contacted through other methods. 
Vital Status. Record vital status (whether the patient is dead or alive) and record the date of death, 
when applicable. 
Pregnancy Status. Record pregnancy status and date of pregnancy, when applicable. Refer to 
Section 10.1.3 for reporting requirements. 
Targeted Safety Information. Refer to Section 10 for more information on reporting and 
recording requirements. 
Safety Information in Newborns of Study Participants. The incidence and outcome of any 
SARS-CoV-2 infection will be collected for newborn infants of patients who were treated in the 
study and were pregnant at randomization or became pregnant at any time in the study. Note that 
this information is in addition to outcome reporting of all pregnancies (Section 10.1.3). 
9.2.6. 
Pregnancy Test for Women of Childbearing Potential 
Pregnancy testing may be satisfied by either serum pregnancy test or by urine β-HCG. Pregnancy 
tests are a requirement for WOCBP only and should be completed regardless of pregnancy status. 
Pregnancy test will be performed at the local laboratory. 
WOCBP are defined as females who are fertile following menarche until becoming 
postmenopausal, unless permanently sterile. A postmenopausal state is defined as no menses for 
12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level 
in the postmenopausal range may be used to confirm a postmenopausal state in women not using 
hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months 
of amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a 
postmenopausal state. The above definitions are according to Clinical Trial Facilitation Group 
(CTFG) guidance. Pregnancy testing is not required for women with documented hysterectomy or 
tubal ligation. 
Information about pregnancy will be recorded as described in Section 10.1.3. 
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9.2.7. 
Laboratory Testing 
Hematology and blood chemistry will be analyzed by a central laboratory. Detailed instructions 
are provided in the laboratory manual.  
Note that the laboratory tests listed below will only be performed based on samples that are 
collected according to the corresponding Schedules of Events. 
Blood Chemistry 
Tests will include: 
Sodium 
Blood urea nitrogen (BUN) 
Alkaline phosphatase  
Potassium 
Aspartate aminotransferase (AST) 
Creatinine 
Chloride 
Alanine aminotransferase (ALT) 
Creatine phosphokinase (CPK) 
Carbon dioxide 
Total bilirubin 
Lactate dehydrogenase (LDH) 
Glucose 
Albumin  
C-reactive protein 
Hematology 
Tests will include: 
Hemoglobin 
Differential: 
Neutrophils 
Hematocrit 
 
Lymphocytes 
Red blood cells (RBCs) 
 
Monocytes 
White blood cells (WBCs) 
 
Basophils 
Platelet count 
 
Eosinophils 
Other Laboratory Tests 
Coagulation tests: D-dimer, prothrombin time (PT/INR), activated partial thromboplastin time 
(aPTT). 
Abnormal Laboratory Values and Laboratory Adverse Events 
All laboratory values must be reviewed by the investigator or authorized designee. 
Significantly abnormal test results that occur after start of treatment must be repeated to confirm 
the nature and degree of the abnormality. When necessary, appropriate ancillary investigations 
should be initiated. If the abnormality fails to resolve or cannot be explained by events or 
conditions unrelated to the study medication or its administration, the Medical/Study Director must 
be consulted.  
The clinical significance of an abnormal test value, within the context of the disease under study, 
must be determined by the investigator. 
Criteria for reporting laboratory values are provided in Section 10.1.1. 
9.2.8. 
Drug Concentration Measurements and Samples 
Note: As of protocol amendment 9 US, the PK sub-study is no longer enrolling new participants. 
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Samples for assessment of drug concentration will be collected at the timepoints indicated in the 
schedule of events. For information concerning unused samples and exploratory research, refer to 
Section 9.2.10. 
In phase 3 cohort 1, approximately 600 patients will be enrolled in a PK sub-study (refer to 
Table 5). This sub-study will only be enrolled at a select number of participating sites. In cohort 1, 
only patients who are enrolled in the PK sub-study will have samples collected for drug 
concentrations. Additional samples for immunogenicity assessment will be also collected in these 
patients.  
9.2.9. 
Immunogenicity Measurements and Samples 
Samples for immunogenicity assessment will be collected for adult patients at the timepoints listed 
in the relevant schedule of events. For pediatric patients, samples may be assessed for ADA and 
NAb, if feasible. For information concerning unused samples and exploratory research, refer to 
Section 9.2.10. 
9.2.10. 
Exploratory Pharmacodynamic/Biomarker Analyses 
This section describes planned exploratory pharmacodynamic/biomarker analyses, some of which 
may not be reported in the CSR. Note that, in this adaptive master protocol, the analyses described 
in this section may be limited to particular or study phases or time periods during a study phase. 
Also note that any biological samples collected during the study which are not used for their 
planned purpose, or for which material remains after their planned analysis, may be kept for up 15 
years after study completion (or for a shorter time period if required per regional laws and 
regulations) for use in exploratory research related to how the study drugs work and to study 
SARS-CoV-2. 
9.2.10.1. Neutrophil–Lymphocyte Ratio 
Exploratory biomarkers, including the neutrophil-lymphocyte ratio (NLR), will be assessed. 
Neutrophil-lymphocyte ratio is as an inflammatory biomarker and is suggested to be an 
independent risk factor of the in-hospital mortality for COVID-19 patients. Assessment of NLR 
trends may help identify individuals with COVID-19 at higher risk of complications (Liu, 2020) 
(Qin, 2020). We will measure NLR as an exploratory endpoint and, as compared to placebo, and 
association with clinical endpoints will be evaluated. 
9.2.10.2. Serum and Plasma Biomarkers 
Changes in circulating concentrations of serum/plasma biomarkers associated with inflammation, 
coagulation, and disease progression will be assessed in REGN10933+REGN10987 group 
compared to the placebo group in phase 1 and phase 2. The association between changes in disease 
related biomarkers with clinical endpoints may be evaluated.  
Biomarkers may include (but are not limited to) CRP, LDH, D-dimer, and ferritin. CRP is a general 
inflammation marker that correlates with severity of COVID-19 including lung lesions, 
supplemental O2 requirements, and death (Luo, 2020) (Qin, 2020). LDH was identified as a 
predictive factor for early recognition of lung injury and advanced COVID-19 cases (Ruan, 2020) 
(Wang, 2020b) (Young, 2020). Ferritin is a general inflammation marker associated with severity 
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of COVID-19 (Qin, 2020). D-dimer levels >1 μg/mL have been reported to identify patients with 
poor prognosis for COVID-19 (Zhou, 2020). 
9.2.10.3. Virology 
Viral Sequencing 
In support of public health initiatives to track SARS-CoV-2 genetic variants, as well as to monitor 
for possible viral resistance, viral genome sequencing may be performed on viral nucleic acid 
isolated from nasopharyngeal swab, nasal swab, and/or saliva samples, at baseline and in cases of 
a positive RT-qPCR result. Sequencing analyses will consist of the entire viral genome, including 
the full gene sequence that encodes the SARS-CoV-2 S protein. 
Viral sequencing may be performed on post-treatment samples to assess the emergence of 
sequence variants and to understand the potential relationship between genetic mutations and mAb 
functional activity. Viral sequencing may also be done on placebo controls to determine whether 
any genetic mutations observed in the mAb treatment group are naturally emergent genetic 
variants.  
Viral variants suspected to confer decreased susceptibility to REGN10933 and/or REGN10987 
will be evaluated in nonclinical work separate from this protocol. 
The results of viral sequencing will be reported separately from the CSR. 
Viral Infectivity 
To explore the effects of REGN10933+REGN10987 on infectivity of SARS-CoV-2, we may use 
PFU, viral culture or viral subgenomic mRNA RT-qPCR assays. In vitro SARS-CoV-2 infectivity 
of cultured cells may be explored using NP samples. Infectivity of cells grown in culture may be 
assessed by PFU assays and/or immunofluorescence assays. We may also use sub-genomic viral 
mRNA transcript assays, such as RT-qPCR or subgenomic mRNA sequencing, or other measures 
of in vivo infectivity potential. Viral sub-genomic mRNA is transcribed only in infected cells and 
is not packaged into virions, and therefore may be an indicator of actively-infected cells. These 
data may be associated with RT-qPCR measuring viral load.  
The results of the viral infectivity assays may not be included in the clinical study report. 
9.2.10.4. Serological Immunoassays for Anti-SARS-CoV-2 Antibodies 
To explore the impact of baseline humoral activity against SARS-CoV-2 on the response to 
REGN10933+REGN10987, serological immunoassays will be used to detect antibodies at 
baseline against the SARS-CoV-2 S protein and/or N protein. Neutralization assays may also be 
used to evaluate the function of endogenous baseline anti-SARS-CoV-2 antibodies. Associations 
will be evaluated with clinical outcomes. Measurement of antibodies against the N protein post-
treatment will also be used to evaluate whether or not REGN10933+REGN10987 effect the 
endogenous humoral immune response to SARS-CoV-2. 
9.2.10.5. Serum and Plasma for Exploratory Research  
Research serum and plasma are being collected and banked for exploratory research related to 
COVID-19, SARS-CoV-2, REGN10933+REGN10987, host and viral biological pathways, and 
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other mechanisms related to disease activity and clinical outcomes. These serum and plasma 
samples may be used for complement and/or cytokine analysis (described below), as well as other 
analyses. 
9.2.10.6. Complement 
Complement activation has been hypothesized to contribute to the maladaptive inflammatory 
response seen in some patients with advanced COVID-19. Circulating complement biomarker 
concentrations may therefore be assessed in order to understand the involvement of the classical 
lectin and/or alternative complement pathways in the pathogenesis of COVID-19 and clinical 
outcomes. 
9.2.10.7. Cytokines 
The initial inflammatory responses to an infection are rapid and non-specific, regulated by 
proinflammatory cytokines such as interleukin-6 (IL-6). As IL-6 has been implicated in the 
severity of COVID-19, IL-6 and other cytokines, including but not limited to IL-8, IL-1ß, IFNγ, 
TNFα, IL-10 and MIP-1 may be measured. Additional cytokines may be interrogated through the 
use of cytokine panels. 
9.2.10.8. Serum and Plasma for Cardiac Biomarkers 
SARS-CoV-2 has been shown to infect the myocardium, and emerging evidence suggests that 
myocardial damage may be a long-term clinical consequence of COVID-19 (Lindner, 2020) 
(Puntmann, 2020). Cardiac biomarkers, including troponins, N-terminal pro B-type natriuretic 
peptide (NT-proBNP), and creatine kinase-MB (CK-MB), can be elevated in patients with 
COVID-19 and have been shown to correlate with adverse outcomes (Puntmann, 2020) (Sandoval, 
2020) (Shi, 2020). Relationships may be evaluated between these biomarkers, as well as other 
biomarkers and clinical outcomes in treatment versus placebo arms.  
If initial analyses reveal no signal of cardiac injury, subsequent analyses may be omitted. 
9.2.11. 
Monitoring for SARS-CoV-2 Reinfection 
Patients in phase 3 cohort 1 will be asked to report any positive SARS-CoV-2 local test results 
obtained outside of the study, starting from the day at which they consent to protocol amendment 
9 US. Test results obtained prior to the date of consent will not be collected. Positive results will 
be reported as an AESI, but will not require expedited reporting (Section 10.1.4). 
Details regarding the positive SARS-CoV-2 local test result (eg, date of testing, specimen type, 
assay used) will be captured in the corresponding AESI data collection page. 
9.2.12. 
Recording New Medical Diagnoses or Conditions 
In phase 3 cohort 1, any new medical condition(s) diagnosed after randomization (eg, newly 
diagnosed diabetes mellitus) will be captured and reported as an AESI, but will not require 
expedited reporting (Section 10.1.4). 
Patients who previously consented to protocol amendment 9 US but have already completed their 
end of study visit will be asked to consent to have this information collected. 
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Details regarding the new diagnoses or conditions (eg, preferred term [PT] for the diagnosis, date 
of diagnosis, and any other available information) will be captured in the corresponding AESI data 
collection page. 
9.2.13. 
Immunoprofiling Sub-Study (Optional) 
Up to 300 patients (cohort 1; cohort 3 ≥18 years old) may be enrolled at selected sites in an optional 
immunoprofiling sub-study to collect whole blood to isolate peripheral blood mononuclear cells 
(PBMCs) for immunoprofiling. Patients who agree to participate will be required to consent to this 
optional sub-study before collection of the samples. PBMCs from participants in this sub-study 
will be isolated from the whole blood at a central lab and stored for analysis. PBMCs will be used 
to 
characterize the 
cellular and humoral immune response to SARS-CoV-2 in 
REGN10933+REGN10987 treated patients as compared to placebo and as compared to baseline. 
Both B cell and T cell immune responses may be studied. Assays for B cell responses may include, 
but will not necessarily be limited to, quantification of spike subdomain specific B cells and plasma 
cells by antigen specific flow cytometry, and quantification of SARS-CoV-2 specific antibody 
responses in either primary ELISPOT assays or re-stimulation assays followed by ELISPOT. 
Studies focused on T cell responses may include, but may not be limited to, flow cytometry with 
isolated PBMCs to characterize immune subsets, quantify SARS-CoV-2 specific T cell responses 
via ex vivo peptide stimulation assays with downstream flow cytometry, or ELISPOT and/or 
cytokine measurements. Cell profiling may include bulk RNA (transcriptome) sequencing, T-cell 
receptor or B-cell receptor RNA or DNA sequencing.  
9.2.14. 
Pharmacogenomics Sub-Study (Optional) 
Eligible patients (≥18 years of age) who agree to participate in the genomics sub-study will be 
required to consent to this optional sub-study before collection of samples. Newly-enrolled patients 
will have blood samples collected for both DNA and RNA; patients who were previously enrolled 
and subsequently consent to the sub-study will only have a blood collection for DNA. Patients 
who have already consented to this sub-study cannot consent a second time. 
The blood sample for RNA must be collected pre-dose on day 1. Blood sample for DNA should 
be collected at the screening/baseline visit but may be collected at any visit.  
The samples will be collected for pharmacogenomics analyses to understand the genetic and/or 
transcriptional determinants of efficacy and safety associated with the treatments in this study and 
the molecular basis of COVID-19 (and long COVID, as applicable). These samples will be single-
coded as defined by the International Council for Harmonisation (ICH) guideline E15. Samples 
will be stored for up to 15 years after the final date of the database lock (or for a shorter time period 
if required per regional laws and regulations). If there are specific site or country requirements 
involving the pharmacogenomic analyses which the Sponsor is unable to comply with, samples 
will not be collected at those sites.  
The purpose of the pharmacogenomic analyses is to identify genomic and/or transcriptional 
associations with clinical or biomarker response to REGN10933+REGN10987, other COVID-19 
clinical outcome measures, and possible targeted TEAEs. In addition, associations between 
genomic variants and prognosis or progression of COVID-19 (and long COVID, as applicable). 
may also be studied. These data may be used or combined with data collected from other studies 
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to identify and validate genomic and transcriptional markers related to the study drug, target 
pathway, COVID-19, or long COVID.  
Analyses may include sequence determination or single nucleotide polymorphism studies of 
candidate genes and surrounding genomic regions. Other methods, including whole-exome 
sequencing, whole-genome sequencing, DNA copy number variation, and transcriptome 
sequencing (or other methods for quantitating RNA expression) may also be performed. The list 
of methods may be expanded to include novel methodology that may be developed during the 
course of this study or sample storage period.  
Results from the genomic and transcriptional analyses will not be reported in the CSR. 
9.2.15. 
Exploratory Patient-Reported Symptoms 
This section describes planned patient-reported symptom analyses, some of which may not be 
reported in the CSR. Note that, in this adaptive master protocol, the analyses described in this 
section may be limited to particular or study phases or time periods during a study phase. Note that 
any symptoms collected by the instruments described below will not be considered AEs and will 
not be reconciled with any AEs. 
SE-C19, PGIS, and PGIC 
The Symptom Evolution of COVID-19 (SE-C19) instrument was developed de novo by 
Regeneron with the aim to better understand the symptomatic course of COVID-19 infection over 
time and is based on current available evidence on symptoms of COVID-19 (Arentz, 2020)    
(Chen, 2020a) (Chen, 2020b) (Huang, 2020) (Lapostolle, 2020) (Mizrahi, 2020) (Song, 2020) 
(Wang, 2020a). Patients self-report symptoms using a compatible electronic device 
(eg, smartphone, tablet, laptop or personal computer). Patients are presented with a list of 
symptoms and are asked to identify all those that they are experiencing.  
Patients rate each identified symptom as mild, moderate, or severe at the worst moment within the 
last 24 hours. An ‘other’ category is also available, where a free text field allows the addition of 
any symptom that is not on the list. Each score is assigned a numeric value: 0 (no symptom), 1 
(mild symptom), 2 (moderate symptom), or 3 (severe symptom). Table 9 provides the symptoms 
evaluated in the SE-C19.  
Table 9: 
Symptoms Evaluated in the Symptom Evolution of COVID-19 (SE-C19) 
Instrument 
SE-C19 Symptoms Recorded and Planned for Analysis 
• Body aches such as 
muscle pain or joint pain 
• Chest pain 
• Chills 
• Confusion1 
• Cough 
• Diarrhea 
• Dizziness 
• Fatigue 
• Feverish 
• Headache 
• Loss of appetite 
• Loss of taste / smell 
• Nausea 
• Pressure / tight chest 
• Rash1 
• Red or watery eyes 
• Runny nose 
• Shortness of breath / difficulty 
breathing 
• Sneezing1 
• Sore throat 
• Sputum / phlegm 
• Stomachache 
• Vomiting1 
 
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1 Not included in the phase 3 key secondary analysis (Section 11.4.3.2)  
To aid interpretation, the SE-C19 is supplemented by the Patient Global Impression of Change 
(PGIC) and the Patient Global Impression of Severity (PGIS), which assess the overall subjective 
experience of symptom severity and change in symptoms over time. 
As a representation of the current available evidence of COVID-19 symptoms, the SE-C19 appears 
to have face validity for tracking symptom onset, severity, and recovery. Content validity was 
confirmed through an interview-based study of patients and clinicians, separate from this study.  
WPAI+CIQ 
Acute respiratory illnesses can lead to a significant economic burden owing to absenteeism and 
loss of workplace productivity (Li, 2007). The Work Productivity and Activity Impairment and 
Classroom Impairment Questions (WPAI+CIQ) questionnaire measures the effect of a specific 
health problem (eg, infection with SARS-CoV-2) on work productivity and activity impairment. 
The specific outcomes measured by the questionnaire are absenteeism (work time missed), 
presenteeism (impairment while working), overall work impairment (absenteeism plus 
presenteeism), and activity impairment (impairment in regular activities). Each score is 
represented as a percentage, with higher scores indicating less productivity or greater impairment. 
EQ-5D-5L  
The COVID-19 pandemic has resulted in a multisectoral global economic burden (Nicola, 2020), 
a significant portion of which is likely attributable to indirect costs related to school absenteeism, 
loss of workspace productivity, as well as health-related quality of life. Assessing the quality of 
life of individuals with SARS-CoV-2 is important, as it can aid in understanding the potential 
impact of interventions from the perspective of cost-utility analysis.  
The EQ-5D-5L is a validated and extensively published self-reported quality of life scale. The EQ-
5D-5L covers 5 health domains: mobility, self-care, usual activities, pain, and anxiety. Patients 
rate each domain on 5 level severity scale: having no problems, having slight problems, having 
moderate problems, having severe problems, and being unable to do/having extreme problems. In 
addition to the 5 domains, patients record their overall health on a visual analog scale, ranging 
from 0 (worst imaginable health state) to 100 (best imaginable health state).  
The EQ-5D-Y is a youth version of the adult scale designed and validated for use by children. It 
includes also 5 domains: mobility, looking after myself, doing usual activities, having pain or 
discomfort and feeling worried, sad or unhappy. 
9.2.16. 
Assessment of Long COVID 
To better understand the nature of long COVID, as well as the potential relationship between prior 
treatment of SARS-CoV-2 infection with REGN10933+REGN10987 and subsequent 
development of long COVID, study participants will be evaluated using questionnaires (SE-LC19, 
PGIS, PGIC return to usual health, return to usual activities, SF-36, WPAI+CIQ, EQ-5D-5L), as 
well as NP swab and blood sample collections. All questionnaires are self-reported using a 
compatible electronic device (eg, smartphone, tablet, laptop or personal computer).  
Note that patient-reported outcome data are generally not reportable as individual AEs, with 
exceptions as described in Section 10.1.1. 
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In addition to the procedures outlined in this study, exit interviews may be conducted by a third 
party as part of a separate study investigating the symptom experience and impact experience of 
COVID-19. Sites will facilitate the identification of eligible patients according to the pre-specified 
eligibility criteria of the separate study, and will provide patient contact information to the third 
party. Patients who meet eligibility criteria for this separate study may be contacted by the third 
party to determine their interest in the study. 
9.2.16.1. Patient-Reported Evaluation of Long COVID 
Symptom Evolution of Long COVID-19 (SE-LC19) 
In an effort to better understand the symptomatic course of long COVID, the Sponsor developed 
the Symptom Evolution of COVID-19 (SE-LC19). The SE-LC19 expands upon the SE-C19, 
which was developed with the aim of evaluating the acute phase of the disease course.  
The SE-LC19 consists of 40 symptoms, identified based on an evaluation of the currently-available 
literature on symptoms associated with long COVID (CDC, 2021) (NHS, 2021) (WHO, 2021).  
Participants are presented with a list of symptoms and are asked to identify all those that they are 
experiencing. Participants rate each symptom as mild, moderate, or severe at the worst moment 
within the last 24 hours. Each score is assigned a numeric value: 0 (no symptom), 1 (mild 
symptom), 2 (moderate symptom), or 3 (severe symptom). Table 10 lists the symptoms evaluated 
in the SE-LC19. 
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Table 10: 
Symptoms Evaluated in the Symptom Evolution of Long COVID-19 (SE-
LC19) Instrument 
Symptom Evolution of Long COVID-19 (SE-LC19) 
All SE-LC19 Symptoms 
SE-LC19 Category A 
SE-LC19 Category B 
SE-LC19 Category C 
Altered or loss of smell  
Altered or loss of smell  
Altered or loss of smell  
Altered or loss of smell  
Altered or loss of taste  
Altered or loss of taste  
Altered or loss of taste  
Altered or loss of taste  
Body aches such as muscle pain 
or joint pain  
Body aches such as muscle 
pain or joint pain  
Body aches such as muscle 
pain or joint pain  
Body aches such as muscle 
pain or joint pain  
Cough  
Cough  
Cough  
Cough  
Fatigue  
Fatigue  
Fatigue  
Fatigue  
Headache  
Headache  
Headache  
Headache  
Shortness of breath or difficulty 
breathing  
Shortness of breath or 
difficulty breathing  
Shortness of breath or 
difficulty breathing  
Shortness of breath or 
difficulty breathing  
Chest pain 
 
Chest pain 
Chest pain 
Feeling depressed  
Symptoms Included: 7 
Feeling depressed  
Feeling depressed 
Rapid, strong or irregular 
heartbeat 
 
Rapid, strong or irregular 
heartbeat 
Rapid, strong or irregular 
heartbeat 
Brain fog  
 
 
Brain fog  
Diarrhea  
 
Symptoms Included: 10 
Diarrhea  
Dizziness  
 
 
Dizziness  
Feeling Anxious  
 
 
Feeling Anxious  
Fever  
 
 
Fever  
Loss of concentration  
 
 
Loss of concentration  
Memory problems  
 
 
Memory problems  
Pins and needles or numbness  
 
 
Pins and needles or numbness  
Pressure or tightness in chest  
 
 
Pressure or tightness in chest  
Rash  
 
 
Rash  
Sore throat  
 
 
Sore throat  
Stomachache  
 
 
Stomachache  
Chills 
 
 
 
Confusion 
 
 
Symptoms Included: 22 
Difficulty sleeping 
 
 
 
Earache 
 
 
 
Feeling irritable 
 
 
 
Feeling lightheaded 
 
 
 
Hair loss 
 
 
 
Hot flushes 
 
 
 
Inability to find the right words  
 
 
Loss of appetite 
 
 
 
Nausea 
 
 
 
Phlegm 
 
 
 
Red or watery eyes 
 
 
 
Ringing or buzzing in ears 
 
 
 
Runny nose  
 
 
 
Sneezing 
 
 
 
Sweats 
 
 
 
Vomiting  
 
 
 
 
 
 
 
Symptoms Included: 40 
 
 
 
Category A: Symptoms defined as “lingering” and identified across all three guidelines. 
Category B: identified across all three guidelines. 
Category C: identified across at least two or three guidelines. 
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Guidelines: (CDC, 2021) (NHS, 2021) (WHO, 2021) 
Global Impression Items 
The Patient Global Impression of Severity (PGIS) and Patient Global Impression of Change 
(PGIC) questionnaires will assess the overall subjective experience of COVID-19 symptom 
severity and change in symptoms over time. The Return to Usual Health and Return to Usual 
Activities questionnaires will evaluate whether patients have returned to their usual health or 
activities prior to their COVID-19 illness. 
SF-36 
The SF-36 is a short-form, 36-question survey assessing health and quality of life. Questions are 
aggregated into eight scales, which each measure a distinct aspect of health. A score from 0 to 100 
is generated for each scale, where higher scores represent less disability on the scale. The scales 
are further aggregated into two summary scores (also ranging from 0 to 100), which measure 
overall physical health and mental health.  
WPAI+CIQ 
The Work Productivity and Activity Impairment and Classroom Impairment Questions 
(WPAI+CIQ) questionnaire measures the effect of a specific health problem (eg, infection with 
SARS-CoV-2) on work productivity and activity impairment. The specific outcomes measured by 
the questionnaire are absenteeism (work time missed), presenteeism (impairment while working), 
overall work impairment (absenteeism plus presenteeism), and activity impairment (impairment 
in regular activities). Each score is represented as a percentage, with higher scores indicating less 
productivity or greater impairment. 
EQ-5D-5L  
The EQ-5D-5L covers 5 health domains: mobility, self-care, usual activities, pain, and anxiety. 
Patients rate each domain on 5 level severity scale: having no problems, having slight problems, 
having moderate problems, having severe problems, and being unable to do/having extreme 
problems. In addition to the 5 domains, patients record their overall health on a visual analog scale, 
ranging from 0 (worst imaginable health state) to 100 (best imaginable health state).  
9.2.16.2. Nasopharyngeal Swab Sample and Blood Sample Collections (Long COVID 
Assessment) 
Nasopharyngeal (NP) swab samples will be collected to assess the presence or absence of SARS-
CoV-2 by RT-qPCR, and may be used for viral sequencing as described in Section 9.2.10.3. 
Additional details regarding sample collection can be found in the laboratory manual. 
In the event of a positive RT-qPCR, the investigator will be notified so that the patient may be 
informed of the result. Clinical management of a positive test result is deferred to the investigator 
or caring physician. As central laboratory test results may not be available in real time, any 
symptoms that may be related to acute COVID-19 infection should be tested and managed 
according to standard of care. 
Serum, plasma, and PBMC samples will be collected and banked for subsequent analyses. Such 
analyses may include, but are not limited to, multiplex proteomic profiling, high-throughput RNA 
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sequencing, flow cytometry, and serologic immunoassays to detect antibodies against SARS-CoV-
2.  
The serum, plasma, and PBMC-based analyses will be used to address scientific questions related 
to long COVID, such as the identification of prognostic biomarkers, understanding whether long 
COVID represents a single versus multiple unique pathologies, and associating biomarker profiles 
with patient-reported outcomes data. Analyses performed from banked samples may also be 
integrated with biomarker and other data from samples that were collected during the acute phase 
of SARS-CoV-2 infection. This will enable relationships between acute and long-term phases of 
COVID-19 to be explored, including better understanding the biology of COVID-19 over time, 
and evaluating potential biomarkers during acute infection that may be predictive of casirivimab 
and imdevimab response during the long-term phase of disease. 
Unused or residual samples may be retained as described in Section 9.2.10. 
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10. 
SAFETY EVALUATION AND REPORTING 
10.1. 
Recording and Reporting Adverse Events  
10.1.1. 
General Guidelines 
Only targeted TEAEs will be recorded: 
• All phases: Treatment-emergent SAEs, up to day 29  
• Phase 1 and phase 2 only: Treatment-emergent AESIs, defined as grade ≥2 IRRs and 
grade ≥2 hypersensitivity reactions (see Section 10.1.3), up to day 29  
• Phase 1 only: TEAEs (grade 3 or grade 4 only), up to day 29  
• Phase 3 only, all cohorts: Treatment-emergent AESIs, defined as grade ≥2 IRRs, 
grade ≥2 hypersensitivity reactions, and any TEAE that led to a medically-attended 
visit (see Section 10.1.3), up to day 29  
• Phase 3 only, all cohorts: Treatment-emergent SAEs from day 30 to day 169  
• Phase 3 only, cohort 2 (and cohort 3 patients <18 years) only: Grade 3 and grade 4 
TEAEs, up to day 29 
• Phase 3 only, cohort 1: Positive SARS-CoV-2 local test result, from the day of consent 
to protocol amendment 9 US until day 169 
• Phase 3 only, cohort 1: Any new medical condition that was diagnosed after 
randomization, until day 169 
The investigator must promptly the above targeted TEAEs occurring during the observation period 
(see Section 11.4.5.1). Note that the length of this period differs in each study phase, owing to 
different final study visit days. Medical conditions that existed or were diagnosed prior to the 
signing of the informed consent will be recorded as part of medical history. Abnormal laboratory 
values and vital signs observed at the time of informed consent should also be recorded as medical 
history. Any subsequent worsening (ie, any clinically significant change in frequency and/or 
intensity) of a pre-existing condition that is temporally associated with the use of the study drug 
should also be recorded as TEAE, provided that it fulfills the above criteria. 
Throughout the study, the investigator will determine whether any targeted TEAEs occurred by 
evaluating the patient. These events may be directly observed, reported spontaneously by the 
patient, or by questioning the patient at each study visit. Patients should be questioned in a general 
way, without asking about the occurrence of any specific symptoms. The investigator must assess 
all TEAEs to determine seriousness, severity, and causality, in accordance with the definitions in 
Section 10.2. The investigator’s assessment must be clearly documented in the site’s source 
documentation with the investigator’s signature. The investigator should follow up on targeted 
TEAEs until they have resolved or are considered clinically stable. 
Always report the diagnosis as the AE term. When a diagnosis is unavailable, report the primary 
sign or symptom as the AE term with additional details included in the narrative until the diagnosis 
becomes available. If the signs and symptoms are distinct and do not suggest a common diagnosis, 
report them as individual entries.  
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Laboratory results, vital signs, and other diagnostic results or findings should be appraised by the 
Investigator to determine their clinical significance. Isolated abnormal laboratory results, vital sign 
findings, or other diagnostic findings (ie, not part of a reported diagnosis) should be reported as 
AEs if they are symptomatic, require corrective treatment, or constitute an AE in the investigator’s 
clinical judgement. For events that are serious due to hospitalization, the reason for hospitalization 
must be reported as the serious adverse event (diagnosis or symptom requiring hospitalization). A 
procedure is not an AE or SAE, but the reason for the procedure may be an AE or SAE. Pre-
planned (prior to signing the informed consent form [ICF]) procedures, treatments requiring 
hospitalization for pre-existing conditions that do not worsen in severity, and admission for 
palliative or social care should not be reported as SAEs (see Section 10.2 for definitions).  
For deaths, the underlying or immediate cause of death should always be reported as an SAE.  
Any SAE occurring subsequent to the reporting period (end of study) that the investigator assesses 
as related to study drug should be reported. In addition, any SAE resulting in death that occurs 
prior to study day 169 should also be reported, regardless of patient withdrawal or early 
termination. 
All treatment-emergent SAEs, AESIs, and pregnancies are to be reported according to the 
procedures in Section 10.1.3. 
Note that patient-reported outcome (PRO) data (eg, patient-reported questionnaires, surveys, and 
instruments) are generally not reportable as individual AEs. However, if the investigator is made 
aware of any AE that (in his or her judgement) is related to study drug, the AE will be reported 
and recorded as described in Section 10.1.2. 
10.1.2. 
Reporting Procedure 
The targeted treatment-emergent AEs defined in Section 10.1.1 must be reported with 
investigator’s assessment of the event’s seriousness, severity, and causality to the blinded study 
drug. A detailed narrative summarizing the course of the event, including its evaluation, treatment, 
and outcome should be provided on the AE eCRF. Specific or estimated dates of event onset, 
treatment, and resolution should be included, when available. Medical history, concomitant 
medications, and laboratory data that are relevant to the event should also be summarized in the 
narrative. For fatal events, the narrative should state whether an autopsy was or will be performed 
and include the results if available. Information not available at the time of the initial report must 
be documented in a follow-up report. Source documents (including hospital or medical records, 
diagnostic reports, etc) will be summarized in the narrative on the AE eCRF and retained at the 
study center and available upon request.  
Urgent safety queries must be followed up and addressed promptly. Follow-up information and 
response to non-urgent safety queries should be combined for reporting to provide the most 
complete data possible within each follow-up. 
10.1.3. 
Events that Require Expedited Reporting to Sponsor 
The following events also require reporting to the Sponsor (or designee) within 24 hours of 
learning of the event: 
Treatment-emergent SAEs. 
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Treatment-emergent AESI (serious and nonserious), defined as:  
• Grade ≥2 infusion-related reactions 
• Grade ≥2 hypersensitivity reactions  
• Phase 3 only: Any treatment-emergent adverse event that led to a medically-attended 
visit, regardless of whether the visit is related to COVID-19 
Note: pre-planned or prescheduled medical appointments will not be considered 
medically-attended visits 
• Pregnancy. Although pregnancy is not considered an AE, it is the responsibility of the 
investigator to report to the Sponsor (or designee), within 24 hours of identification, 
any pregnancy occurring in a female study patient during the study or existing at the 
time of signing the informed consent form. A paper pregnancy report form must be 
completed for each patient who becomes pregnant or is pregnant at the signing of 
consent.  
Any complication of pregnancy affecting a female study patient and/or fetus and/or 
newborn that meets the SAE criteria must be reported as an SAE. Outcome for all 
pregnancies should be reported to the Sponsor, including testing results for 
SARS-CoV-2 infection in the newborn, if performed. 
10.1.4. 
Other Adverse Events of Special Interest That Do Not Require Expedited 
Reporting to Sponsor 
The following is considered an AESI and will require additional data collection. However, these 
AESIs do not require expedited reporting to the Sponsor: 
• Phase 3 cohort 1 only: positive SARS-CoV-2 local test result (Section 9.2.11)  
• Phase 3 cohort 1 only: any new medical condition that was diagnosed after 
randomization (Section 9.2.12) 
10.2. 
Definitions 
10.2.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study drug which may or 
may not have a causal relationship with the study drug. Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease which is temporally 
associated with the use of a study drug, whether or not considered related to the study drug (ICH 
E2A Guideline. Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting, Oct 1994). 
10.2.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death – includes all deaths, even those that appear to be completely unrelated 
to study drug (eg, a car accident in which a patient is a passenger). 
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• Is life-threatening – in the view of the investigator, the patient is at immediate risk of 
death at the time of the event. This does not include an adverse event that had occurred 
in a more severe form, might have caused death. 
• Requires in-patient hospitalization (admission after discharge) or prolongation of 
existing hospitalization. In-patient hospitalization is defined as a hospital admission 
(any duration) or an emergency room visit for longer than 24 hours. Prolongation of 
existing hospitalization is defined as a hospital stay that is longer than was originally 
anticipated for the event or is prolonged due to the development of a new adverse event 
as determined by the investigator or treating physician. 
• Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions).  
• Is a congenital anomaly/birth defect 
• Is an important medical event – Important medical events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or 
may require intervention to prevent one of the other serious outcomes listed above (eg, 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse).  
Criteria for reporting SAEs must be followed for these events (refer to Section 10.1.1 
Section 10.1.2).  
10.2.3. 
Adverse Events of Special Interest 
An AESI (serious or non-serious) is one of scientific and medical interest specific to the Sponsor’s 
product or program, for which ongoing monitoring and rapid communication by the investigator 
to the Sponsor can be appropriate. Such an event might warrant further investigation in order to 
characterize and understand it.  
Adverse events of special interest for this study are defined in Section 10.1.3. 
10.2.4. 
Infusion-Related Reactions and Hypersensitivity Reactions 
Infusion-related reactions are defined as any relevant adverse events that occurs during the infusion 
or up to day 4.  
Hypersensitivity reactions are defined as any relevant adverse event that occurs during the infusion 
or up to study day 29. 
10.2.5. 
Severity 
The severity of adverse events (including test findings classified as adverse events) will be graded 
using the current version of the NCI-CTCAE v5.0 (Division of Cancer Treatment and Diagnosis 
[DCTD], 2020). 
Treatment-emergent AEs, SAEs or AESIs not listed in the NCI-CTCAE will be graded according 
to the scale in Table 11. 
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Table 11: 
NCI-CTCAE Severity Grading System for Adverse Events (v5.0)  
Grade 
Severity 
Description 
1  
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
2  
Moderate 
Minimal, local, or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (ADL)1 
3  
Severe 
Severe or medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL2 
4  
Life-threatening 
Life threatening consequences; urgent intervention indicated 
5  
Death 
Death related to adverse events 
1 Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
2 Self-care ADL refers to bathing, dressing, and undressing, feeding self, using the toilet, taking medications, and 
not bedridden.  
10.2.6. 
Causality 
The investigator must provide causality assessment as whether or not there is a reasonable 
possibility that the drug caused the adverse event, based on evidence or facts, his/her clinical 
judgment, and the following definitions. The causality assessment must be made based on the 
available information and can be updated as new information becomes available. 
The following factors should be considered when assessing causality: 
• Temporal relationship: time to onset versus time drug was administered 
• Nature of the reactions: immediate versus long term 
• Clinical and pathological features of the events  
• Existing information about the drug & same class of drugs  
• Concomitant medications  
• Underlying and concurrent illnesses  
• Patient’s medical and social history  
Causality to the study drug (including study drug administration): 
• Related: 
− The adverse event follows a reasonable temporal sequence from study drug 
administration and cannot be reasonably explained by the nature of the reaction, 
patient’s clinical (eg, disease under study, concurrent diseases, concomitant 
medications), or other external factors. 
or 
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− The adverse event follows a reasonable temporal sequence from study drug 
administration and is a known reaction to the drug under study or its class of drugs 
or is predicted by known pharmacology. 
• Not Related: 
− The adverse event does not follow a reasonable sequence from study drug 
administration or can be reasonably explained by the nature of the reaction, 
patient’s clinical state (eg, disease under study, concurrent diseases, and 
concomitant medications) or other external factors. 
Causality to the study conduct (protocol specified procedure): 
• Related: 
− The adverse event follows a reasonable temporal sequence from a protocol 
specified procedure and cannot be reasonably explained by the nature of the 
reaction, patient’s clinical (eg, disease under study, concurrent diseases, 
concomitant medications), or other external factors. 
• Not Related: 
− The adverse event does not follow a reasonable sequence from a protocol specified 
procedure or can be reasonably explained by the nature of the reaction, patient’s 
clinical state (eg, disease under study, concurrent diseases, and concomitant 
medications) or other external factors. 
10.3. 
Safety Monitoring 
The investigator will monitor the safety of study patient at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP). Any questions or 
concerns should be discussed with the Sponsor in a timely fashion. The Sponsor will monitor the 
safety data from across all study sites. The Medical/Study Director will have primary responsibility 
for the emerging safety profile of the compound, but will be supported by other departments 
(eg, Global Patient Safety; Biostatistics and Data Management). Safety monitoring will be 
performed on an ongoing basis (eg, individual review of SAEs) and on a periodic cumulative 
aggregate basis. 
10.4. 
Notifying Health Authorities, Institutional Review Board, Ethics 
Committee, and Investigators 
During the study, the Sponsor and/or the CRO will inform health authorities, ECs/Institutional 
Review Board (IRBs), and the participating investigators of any SUSARs (Suspected Unexpected 
Serious Adverse Reactions) occurring in other study centers or other studies of the active study 
drug, as appropriate per local reporting requirements. In addition, the Sponsor and/or CRO will 
comply with any additional local safety reporting requirements. All notifications to investigators 
will contain only blinded information.  
Upon receipt of the Sponsor’s notification of a SUSAR that occurred with the study drug, the 
investigator will inform the IRB/EC unless delegated to the Sponsor. 
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Event expectedness for study drug is assessed against the Reference Safety Information section of 
the Investigator’s Brochure that is effective for expedited safety reporting.  
At the completion of the study, the Sponsor will report all safety observations made during the 
conduct of the trial in the Clinical Study Report to health authorities and ECs/IRB as appropriate. 
11. 
STATISTICAL PLAN 
This section provides the basis for the statistical analysis plans (SAPs) for the study. The SAPs 
may be revised during the study to accommodate amendments to the clinical study protocol, and 
to make changes to adapt to unexpected issues in study execution and data that may affect the 
planned analyses. The initial phase 1/2 SAP describes the interim descriptive analysis of data from 
the first 275 symptomatic patients enrolled in this study. The phase 2 SAP describes the primary 
phase 2 analysis based on data from the first 799 symptomatic patients in the study. A SAP for 
phase 3 will provide additional details for the analysis of phase 3 data. The final SAPs will be 
issued before the database lock in each portion of the study.  
This master protocol is intended to allow for adaptations, including dropping of a treatment group, 
addition of new treatment arms with other anti-SARS-CoV-2 S protein mAbs as they become 
available for clinical testing, determination of the primary endpoints for phase 3, and sample size 
re-estimation for phase 2 and 3. Therefore, treatment groups in phase 3 and analyses for phase 3 
will depend on the final endpoints and treatment groups selected based on phase 2 results. 
Phase 3 will be powered and analyzed independently of phase 2, in order to ensure that phase 3 is 
confirmatory and to avoid inflating type I error rate in phase 3. 
Endpoints are listed in Section 3.2.1.6. Analysis variables are summarized in Section 5.  
11.1. 
Statistical Hypothesis  
Phase 1 
The safety and tolerability objectives of phase 1 will be evaluated by estimating the proportion of 
patients with treatment-emergent SAEs through day 29, hypersensitivity reactions (grade ≥2) 
through day 29, and infusion-related reactions through day 4.  
Phase 2 
The statistical hypotheses for the primary virologic efficacy endpoint for the phase 2 symptomatic 
cohort portion of the study are as follows: 
• H0: There is no treatment difference between REGN10933+REGN10987 2400 mg and 
8000 mg combined group and placebo in terms of time weighted average change from 
baseline in viral load (log10 copies/mL) from day 1 to day 7  
• H1: There is treatment difference between REGN10933+REGN10987 2400 mg and 
8000 mg combined group and placebo in terms of time weighted average change from 
baseline in viral load (log10 copies/mL) from day 1 to day 7  
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Phase 3 
The statistical hypotheses for the primary clinical efficacy endpoint for the phase 3 cohort 1 portion 
of the study are as follows: 
• H0: The risk of a patient having ≥1 COVID-19-related hospitalization, or all-cause 
death through day 29 for REGN10933+REGN10987 2400 mg group is the same as that 
for placebo 
• H1: The risk of a patient having ≥1 COVID-19-related hospitalization, or all-cause 
death through day 29 for REGN10933+REGN10987 2400 mg group is not the same as 
that for placebo 
11.2. 
Justification of Sample Size 
Phase 2  
The sample size for phase 2 is based on the primary virologic endpoint of time-weighted average 
change from baseline in viral load (log10 copies/mL) from day 1 to day 7, using a two-sample t-test 
at a two-sided significance of α=0.05.  
Due to lack of published data on the variation of time-weighted average change from baseline in 
viral load in COVID-19, the standard deviation of actual viral load values at a timepoint from the 
literature was used for sample size calculation.  
Assuming standard deviation of 2.1 log10 copies/mL (Cao, 2020), a sample size of 20 patients per 
arm in phase 1 will have at least 80% power to detect a difference of 1.91 log10 copies/mL. The 
smallest treatment difference that will result in p<0.05 is approximately 1.34 log10 copies/mL. A 
total sample size of 60 patients is planned for phase 1 including patients randomized to placebo 
and the 2 REGN10933+REGN10987 combination therapy arms. 
Assuming that 23% of the patients may have missing baseline values or drop out early, and 
assuming a standard deviation of 2.1 log10 copies/mL (Cao, 2020), a sample size of 130 patients 
per arm per cohort in phase 2 will have at least 80% power to detect a difference of 
0.84 log10 copies/mL. If a standard deviation of 3.8 log10 copies/mL is assumed (Wang, 2020c), 
the detectable difference would be 1.51 log10 copies/mL. Based on this per-arm per cohort sample 
size calculation, a total sample size of approximately 780 patients is needed. This includes 
390 patients in the symptomatic and asymptomatic cohorts (randomized to placebo and to the 
2 REGN10933+REGN10987 combination therapy doses). For the clinical endpoint of proportion 
of patients with ≥1 COVID-19-related medically-attended visit, assuming a 30% rate in the control 
arm, the smallest treatment difference that will result in p<0.05 is approximately 11%. 
Phase 3 Cohort 1 
The sample size of phase 3 cohort 1 is based on having sufficient power to analyze the primary 
endpoint (Section 4.1) in the modified full analysis set (mFAS; Section 11.3.1).  
Based on data from the phase 2 analysis involving the first 799 symptomatic patients enrolled, as 
well as blinded phase 3 data, the Sponsor assumes an event rate of 3.4% for COVID-19-related 
hospitalization or all-cause death among patients on placebo in the mFAS (patients with at least 1 
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risk factor for severe COVID-19 and a positive SARS-CoV-2 RT-qPCR test at baseline), and that 
83% of randomized patients will have a positive SARS-CoV-2 RT-qPCR test at baseline.  
Table 12 presents estimated number of randomized patients with at least 1 risk factor for severe 
COVID-19 at each analysis time point for cohort 1 efficacy analysis. 
Table 12: 
Estimated Sample Sizes at Each Analysis Time Point for Phase 3 Patients 
with ≥1 Risk Factor for Severe COVID-19 
 
Placebo 
FAS (mFAS)1 
1200 mg 
FAS (mFAS)1 
2400 mg 
FAS (mFAS)1 
8000 mg 
FAS (mFAS)1 
Total 
FAS (mFAS)1 
Pre-Amendment 6 patients 
662 (550) 
Not 
applicable 
662 (550) 
662 (550) 
1986 (1650) 
Amendment 6/7 randomized by 
17 January 2021 
841 (698) 
841 (698) 
841 (698) 
N/A 
2523 (2094) 
Final analysis, 2400 mg vs. 
placebo (randomized by 17 
January 2021) 
1503 (1248) 
 
1503 (1248) 
 
 
Interim analysis, 1200 mg vs. 
placebo 
(randomized 
by 
17 
January 2021) 
841 (698) 
841 (698) 
 
 
 
Amendment 6/7 randomized by 
24 February 2021 
1352 (1122) 1352 (1122) 1352 (1122) 
N/A 
4056 (3366) 
Final analysis, 1200 mg vs. 
placebo (randomized by 24 
February 2021) 
1352 (1122) 1352 (1122) 
 
 
 
1 FAS estimates only include those in FAS with ≥1 risk factor for severe COVID-19. 
The final primary efficacy analysis for the 2400 mg dose group versus placebo comparison will be 
performed based on patients randomized on or before 17 January 2021, which includes 
approximately 1503 randomized patients with COVID-19 risk factors per group in the 2400 mg 
dose group and the placebo group (1248 per group in the mFAS). With this sample size, the study 
will have approximately 76% power to detect a significant treatment effect in the proportion of 
patients with ≥1 COVID-19-related hospitalization or all-cause death in mFAS at a 2-sided α of 
0.05, assuming 3.4% of patients in the placebo group and 1.7% of patients in the 2400 mg group 
have an event (ie, a 50% reduction with REGN10933+REGN10987 treatment). If there is a greater 
treatment difference, such as a 60% reduction, the study will have at least 90% power to detect a 
significant treatment effect in the proportion of patients with ≥1 COVID-19-related hospitalization 
or all-cause death. 
The final efficacy analysis of the 1200 mg dose group versus placebo comparison will be 
performed in approximately 1352 patients with COVID-19 risk factors per dose group 
(approximately 1122 per dose group estimated in the mFAS), representing the cohort of patients 
enrolled starting in Protocol Amendment 6 (ie, when the 1200 mg dose was introduced) through 
February 24, 2021, the last date that enrollment into the placebo group was allowed. This analysis 
will only include patients who were concurrently randomized to either the 1200 mg dose group or 
the placebo group. The study will have approximately 72% power to detect a significant treatment 
effect in the proportion of patients with ≥1 COVID-19-related hospitalization or all-cause death in 
the mFAS at a 2-sided α of 0.05 assuming 3.4% of patients in the placebo group and 1.7% of 
patient in the 1200 mg group have an event (ie, a 50% reduction). If there is a greater treatment 
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difference, such as a 60% reduction, the study will have approximately 88% power to detect a 
significant treatment effect in the proportion of patients with ≥1 COVID-19-related hospitalization 
or all-cause death. 
From 25 February 2021 onward, the Sponsor plans to randomize up to 1500 patients 1:1 to either 
the 1200 mg dose group or the 2400 mg dose group, in addition to the patients already enrolled 
under protocol amendment 6 and protocol amendment 7, to have adequate precision to estimate 
the difference in the proportion of patients with a COVID-19-related hospitalization or death 
between the 2 dose groups. For example, assuming an event rate of 1.7% in each group, with a 
total of approximately 2100 concurrently randomized patients per arm (1744 per arm in mFAS) in 
1200 mg and 2400 mg dose groups, a 2-sided 95% confidence interval for the difference will 
extend approximately 1% from the observed difference. Blinded sample size re-estimation may be 
performed based on the pooled observed event rates. 
EAST v6.0 software was used for sample size calculation. 
Phase 3 Cohort 2 and Cohort 3 
Up to approximately 180 pediatric patients in cohort 2 is planned with a goal of approximately 
52 patients exposed to each dose of study drug, which is considered adequate to describe the drug 
concentrations over time. In cohort 2, there will be an enrollment of approximately 20 patients 
<10 kg (10 per treatment group) and 20 patients between ≥10 kg and <40 kg (10 per treatment 
group). 
In cohort 3, no minimum or maximum enrollment is planned. Cohort 3 will be analyzed 
descriptively for safety and may be analyzed descriptively for clinical and virologic outcomes. 
Note that cohort 2 and cohort 3 may continue to enroll after enrollment of cohort 1 has been 
completed. 
11.3. 
Analysis Sets  
11.3.1. 
Efficacy Analysis Sets 
Phase 1/2 (Symptomatic) 
The phase 1/2 portion of the study includes all symptomatic patients up to the 799th randomized 
symptomatic patient. The full analysis set (FAS) includes all randomized symptomatic patients in 
phase 1/2 and is based on the treatment allocated (as randomized). The modified full analysis set 
(mFAS) includes all randomized patients with positive RT-qPCR in NP swab samples at 
randomization and is based on the treatment allocated (as randomized). The seronegative FAS or 
seronegative mFAS are defined as all randomized patients with documented seronegative status at 
baseline in FAS or mFAS, respectively. Both mFAS and FAS will be used for the summaries of 
demographic and baseline characteristics and analysis of clinical/biomarker endpoints. mFAS will 
be used for the analysis of all efficacy endpoints, based on the principle that an anti-viral agent 
would only be anticipated to provide efficacy in patients with measurable virus at baseline. The 
seronegative mFAS will be used for the analysis of certain virologic endpoints and in descriptive 
analyses of certain clinical endpoints. 
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Phase 2 (Asymptomatic) 
Full analysis set (FAS), mFAS, and seronegative mFAS for asymptomatic patients are defined 
similarly as above.  
Phase 3 (Cohort 1) 
Only patients with COVID-19 symptoms will be included in phase 3. All symptomatic patients 
from the 800th randomized symptomatic patient will be included in phase 3. For phase 3 cohort 1, 
the full analysis set (FAS) includes all randomized symptomatic patients and is based on the 
treatment allocated (as randomized). The FAS includes patients with and without risk factors for 
severe COVID-19. 
The definition of the modified full analysis set (mFAS) for phase 3 is different from phase 2. In 
phase 3, the mFAS includes all randomized patients with a positive SARS-CoV-2 central lab-
determined RT-qPCR test from nasopharyngeal (NP) swab samples at randomization, and with at 
least one risk factor for severe COVID-19 at baseline. If pre-dose virologic results from the 
qualitative test are missing, then results from post-dose sample may be used to determine the 
qualitative PCR status at baseline, as long as the sample was collected within 2 hours after starting 
the study drug infusion. The mFAS is based on the treatment allocated (as randomized). The 
seronegative mFAS is defined as all randomized patients with documented seronegative status at 
baseline in the mFAS.  
Both mFAS and FAS will be used for the summaries of demographic and baseline characteristics. 
The mFAS will be used for the analysis of clinical, symptoms, and virologic endpoints. The 
seronegative mFAS will be used for the analysis of certain virologic endpoints and in analyses of 
certain clinical endpoints. Data from patients with no risk factors will be summarized descriptively. 
For the analyses of the 1200 mg group comparing to placebo, only patients concurrently 
randomized (ie, after protocol amendment 6 is implemented) will be included in the above analysis 
sets. 
Phase 3 (Cohort 2) 
The FAS includes all randomized patients in phase 3 cohort 2 and is based on the treatment 
allocated (as randomized). The modified full analysis set (mFAS) includes all randomized patients 
with positive RT-qPCR in NP swab samples at randomization and is based on the treatment 
allocated (as randomized). If pre-dose results from the qualitative test are missing, then results 
from post-dose sample may be used to determine the qualitative PCR status at baseline, as long as 
the sample was collected within 2 hours after starting the study drug infusion. The seronegative 
mFAS is defined as all randomized patients with documented seronegative status at baseline in the 
mFAS. 
Phase 3 (Cohort 3) 
Data on all patients in cohort 3 will be utilized in the analyses. 
11.3.2. 
Safety Analysis Set 
The safety analysis set (SAF) includes all randomized patients who received any study drug; it is 
based on the treatment received (as treated). Determination of “as treated” will be based on the 
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actual study drug received on day 1. Demographic and baseline characteristics, treatment 
compliance/administration and all clinical safety variables will be analyzed using the SAF. 
11.3.3. 
Pharmacokinetic Analysis Set 
The PK analysis population includes all patients who received any study drug and who had at least 
1 non-missing result following the first dose of study drug. Patients will be analyzed based on 
actual treatment received. 
11.3.4. 
Immunogenicity Analysis Sets 
The ADA analysis set (AAS) includes all patients who received study drug and had at least 1 non-
missing ADA result from the ADA assay after first dose of the study drug. Patients will be analyzed 
according to the treatment actually received.  
Samples positive in the ADA assay will be characterized further for ADA titers and for the 
presence of neutralizing antibody (Nab). The NAb analysis set (NAS) includes all patients who 
received any study drug and who are negative in the ADA assay or with at least one non-missing 
result in the NAb assay after first dose of the study drug. Patients will be analyzed according to 
the treatment actually received.  
11.4. 
Statistical Methods  
For continuous variables, descriptive statistics will include the following information: the number 
of patients reflected in the calculation (n), mean, standard deviation, Q1, median, Q3, minimum, 
and maximum. For categorical or ordinal data, frequencies and percentages will be displayed for 
each category. 
Stratification factors are provided in Section 8.5.1. 
Statistical analyses will be performed using Statistical Analysis System (SAS) Version 9.4 or 
higher. 
11.4.1. 
Patient Disposition 
The following will be provided: 
• The total number of screened patients: informed consent was signed (by the patient if 
at or above the country’s age of legal adulthood, or by patient’s parent[s] or legal 
guardian[s] if below the country’s age of legal adulthood)  
• The total number of randomized patients: received a randomization number 
• The total number of patients who discontinued the study, and the reasons for 
discontinuation 
• The total number of patients who discontinued from study treatment, and the reasons 
for discontinuation 
• A listing of patients treated but not randomized, patients randomized but not treated, 
and patients randomized but not treated as randomized 
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• A listing of patients prematurely discontinued from treatment, along with reasons for 
discontinuation 
11.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics including medical history will be summarized 
descriptively for each phase by treatment group, and by all patients combined.  
11.4.3. 
Efficacy Analyses 
11.4.3.1. Primary Efficacy Analysis 
Phase 2 
The primary virologic efficacy variable for phase 2 is time-weighted average change from baseline 
in viral load from day 1 to day 7, as measured by RT-qPCR in NP swab samples for the 
symptomatic cohort. The estimand for the primary hypothesis is the difference in means between 
each of the anti-spike SARS-CoV-2 mAb treatments and placebo (as well as pooled doses and 
placebo). Data collected after use of convalescent serum therapy will be excluded from efficacy 
analysis. All other available data will be used in the analysis regardless of intercurrent events such 
as rescue medication or discontinuation, ie, treatment policy approach. Analysis will be performed 
for patients with baseline viral load >107 copies/mL in the mFAS, for patients with baseline viral 
load >106 copies/mL in the mFAS, seronegative mFAS and for mFAS (with serostatus added to 
the ANCOVA model as a factor). 
The analyses will be based on the observed data with no imputation for missing data except the 
following cases: uncertain viral load values with less than the lower limit of quantification of the 
PCR assay but with positive qualitative results are imputed with half of lower limit of 
quantification of the PCR assay; uncertain values with negative RNA are imputed with 
0 log10 copies/mL if the reason for the uncertain values is not a failed test. The primary efficacy 
variable will be calculated using trapezoidal rule, ie, area under the curve for change from baseline 
at each time point from day 1 to last observation divided by the number of days from day 1 to day 
of last observation. The variable is analyzed using an Analysis of Covariance (ANCOVA) model 
with treatment group, country, and risk factor (no risk factor versus at least 1 risk factor) based on 
clinical database data as fixed effects and baseline viral load and treatment by baseline interaction 
as covariates. 
The least squares means estimates for the time-weighted average mean change from baseline in 
viral load for each treatment group, as well as the difference between each anti-spike mAb 
treatment arm and placebo as well as between combined dose group and placebo, will be presented 
along with the corresponding p-value, standard error, and associated 95% confidence interval. 
Accompanying descriptive analyses will be provided at the individual timepoints used to calculate 
the TWA. 
At time of writing of protocol amendment 6, phase 2 analyses were complete and the protocol has 
been updated for consistency with the SAP for phase 2. 
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Phase 3 Cohort 1 
The primary efficacy endpoint for phase 3 cohort 1 is the proportion of patients with ≥1 
COVID-19-related hospitalization or all-cause death through day 29, which will be compared 
between each dose group and placebo using the stratified Cochran-Mantel-Haenszel (CMH) test 
with country as a stratification factor. P-values from the stratified CMH test and 95% confidence 
intervals for the risk ratio and relative risk reduction (1-risk ratio) using Farrington-Manning 
method will be presented. Exact method for p-values and confidence intervals will be used if the 
expected frequencies in all cells are not at least 5. The primary analysis will be performed based 
on mFAS. As key secondary analyses, the same analyses will be performed for patients with high 
baseline viral load (>106 copies/mL) in the mFAS and for seronegative mFAS, and for proportion 
of patients with a COVID-19-related hospitalization or all-cause death from day 4 through day 29 
in the mFAS. The comparison of 1200 mg dose group to placebo will include only the subset of 
placebo patients concurrently randomized with 1200 mg dose group. Sensitivity and supportive 
analyses will be described in the SAP.  
11.4.3.2. Secondary Efficacy Analysis 
Phase 3 
The following section describes analyses planned for phase 3 cohort 1. Analysis of asymptomatic 
patients (phase 2), pediatric patients (phase 3 cohort 2), and pregnant patients (phase 3 cohort 3) 
will be descriptive and detailed in the SAP. 
Phase 3, Cohort 1 Patient-Reported Symptoms Endpoint 
Time to COVID-19 symptoms resolution will be analyzed using the stratified log-rank test with 
randomization strata as stratification factor. The analyses will be performed in the mFAS. 
Estimates of median times and associated 95% confidence intervals using the Kaplan-Meier 
method will be reported. The hazard ratio and 95% CI for time to COVID-19 symptoms resolution 
of COVID-19 symptoms endpoint will be estimated by the Cox regression model with terms for 
treatment group and randomization strata. The P-value from the stratified log-rank test will be 
reported. Patients who do not experience resolution of symptoms will be censored at the last 
observation time point. Patients who died or had COVID-19-related hospitalization prior to day 
29 will be censored at day 29. Patients with a baseline raw score ≤3 will be censored at day 0. 
Patients with missing baseline assessment will not be included in the analysis. Subgroup analyses 
may be performed among patients with more than one risk factor, with high baseline viral load, or 
who are seronegative at baseline. 
COVID-19 symptoms included in the analysis are as follows: Body aches such as muscle pain or 
joint pain, Chest pain, Chills, Cough, Diarrhea, Dizziness, Fatigue, Feverish, Headache, Loss of 
appetite, Loss of taste/smell, Nausea, pressure/tight chest, Red or watery eyes, Runny nose, 
Shortness of breath/difficulty breathing, Sore throat, Sputum/Phlegm, and Stomachache. 
Time to COVID-19 symptoms resolution will be defined as time from randomization to the first 
day during which the subject scored ‘no symptom’ (score of 0) on all of the above symptoms 
except Cough, Fatigue, and Headache, which can be ‘mild/moderate symptom’ (score of 1) or ‘no 
symptom’ (score of 0).  
Additional information regarding the SE-C19 scoring instrument is provided in Section 9.2.15. 
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Phase 3 Cohort 1 Clinical Endpoints 
Proportion endpoints such as proportion of patients with a COVID-19-related hospitalization, ER 
visit, or all-cause death and proportion of patients with a COVID-related MAV or all-cause death 
will be compared between each dose group and placebo using the stratified Cochran-Mantel-
Haenszel (CMH) test with country as a stratification factor. P-values from the stratified CMH test 
and 95% confidence intervals for risk ratio and relative risk reduction (1-risk ratio) using 
Farrington-Manning method will be presented. Exact method for p-values and confidence intervals 
will be used if the expected frequencies in all cells are not at least 5. The analyses will be performed 
based on observed data for the mFAS for secondary analyses, and for seronegative mFAS and FAS 
as additional analyses. Similar analysis will be performed for the proportion of patients with a 
COVID-19-related hospitalization, ER visit, or urgent care visit as well as proportions of patients 
with each type of COVID-19-related MAV. Risk difference and its 95% confidence interval based 
on stratified Newcombe method for the proportion endpoints between 1200 mg and 2400 mg dose 
groups will calculated based on patients concurrently randomized, ie, under protocol amendments 
6/7/8, for the mFAS. 
Analyses will be performed for the cumulative incidence of patients having a COVID-19-related 
hospitalization or all-cause death through day 29 based on the time to first COVID-19-related 
hospitalization or all-cause death using the stratified log-rank test with randomization strata as 
stratification factor for mFAS. Estimates of cumulative event rate at different time points and 
associated 95% confidence intervals using the Kaplan-Meier method will be reported. The hazard 
ratio and its 95% CI for patients having event will be estimated by the Cox regression model with 
terms for treatment group (2400 mg dose groups versus placebo), and randomization strata. The 
p-value from the stratified log-rank test for risk of having events will be reported. Similar analysis 
will be performed comparing 1200 mg dose group to placebo including only the subset of patients 
concurrently randomized. A patient who has no COVID-19-related hospitalization will be 
censored at last known date of contact up to day 29. A patient who dies on or before day 29 will 
be considered as having an event at the date of death. A patient with multiple COVID-19 related 
hospitalizations and/or who dies will be counted as having one event. Similar secondary analyses 
will be performed for cumulative incidence of COVID-19-related hospitalization, ER visit, or 
all-cause death and cumulative incidence of patients having a COVID-19-related MAV or all cause 
death through day 29 for the mFAS. Additional landmark analysis for time to event endpoint such 
as cumulative incidence of COVID-19 related hospitalization or death may be performed if the 
proportional hazard assumption is considered not valid. Sensitivity analyses will be performed 
using FAS. 
Additional analyses will be performed to examine the relationship between viral load and 
COVID-19-related MAVs in patients who underwent an intensive sampling schedule. For 
example, viral load over time will be compared between patients with and without a 
COVID-19-related MAV. 
Virologic Endpoints  
For phase 3 cohort 1, virologic analyses will be descriptive. The time-weighted average change 
from baseline in viral load (log10 copies/mL) from day 1 to post-baseline visit timepoints will be 
analyzed using the same method as the phase 2 primary virologic endpoint based on mFAS for 
seronegative patients and seropositive patients separately. In cohort 1, the TWA analysis will be 
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limited to patients who were randomized prior to protocol amendment 6. A similar analysis will 
be performed for mFAS with baseline serostatus as an additional term to the ANCOVA model. 
The least squares means estimates for the time-weighted average mean change from baseline in 
viral load for each treatment group, as well as the difference comparing each anti-spike mAb 
treatment arm versus placebo, will be presented along with the corresponding p-value, standard 
error, and associated 95% confidence interval. Subgroup analysis of the TWA change from 
baseline in viral load at each visit will also be performed by baseline viral load categories 
(>104 copies/mL, >105 copies/mL, >106 copies/mL, >107 copies/mL). 
For phase 2, time to negative RT-PCR results through day 15 for seronegative mFAS will be 
analyzed using the stratified log-rank test with randomization strata as a stratification factor. 
Estimates of median times and associated 95% confidence intervals using the Kaplan-Meier 
method will be reported. The hazard ratio and its 95% CI for time to negative RT-PCR results 
through day 15 will be estimated by the Cox regression model with terms for treatment group, 
baseline viral load, treatment by baseline interaction, randomization strata. P-value from the 
stratified log-rank test for time to negative RT-PCR results through day 15 will be reported. Similar 
analysis will be performed for the mFAS with baseline serostatus as an additional term to the 
model.  
Proportion endpoints based on observed virologic data will be compared between groups using 
similar method as the proportion clinical endpoints. The analyses will be performed for 
seronegative mFAS as well as for mFAS. 
To assess the time course of treatment effect in viral load, the change from baseline in viral load 
(log10 copies/mL) at each visit for seronegative mFAS and mFAS will be analyzed using a mixed-
effect model for repeated measures (MMRM) with terms for baseline viral load, randomization 
strata, treatment, visit, treatment by baseline viral load interaction, baseline viral load by visit 
interaction, and treatment-by-visit interaction. Within-patient errors will be modeled with an 
unstructured, heterogeneous autoregressive (1), or compound symmetry covariance matrix in that 
order if a model does not converge. The least squares means estimates for the mean at each visit 
and mean change from baseline to each visit as well as the difference of these estimates between 
treatment arm and placebo will be provided along with the corresponding standard error, p-value, 
and associated 95% confidence interval. Subgroup analysis of the change from baseline in viral 
load at each visit will also be performed by baseline viral load categories (>104 copies/mL, 
>105 copies/mL, >106 copies/mL, >107 copies/mL).  
11.4.3.3. Exploratory Analysis 
Phase 2 Patient-Reported Symptom Endpoints (Exploratory) 
Time to alleviation or resolution of COVID-19 symptoms endpoints for the symptomatic patients 
will be analyzed using the stratified log-rank test with randomization strata as stratification factor. 
The analyses will be performed for seronegative mFAS as well as for mFAS with baseline 
serostatus as an additional term to the model. Estimates of median times and associated 95% 
confidence intervals using the Kaplan-Meier method will be reported. The hazard ratio and its 95% 
CI for time to alleviation or improvement of COVID-19 symptoms endpoints will be estimated by 
the Cox regression model with terms for treatment group, randomization strata. P-value from the 
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stratified log-rank test will be reported. Subgroup analysis may be performed for patients with 
more than one risk factor, with high baseline viral load, or are seronegative at baseline. 
Analysis for data from asymptomatic patients, pediatric patients, and pregnant patients will be 
descriptive and detailed in the SAP. 
Long COVID 
Exploratory analyses related to long COVID will be summarized descriptively. Additional details 
will be provided in a separate long COVID statistical analysis plan (SAP) from the study SAP. 
This SAP may also describe additional analyses of symptoms and/or biomarkers. 
11.4.4. 
Control of Multiplicity 
Phase 1 
For phase 1 primary analysis of safety endpoints, no multiplicity adjustment will be applied. The 
primary virologic efficacy endpoint will be tested at α = 0.05. 
Primary Phase 2 Analysis of Virologic and Clinical Endpoints 
The primary analysis of virologic and clinical endpoints will be conducted at α = 0.05 (Table 13). 
Eight virologic endpoints and 2 clinical endpoints will be tested hierarchically in the following 
order: 
 
Table 13: 
Statistical Testing Hierarchy, Primary Phase 2 Analysis 
Hierarchy 
Number 
Description 
1 
Time-weighted average change from baseline in viral load (log10 copies/mL) from 
day 1 through day 7 in the mFAS patients with baseline viral load >107 copies/mL 
for REGN10933+REGN10987 2400 mg and 8000 mg combined group versus 
placebo (descriptive analysis will be provided for individual timepoints comprising 
the time-weighted average for this and all subsequent endpoints) 
2 
Time-weighted average change from baseline in viral load (log10 copies/mL) from 
day 1 through day 7 in the mFAS patients with baseline viral load >106 copies/mL 
for REGN10933+REGN10987 2400 mg and 8000 mg combined group versus 
placebo 
3 
Time-weighted average change from baseline in viral load (log10 copies/mL) from 
day 1 through day 7 in the Seronegative mFAS for REGN10933+REGN10987 
2400 mg and 8000 mg combined group versus placebo 
4 
Time-weighted average change from baseline in viral load (log10 copies/mL) from 
day 1 through day 7 in the mFAS for REGN10933+REGN10987 2400 mg and 
8000 mg combined group versus placebo 
5 
Time-weighted average change from baseline in viral load (log10 copies/mL) from 
day 1 through day 7 in the mFAS patients with baseline viral load >107 copies/mL 
for REGN10933+REGN10987 8000 mg group versus placebo 
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Hierarchy 
Number 
Description 
6 
Time-weighted average change from baseline in viral load (log10 copies/mL) from 
day 1 through day 7 in the mFAS patients with baseline viral load >107 copies/mL 
for REGN10933+REGN10987 2400 mg group versus placebo 
7 
Time-weighted average change from baseline in viral load (log10 copies/mL) from 
day 1 through day 7 in the mFAS patients with baseline viral load >106 copies/mL 
for REGN10933+REGN10987 8000 mg group versus placebo 
8 
Time-weighted average change from baseline in viral load (log10 copies/mL) from 
day 1 through day 7 in the mFAS patients with baseline viral load >106 copies/mL 
for REGN10933+REGN10987 2400 mg versus placebo. 
9 
Proportion of patients with MAVs through day 29 in the mFAS for 
REGN10933+REGN10987 2400 mg and 8000 mg combined group versus placebo 
(patients 1 through 799)  
10 
Proportion of patients with subset of MAVs consisting only of hospitalization or 
ER visit or urgent care visit through day 29 in the mFAS for 
REGN10933+REGN10987 2400 mg and 8000 mg combined group versus placebo 
(patients 1 through 799) 
 
Phase 3  
Cohort 1 
The primary endpoint and key secondary endpoint will be tested hierarchically (Table 14), 
adjusting for interim analysis as described below. 
Table 14: 
Statistical Testing Hierarchy, Phase 3 Cohort 1 Analysis 
Hierarchy 
Number 
Description 
1 
Proportion of patients with ≥1 COVID-19-related hospitalization or all-cause 
death through day 29 in the mFAS for REGN10933+REGN10987 2400 mg group 
versus placebo 
2 
Proportion of patients with ≥1 COVID-19-related hospitalization or all-cause 
death through day 29 in the mFAS for REGN10933+REGN10987 1200 mg group 
versus placebo  
3 
Proportion of patients with ≥1 COVID-19-related hospitalization or all-cause 
death through day 29 in the mFAS patients with baseline viral load >106 
copies/mL for REGN10933+REGN10987 2400 mg group versus placebo  
4 
Proportion of patients with ≥1 COVID-19-related hospitalization or all-cause 
death through day 29 in the mFAS patients who are seronegative at baseline for 
REGN10933+REGN10987 2400 mg group versus placebo  
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Hierarchy 
Number 
Description 
5 
Proportion of patients with ≥1 COVID-19-related hospitalization or all-cause 
death through day 29 in the mFAS patients with baseline viral load >106 
copies/mL for REGN10933+REGN10987 1200 mg group versus placebo  
6 
Proportion of patients with ≥1 COVID-19-related hospitalization or all-cause 
death through day 29 in the mFAS patients who are seronegative at baseline for 
REGN10933+REGN10987 1200 mg group versus placebo  
7 
Proportion of patients with ≥1 COVID-19-related hospitalization or all-cause 
death from day 4 through day 29 in the mFAS for REGN10933+REGN10987 
2400 mg group versus placebo 
8 
Proportion of patients with ≥1 COVID-19-related hospitalization or all-cause 
death from day 4 through day 29 in the mFAS for REGN10933+REGN10987 
1200 mg group versus placebo 
9 
Time to COVID-19 symptoms resolution in the mFAS for 
REGN10933+REGN10987 2400 mg group versus placebo  
10 
Time to COVID-19 symptoms resolution in the mFAS for 
REGN10933+REGN10987 1200 mg group versus placebo 
 
The final analysis of the primary efficacy endpoint, ie, proportion of patients with ≥1 COVID-19-
related hospitalization or all-cause death through day 29 for the 2400 mg group versus placebo 
comparison will be performed based on patients randomized on or before 17 January 2021 in the 
mFAS, at α level of 0.05. 
If the 2400 mg group versus placebo comparison for the primary endpoint is positive, an interim 
analysis of the primary efficacy endpoint for the 1200 mg group versus placebo comparison (2 in 
Table 14) will be performed at α level of 0.01 based on patients randomized on or before 
17 January 2021 in the mFAS. If the comparison is positive, this analysis will be considered as the 
final analysis of the proportion of patients with ≥1 COVID-19-related hospitalization or all-cause 
death through day 29 for the 1200 mg group versus placebo comparison. Final analysis of the 
primary and key endpoints for comparisons 3 to 10 (Table 14) will then be performed based on 
patients randomized on or before 17 January 2021 in the mFAS in the hierarchical order above at 
α level of 0.05. 
If the interim analysis of the primary efficacy endpoint for the 1200 mg group versus placebo 
comparison is negative at α level of 0.01, no tests will be performed for the primary and key 
endpoints for comparisons 3 to 10 based on patients randomized on or before 17 January 2021. 
Final analysis of the proportion of patients with ≥1 COVID-19-related hospitalization or all-cause 
death through day 29 for the 1200 mg group versus placebo comparison (2 in Table 14) and other 
comparisons 3 to 10 will be performed based on all patients randomized on or before 24 February 
2021 and tested hierarchically at an alpha level adjusted based on the information fraction at the 
interim analysis using Gamma family alpha spending function, eg, at 0.047 level as illustrated in 
the example in Table 15.  
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The Gamma family alpha spending function based on the primary endpoint of proportion of 
patients with ≥1 COVID-19-related hospitalization or all-cause death through day 29 for the 
1200 mg versus placebo comparison will be used to control for type I error for the planned interim 
and final analyses. The parameter for the Gamma family spending function will be calculated 
based on the information fraction of the interim analysis, such that the alpha level at the interim 
analysis is equal to 0.01 and the remaining alpha level is calculated based on the gamma parameter. 
The information fraction will be determined based on the sample size in the mFAS at the interim 
analysis and at the final analysis of the primary endpoint for the 1200 mg group versus placebo 
comparison.  
Table 15 provides an example alpha spending boundary for the interim analysis and final analysis 
of the primary and key secondary endpoints. Under protocol amendment 6and protocol amendment 
7 combined, a total of 2524 patients were randomized to the 1200 mg, 2400 mg, and placebo 
groups on or before 17 January 2021 for the planned interim analysis, and 4056 patients were 
randomized on or before 24 February 2021 for the final analysis of 1200 mg versus placebo 
comparisons. With these sample sizes utilized in each analysis, the information fraction is 
approximately 62% (gamma = -4), assuming the proportions of RT-qPCR-positive patients in the 
FAS are the same at the interim and final analysis. The resulting overall alpha for the final analysis 
would then be 0.047. 
Table 15: 
Example Alpha Spending Function for Analysis of Primary Endpoint 
Information Time 
Value 
Overall α for Proportion 
Analysis = 0.05 
62% of the mFAS patients completing day 29 
α (2-sided) 
0.01 
Final analysis 
α (2-sided) 
0.047 
 
Cohort 2 and Cohort 3 
Analysis of cohort 2 and cohort 3 will be descriptive. No multiplicity adjustment will be applied.  
11.4.5. 
Safety Analysis 
11.4.5.1. Adverse Events 
Definitions 
For safety variables, 2 periods are defined: 
• The pretreatment period is defined as the time from signing the ICF to before study 
drug administration 
• The observation period is defined as the time of study drug administration to the last 
study visit 
Treatment-emergent adverse events are defined as those that are not present at baseline or represent 
the exacerbation of a pre-existing condition during the observation period. 
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Analysis 
All adverse events reported in this study will be coded using the currently available version of the 
Medical Dictionary for Regulatory Activities (MedDRA®). Coding will be to lowest level terms. 
The preferred term (PT), and the primary system organ class (SOC) will be listed. 
Summaries by treatment group will include the following: 
• The number (n) and percentage (%) of patients with at least 1 treatment-emergent 
serious adverse events (SAEs) through day 29 by system organ class and PT 
• The number (n) and percentage (%) of patients with at least 1 infusion-related reactions 
(grade ≥2), through day 4 by PT 
• The number (n) and percentage (%) of patients with at least 1 hypersensitivity reactions 
(grade ≥2), through day 29 by PT 
For each phase, summaries by treatment group will include: 
• The number (n) and percentage (%) of patients with at least 1 event by SOC and PT 
• SAEs and AESIs by severity (according to the grading scale outlined in Section 10.2.5), 
presented by SOC and PT 
• SAEs and AESIs by relationship to treatment (related, not related), presented by SOC 
and PT 
• Treatment-emergent SAEs and AESIs  
• Treatment-emergent grade 3 or 4 AEs (phase 1, phase 3 cohort 2, and phase 3 cohort 3 
<18 years only) by SOC and PT 
Deaths and other SAEs will be listed and summarized by treatment arm. 
11.4.5.2. Other Safety 
Vital Signs 
Vital signs (temperature, pulse, blood pressure, and respiration rate) will be summarized by 
baseline and change from baseline to each scheduled assessment time with descriptive statistics. 
Laboratory Tests 
Laboratory test results will be summarized by baseline and change from baseline to each scheduled 
assessment time with descriptive statistics. 
Number and percentage of patients with a potentially clinically significant value (PCSV) at any 
post-randomization time point will be summarized for each clinical laboratory test for all patients 
and separately for patients in whom the PCSV criterion was normal or missing at baseline.  
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest. 
Listings will be provided with flags indicating the out of laboratory range values. 
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11.4.5.3. Treatment Exposure 
The number and percentage of patients randomized and exposed to double-blind study drug, and 
duration of exposure to treatment during the study will be presented by treatment group.  
11.4.5.4. Treatment Compliance 
Treatment compliance in terms of total dose and infusion interruption will be summarized. The 
analysis methods will be detailed in the SAP. 
11.4.6. 
Pharmacokinetics 
11.4.6.1. Analysis of Drug Concentration Data 
Phase 1 (Dense Sampling) 
The PK parameters may include, but are not limited to Cmax, Cmax/dose, tmax, and AUClast. 
The concentrations of REGN10933 and REGN10987 in serum over time and selected 
pharmacokinetic parameters will be summarized descriptively for each of the treatment groups. 
Phase 2 and Phase 3 (Sparse Sampling) 
The concentrations of REGN10933 and REGN10987 in serum over time will be summarized 
descriptively for each of the treatment groups  
11.4.7. 
Pharmacokinetics and Pharmacokinetics/Pharmacodynamics Analyses 
Exposure-response analyses for select efficacy and safety endpoints and/or biomarkers may be 
performed, as appropriate. 
11.4.8. 
Analysis of Immunogenicity Data 
Immunogenicity will be characterized by the ADA and NAb responses and titers observed in 
patients in the ADA and NAb analysis sets. ADA response categories and titer categories are 
defined as follows: 
ADA Response Categories:  
• ADA Negative, defined as ADA negative response in the ADA assays for all time 
points regardless of any missing samples 
• Pre-existing immunoreactivity, defined as either an ADA positive response in the ADA 
assay response at baseline with all post first dose ADA results negative, or a positive 
assay response at baseline with all post first dose ADA assay responses less than 9-fold 
over baseline titer levels. 
• Treatment-emergent response, defined as an ADA positive response in the ADA assay 
post first dose when baseline results are negative or missing.  
• Treatment boosted ADA response, defined as a positive response in the ADA assay 
post first dose that is greater than or equal to 9-fold over baseline titer levels when 
baseline results are positive 
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Titer categories (Maximum titer values): 
• Low (titer <1,000) 
• Moderate (1,000 ≤ titer ≤10,000) 
• High (titer >10,000)  
The following analysis will be provided: 
• Number (n) and percent (%) of ADA-negative patients (pre-existing immunoreactivity 
or negative in the ADA assay at all time points) by treatment groups  
• Number (n) and percent (%) of treatment-emergent ADA positive patients by treatment 
groups and ADA titer categories and at the 
• Number (n) and percent (%) of treatment-boosted ADA positive patients by treatment 
groups and ADA titer categories  
Listing of all ADA titer levels will be provided for patients with pre-existing, treatment-emergent 
and treatment-boosted ADA response. 
The absolute occurrence (n) and percent of patients (%) with NAb status in the NAb analysis set 
will be provided by treatment groups. 
11.5. 
Interim Analysis  
Phase 1/2 
An initial phase 1/2 descriptive analysis of data from the first 275 symptomatic patients enrolled 
in this study was conducted based on a database lock on 23 Sep 2020. 
 
Phase 3 
Cohort 1 
An interim analysis of the primary and key secondary endpoints for the 1200 mg treatment group 
will be performed when the final analysis of the primary efficacy endpoint for the 2400 mg 
treatment group is conducted. Refer to Section 11.4.4 for more information regarding these 
analyses. 
Cohort 2 and 3 
An interim descriptive analysis of phase 3 cohort 2 and 3 may be conducted for regulatory purposes 
when the phase 3 cohort 1 primary analysis is performed.  
11.6. 
Statistical Considerations Surrounding the Premature Termination 
of a Study  
If the study is terminated prematurely, only those parameters required for the development 
program and/or reporting to regulatory authorities will be summarized. Investigator and Sponsor 
responsibilities surrounding the premature termination of a study are presented in Section 15.1. 
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12. 
QUALITY CONTROL AND QUALITY ASSURANCE  
In accordance with ICH E6, the Sponsor is responsible for quality assurance to ensure that the 
study is conducted, and the data generated, recorded, and reported in compliance with the protocol, 
GCP, and any applicable regulatory requirement(s). The planned quality assurance and quality 
control procedures for the study are described in this section.  
12.1. 
Data Management and Electronic Systems 
12.1.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study (including 
data validation [quality-checking], cleaning, correcting, releasing) will be maintained and stored 
at Regeneron (Sponsor). 
A medical coding plan will specify the processes and the dictionary used for coding. All data 
coding (eg, SAEs, baseline findings, medication, medical history) will be done using 
internationally recognized and accepted dictionaries. 
The eCRF data for this study will be collected with an electronic data capture (EDC) Medidata 
Rave. 
12.1.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
• IWRS system – randomization, study drug supply 
• EDC system – data capture – Medidata Rave 
• Statistical Analysis System (SAS) – statistical review and analysis 
• Pharmacovigilance safety database 
• Electronic Clinical Outcome Assessment (eCOA) system – electronic patient diary and 
patient reported outcomes 
12.2. 
Study Monitoring  
12.2.1. 
Monitoring of Study Sites 
Regeneron uses a study-specific risk-based approach to study monitoring and oversight, aligned 
with risk-based quality principles, outlined in ICH E6 (R2) Guideline for Good Clinical Practice. 
Risk-Based Quality Monitoring (RBQM) methodology focuses on employing a fit-for-purpose 
monitoring strategy, supported either directly by Regeneron as sponsor, or via our CRO partners. 
RBQM strategies include reduced source data verification (SDV), targeted source data review 
(SDR), the use of off-site/remote and triggered on-site monitoring visits, and Centralized 
Monitoring to identify site level risks and study level trends.  
The investigator must allow study related monitoring activities to occur. The study monitors will 
perform ongoing source data review to verify that data recorded in the eCRF by authorized site 
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personnel are accurate, complete, and verifiable from source documents, that the safety and rights 
of patients are being protected, and that the study is being conducted in accordance with the current 
approved protocol version and any other study agreements, ICH GCP, and all applicable regulatory 
requirements. 
12.2.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents). The site is responsible to ensure quality within their records and systems and are 
accountable for ensuring that all source data and eCRF data are timely, accurate and complete. 
The investigator must keep all source documents on file with the eCRF. Case report forms and 
source documents must be available at all times for inspection by authorized representatives of the 
Sponsor and regulatory authorities. 
12.2.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on electronic Case Report 
Forms (eCRFs) within the EDC system by trained site personnel. All required eCRFs must be 
completed for each and every patient enrolled in the study. The investigator must ensure the 
accuracy, completeness, and timeliness of the data reported to the Sponsor in the eCRFs. After 
review of the clinical data for each patient, the investigator must provide an electronic signature. 
A copy of each patient eCRF casebook is to be retained by the investigator as part of the study 
record and must be available at all times for inspection by authorized representatives of the 
Sponsor and regulatory authorities. 
Corrections to the eCRF will be entered in the eCRF by the investigator or an authorized designee. 
All changes, including date and person performing corrections, will be available via the audit trail, 
which is part of the EDC system. For corrections made via data queries, a reason for any alteration 
must be provided. 
12.3. 
Audits and Inspections  
This study may be subject to a quality assurance audit or inspection by the Sponsor regulatory 
authorities. Should this occur, the investigator is responsible for: 
• Informing the Sponsor of a planned inspection by the authorities as soon as notification 
is received, and authorizing the Sponsor’s participation in the inspection 
• Providing access to all necessary facilities, study data, and documents for the inspection 
or audit 
• Communicating any information arising from inspection by the regulatory authorities 
to the Sponsor immediately 
• Taking all appropriate measures requested by the Sponsor to resolve the problems 
found during the audit or inspection 
Documents subject to audit or inspection include but are not limited to all source documents, 
eCRFs, medical records, correspondence, ICFs, IRB/EC files, documentation of certification and 
quality control of supporting laboratories, and records relevant to the study maintained in any 
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supporting pharmacy facilities. Conditions of study material storage are also subject to inspection. 
In addition, representatives of the Sponsor may observe the conduct of any aspect of the clinical 
study or its supporting activities both within and outside of the investigator's institution. 
In all instances, the confidentiality of the data must be respected. 
12.4. 
Study Documentation 
12.4.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the eCRF must be signed 
electronically by the investigator. This signed declaration accompanies each set of patient final 
eCRF that will be provided to the Sponsor. 
12.4.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs, source documents, 
investigator copies of eCRFs, and drug accountability records for at least 15 years following the 
completion or discontinuation of the study, or longer, if a longer period is required by relevant 
regulatory authorities. The investigator must obtain written approval from the Sponsor before 
discarding or destroying any essential study documents during the retention period following study 
completion or discontinuation. Records must be destroyed in a manner that ensures confidentiality. 
If the investigator's personal situation is such that archiving can no longer be ensured, the 
investigator must inform the Sponsor (written notification) and the relevant records will be 
transferred to a mutually agreed-upon destination. 
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13. 
ETHICAL AND REGULATORY CONSIDERATIONS  
13.1. 
Good Clinical Practice Statement  
It is the responsibility of both the Sponsor and the investigator(s) to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable regulatory 
requirements. 
13.2. 
Informed Consent 
The principles of informed consent are described in ICH guidelines for GCP. 
An informed consent form (ICF) can be defined as either a paper consent form or an electronically-
delivered consent (eConsent). An eConsent may be provided only where allowable by local laws 
and regulations and by site policies.  
Due to disease severity, quarantine restrictions, and/or other reasons related to COVID-19, it may 
be necessary to implement temporary or alternative measures to obtain informed consent per 
procedures outlined in the investigator site file.  
Adult Patients 
The ICF used by the investigator must be reviewed and approved by the Sponsor prior to 
submission to the appropriate IRB/EC. A copy of the IRB/EC-approved ICF and documentation 
of approval must be provided to the Sponsor before study drug will be shipped to the study site. 
For patients at or above the legal age of adulthood, it is the responsibility of the investigator or 
authorized designee (if acceptable by local regulations) to obtain informed consent from each 
patient prior to his/her participation in the study and after the aims, methods, objectives, and 
potential hazards of the study have been explained to the patient in language that he/she can 
understand. The ICF should be signed and dated by the patient and by the investigator or authorized 
designee who reviewed the ICF with the patient:  
• Patients who can write but cannot read will have the ICF read to them before signing 
and dating the ICF. 
• Patients who can understand but who can neither write nor read will have the ICF read 
to them in the presence of an impartial witness, who will sign and date the ICF to 
confirm that informed consent was given. 
The original ICF must be retained by the investigator as part of the patient’s study record, and a 
copy of the signed ICF must be given to the patient. 
If new safety information results in significant changes in the risk/benefit assessment, or if there 
are significant changes to the study procedures, the ICF must be reviewed and updated 
appropriately. All study patients must be informed of the new information and provide their written 
consent if they wish to continue in the study. The original signed revised ICF must be maintained 
in the patient’s study record and a copy must be given to the patient. 
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Patients Under 18 Years of Age (or Under Country’s Legal Age of Adulthood) 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB/EC. A copy of the IRB/EC-approved ICF and documentation 
of approval must be provided to the sponsor before study drug will be shipped to the study site. 
For patients under the legal age of adulthood, it is the responsibility of the investigator or 
authorized designee (if acceptable by local regulations) to obtain written informed consent from 
the patient’s parent(s) or legal guardian(s) prior to the patient’s participation in the study and after 
the aims, methods, objectives, and potential hazards of the study have been explained to the fullest 
possible extent in language that the patient’s parent(s) or legal guardian(s) can understand. The 
ICF should be signed and dated by the patient’s parent(s) or legal guardian(s) and by the same 
investigator or designee who explained the ICF.  
Local law and site policies must be observed by the investigator in deciding whether the consent 
of 1 or both parents/guardians is required. If only 1 parent or guardian signs the ICF, the 
investigator must document the reason the other parent or guardian did not sign.  
The investigator (or authorized designee) may also be required to obtain assent from the patient,, 
as determined by the IRB/EC and in accordance with the local regulations and requirements: 
• Patients who can write but cannot read will have the assent form read to them before 
writing their name on the form 
• Patients who can understand but who can neither write nor read will have the assent 
form read to them by the person obtaining assent, who will sign and date the ICF to 
confirm that assent was given 
The original ICF must be retained by the investigator as part of the patient’s study record, and a 
copy of the signed ICF must be given to the patient’s parent(s) or legal guardian(s). 
13.3. 
Patient Confidentiality and Data Protection 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
patient will be maintained. Patients should be identified by a patient identification number only, 
on eCRFs or other documents submitted to the Sponsor. Documents that will not be submitted to 
the Sponsor (eg, signed ICF) must be kept in strict confidence. 
The patient’s and investigator's personal data, which may be included in the Sponsor database, will 
be treated in compliance with all applicable laws and regulations. The Sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized third party. 
13.4. 
Institutional Review Board/Ethics Committee 
An appropriately constituted IRB/EC, as described in ICH guidelines for GCP, must review and 
approve: 
• The protocol, ICF, and any other materials to be provided to the patients 
(eg, advertising) before any patient may be enrolled in the study 
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• Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the patient, in which 
case the IRB/EC should be informed as soon as possible  
• Ongoing studies on an annual basis or at intervals appropriate to the degree of risk  
In addition, the IRB/EC should be informed of any event likely to affect the safety of patients or 
the continued conduct of the clinical study. 
A copy of the IRB/EC approval letter with a current list of the IRB/EC members and their functions 
must be received by the Sponsor prior to shipment of drug supplies to the investigator. The 
approval letter should include the study number and title, the documents reviewed, and the date of 
the review. 
Records of the IRB/EC review and approval of all study documents (including approval of ongoing 
studies) must be kept on file by the investigator. 
13.5. 
Clinical Study Data Transparency 
Final study results will be published on a public clinical trial website according to applicable local 
guidelines and regulations. Treatment codes will be disseminated to each investigation site 
thereafter. 
14. 
PROTOCOL AMENDMENTS 
The Sponsor may not implement a change in the design of the protocol or ICF without an IRB/EC-
approved amendment. Where required per local legislation, regulatory authority approval will also 
be sought. 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-
OUT OF A SITE 
15.1. 
Premature Termination of the Study 
The Sponsor has the right to terminate the study prematurely. Reasons may include efficacy, 
safety, or futility, among others. Should the Sponsor decide to terminate the study, the 
investigator(s) will be notified in writing. 
15.2. 
Closeout of a Site 
The Sponsor and the investigator have the right to close out a site prematurely. 
Investigator’s Decision 
The investigator must notify the Sponsor of a desire to close-out a site in writing, providing at least 
30 days’ notice. The final decision should be made through mutual agreement with the Sponsor. 
Both parties will arrange the close-out procedures after review and consultation. 
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Sponsor’s Decision 
The Sponsor will notify the investigator(s) of a decision to close-out a study site in writing. 
Reasons may include the following, among others:  
• The investigator has received all items and information necessary to perform the study, 
but has not enrolled any patient within a reasonable period of time 
• The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines  
• The total number of patients required for the study are enrolled earlier than expected 
In all cases, the appropriate IRB/EC and Health Authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection of 
the patients’ interests. 
16. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
17. 
FINANCING AND INSURANCE  
Financing and insurance information is provided as a separate agreement. 
18. 
PUBLICATION POLICY  
Publication rights and procedures will be outlined in a separate clinical study agreement. 
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20. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol, “A Master Protocol Assessing the Safety, Tolerability, and 
Efficacy of Anti-Spike (S) SARS-CoV-2 Monoclonal Antibodies for the Treatment of Ambulatory 
Patients with COVID-19”, and agree to abide by all provisions set forth therein. 
I agree to comply with the current International Council for Harmonisation Guideline for Good 
Clinical Practice and the laws, rules, regulations, and guidelines of the community, country, state, 
or locality relating to the conduct of the clinical study. 
I also agree that persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on studies for the Sponsor or a 
partnership in which the Sponsor is involved. I will immediately disclose it in writing to the 
Sponsor if any person who is involved in the study is debarred, or if any proceeding for debarment 
is pending, or, to the best of my knowledge, threatened. 
This document contains confidential information of the Sponsor, which must not be disclosed to 
anyone other than the recipient study staff and members of the IRB/EC. I agree to ensure that this 
information will not be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of the Sponsor. 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 
 
 
 
(Printed Name) 
 
 
 
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SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(Medical/Study Director, Regulatory Representative, Clinical Study Lead, and 
Biostatistician) 
To the best of my knowledge, this report accurately describes the planned conduct of the study. 
Study Title: A Master Protocol Assessing the Safety, Tolerability, and Efficacy of Anti-Spike (S) 
SARS-CoV-2 Monoclonal Antibodies for the Treatment of Ambulatory Patients with COVID-19 
Protocol Number: 
R10933-10987-COV-2067 
Protocol Version:  
Amendment 10 US 
 
See appended electronic signature page 
Sponsor’s Responsible Medical/Study Director 
 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Liaison 
 
 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
 
 
 
 
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Signature Page for VV-RIM-00163381 v1.0
Signature Page for VV-RIM-00163381 v1.0 Approved
ESig Approval
13-Aug-2021 17:17:10 GMT+0000
ESig Approval
14-Aug-2021 13:09:48 GMT+0000
ESig Approval
16-Aug-2021 00:55:01 GMT+0000
ESig Approval
16-Aug-2021 11:56:21 GMT+0000
                                        VV-RIM-00163381-1.0 Approved - 16 Aug 2021 GMT-5:00
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