Conditions: Long Bone Delayed-Union Fracture
Keywords: Delayed-Union Fractures Impaired Healing Fractures Orthopedics Bone Musculoskeletal Disorders
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 25
Healthy volunteers: no

Brief summary:
Fracture healing is a complex physiological process caused by interaction of cellular elements, cytokines and signaling proteins, which results in the formation of new bone. There is for now no universally accepted approach to evaluate the progression of fracture healing. Typically, a fracture is considered as a delayed-union when the bone has not united within a period of time that would be considered adequate for bone healing. Delayed-union suggests that union is slow but will eventually occur without additional surgical or non-surgical intervention, whereas non-union is defined as the cessation of all reparative process of healing.

The incidence of impaired healing is estimated to range from 5 to 10% of all long bone fractures, depending on the fracture site, the type and degree of injury, among other factors. Currently the treatment of choice remains bone allograft or autograft. This procedure shows in general good results but requires an invasive surgery of several hours under general anesthesia, followed by a few days of hospitalization. Because of this, major complications have been reported in up to 20-30% of patients.

The present Phase 1/2a study aims at demonstrating the safety and efficacy of ALLOB®, a proprietary population of allogeneic osteoblastic cells, in the treatment of delayed-union fractures of long bones. In this study, delayed-union is defined at the time of screening as an absence of healing of minimum 3 months and maximum 7 months (+/- 2 weeks) after the onset of the fracture.

Detailed description:

Arms:
arm 1: One arm: ALLOB® Implantation

Interventions: intervention 1: ALLOB® implantation
Intervention descriptions: intervention 1: Each patient will undergo a single administration of ALLOB® into the delayed-union site under anesthesia.

Protocol document:
Prot_SAP_000.pdf: 
CONFIDENTIAL 
ALLOB-DU1 - Clinical Study Protocol 
ALLOB-DU1_CSP 
V 05 
Date: February 02.2017 
Pg. 1/1 
 
 
CLINICAL STUDY PROTOCOL 
Study ALLOB-DU1 
EudraCT number: 2012-005333-36 
Protocol Number: 000005/BT 
NTC Number: 02020590 
 
 
 
A pilot Phase I/IIa, multicentre, open, proof-of-concept study on the efficacy and safety 
of allogeneic osteoblastic cells (ALLOB®) implantation in non-infected delayed-union 
fractures 
 
 
Sponsor 
Bone Therapeutics S.A. 
Rue Auguste Piccard, 37 
B-6041 Gosselies, Belgium 
 
Good Clinical Practice (GCP) Statement  
This study will be performed in compliance with Good Clinical Practice (GCP), the 
Declaration of Helsinki (with amendments), and all applicable Community and national 
legislation and regulatory requirements 
 
All rights reserved. Unauthorized copying or use of this information is prohibited 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 /1 3 6  
 
 
 
 
Cli nic al St u d y Pr ot oc ol 
St u d y A L L O B -D U 1  
E u dr a C T n u m ber: 2 0 1 2- 0 0 5 3 3 3- 3 6 
Pr ot oc ol N u m ber: 0 0 0 0 0 5/ B T 
 
Title 
A pil ot P hase I/IIa, m ultice ntre, o p e n pr o of- of-c o nce pt st u d y o n t he effi cac y a n d safet y of 
all o ge n eic oste o blastic cells ( A L LO B ® ) i m pla ntati o n i n n o n-i nfecte d d ela ye d- u ni o n fract ures 
 
S p o ns or 
B o ne T h era p e utics S. A. 
R ue A u g uste Piccar d, 3 7 
B - 6 0 4 1 G osselies, Bel gi u m 
G o o d Cli nic al Pr actice ( G C P) St ate m e nt 
T his st u dy will be perf or me d i n c o m pli a nce wit h G o o d Cli nic al Pr actice ( G C P), t h e 
Decl ar ati o n of Helsi nki ( wit h a me n d me nts), a n d all a p plic a ble C o m m u nity a n d n ati o n al 
le gisl ati o n a n d re g ul at ory re q uire me nts. 
 
 
All ri g hts reser v e d. U n a ut h orise d c o p yi n g or use of t his i nf or m ati o n is pr o hi bite d 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 2 /1 3 6  
 
S P O N S O R SI G N A T O R Y A P P R O V A L  
 
E u dr a C T n u m ber : 2 0 1 2- 0 0 5 3 3 3- 3 6  
P r ot oc ol N u m ber : 0 0 0 0 0 5/ B T  
 
Title of t he pr ot oc ol :  
A pil ot P hase I/IIa, m ultice ntre, o pe n pr o of- of-c o nce pt st u d y o n t he effi cac y a n d safet y of 
all o ge n eic oste o blastic cells ( A L L O B ® ) i m pla ntati o n i n n o n-i nfecte d d ela ye d- u ni o n fract ures 
 
 
 
 
S p o ns or’s re pres e ntati ve  
 
 
 
 
G u y H e y ne n, M D  
C hief Cli nical a n d Re g ul at or y Officer  
 
 
Na me a n d Title  
 
Date  
Si g nat ure  
 
 
 
 
 
 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 3 /1 3 6  
 
I N V E S TI G A T O R SI G N A T U R E A N D A G R E E M E N T WI T H T H E P R O T O C O L 
I, t he u n d ersi g ne d, 
A gree t o c o n d u ct t his st u d y i n c o m plia nce wit h t his Pr ot oc ol a n d t o ass u me res p o nsi bilit y f or 
t he pr o per c o n d uct of t he st u d y at t his site. 
A gree t h at t he cli nical tri al will be carrie d o ut i n acc or da nce wit h a n y a n d all a p plica ble la ws, 
re g ulati o ns, g ui da nce, g ui deli nes, a n d pri nci ples re gar di n g t he: 
- Et hical pri nci ples f or me dical researc h i n v ol vi n g h u ma n s u bjects 
- G o o d Cli nical Practice as re gar ds c o n d u ct of cli nical trials a n d i n v esti gati o nal me dici nal 
pr o d ucts f or h u ma n us e 
- Cli nical safet y d ata ma n a ge m e nt, n otificati o n, a n d re p orti n g  
- A d va nce d T h era p y Me di ci nal Pr o d ucts 
A gree:  
- T hat m y pri mar y res p o nsi bilit y is t o safe g uar d t he ri g hts a n d well- bei n g of eac h s u bject 
partici pati n g i n t his st u d y, a n d t hat t he s u bject’s ri g hts a n d well- b ei n g m ust t a ke prece de nce 
o ver t he g oals a n d re q uir e me nts of t he st u d y. 
- T o  e ns ure t he c o nfi de ntialit y a n d pr otecti o n of all i nf or mati o n o btai ne d fr o m a n d a b o ut t he 
partici pa nts. 
- T o o btai n t he i nf or me d c o nse nt of t he s u bjects pri or t o t heir partici pati o n i n t he st u d y a n d 
e ns ure t hat:  
* Ver bal i nf or mati o n, a d a pte d t o t he st u d y p artici pa nt, has bee n pr o vi de d, a v oi di n g direct 
or i n dire ct c o erci o n, a n d t hat t he s u bject has u n derst o o d t he st u d y; 
* T he patie nt i nf or mati o n s heet a n d writte n i nf or me d c o nse nt f or m ( date d a n d n u m bere d 
versi o n a p pr o ve d b y t he Et hics C o m mittee) has bee n pr o vi de d; 
* T he patie nt has bee n all o we d a reas o n a ble peri o d of reflecti o n ( o p p ort u nit y t o i n q uire 
ab o ut details of t he trial a n d t o deci de w het h er or n ot t o partici pate i n t he trial). 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 4 /1 3 6  
 
- T o kee p t he writte n pr o of of t he i nf or me d c o nse nt of t he s u bjects or t heir a ut h orise d le gal 
re pres e ntati ve. 
- T o ac q uire t he refere n ce ra n ges f or la b orat or y test perf or me d l ocall y a n d if re q uire d b y 
l ocal re g ulati o ns, o btai n t he la b orat or y’s c urre nt certificati o n or Q ualit y Ass ura n ce 
pr oce d ure ma n ual. 
- T o e ns ure t h at n o cli nical sa m ples are ret ai ne d o nsite or else w h ere wit h o ut t he a p pr o val of 
t he S p o ns or a n d t he e x press writte n c o nse nt of t he s u bject. 
- T o perf or m n o ot her bi ol o gic al assa ys o n t he cli nical sa m ples e x ce pt t h ose descri be d i n t he 
pr ot oc ol or its a me n d me nt(s). 
- T o pr o m ptl y re p ort a n y u na ntici pate d pr o ble ms t hat i n v ol ve a n y ris k t o s u bject i n res earc h 
c o vere d u n d er t his a gree me nt. 
- T o e ns ure t he tra nsfer of t he i nf or mati o n a n d t he data c ollecte d f or t he st u d y ( C R F) i n a 
clear, le gi ble wa y a n d i n c o nf or mit y wit h t he s o urce d oc u me nts (s u bject fil e).   
- T o e ns ure t o ha ve t he necessar y res o urces (e. g., q u alifie d pers o n nel a n d material res o urces) 
t o s uccessf ull y c o m plete t he st u d y wit h re gar d t o dea dli nes. 
I ac k n o wle d ge, 
- T hat I h a ve bee n i nf or m e d t hat certai n Re g ul at or y A ut h orities re q uir e t he S p o ns or t o o btai n 
a n d s u p pl y, as necessar y, details a b o ut t he I n vesti gat or’s o w ners hi p i nterest i n t he S p o ns or 
or t he i n vesti gati o nal pr o d uct, a n d m ore ge nerall y a b o ut his/ her fi na ncial ties wit h t he 
S p o ns or. T he S p o ns or will use a n d discl ose t he i nf or mati o n s olel y f or t he p ur p ose of 
c o m pl yi n g wit h re g ulat or y re q uire me nts 
 
 
Pri nci pal I n v esti gat or  
 
 
 
 
 
 
 
 
Na me a n d Title  
 
Date  
Si g nat ure  


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 5 /1 3 6  
 
T A B L E O F C O N T E N T S 
S T U D Y S Y N O P SI S .............................................................................................................................. 1 0  
LI S T O F T A B L E S ................................................................................................................................ 1 6  
L I S T O F A B B R E VI A TI O N S ............................................................................................................... 1 7 
D E FI NI TI O N S O F T E R M S .................................................................................................................. 2 0  
1  
IN T R O D U C TI O N  ............................................................................................................. 2 5  
1. 1  
Ge neral Bac k gr o u n d  ................................................................................................. 2 5  
1. 1. 1  I m paire d Fract ure Heali n g ............................................................................... 2 5  
1. 1. 2  Dia g n osis of Dela ye d or N o n -u ni o ns a n d F oll o w -u p of t he Heali n g Pr ocess  . 2 6  
1. 1. 3  I nci de nce of Dela ye d- a n d N o n-U ni o n Fract ures  ............................................ 2 6  
1. 1. 4  Aeti ol o g y of Dela ye d - a n d N o n-U ni o n Fract ures  ........................................... 2 6  
1. 1. 5  Treat me nt of  Dela ye d Fract ures  ...................................................................... 2 7  
1. 1. 6  B o ne A ut o graft  ................................................................................................ 2 7  
1. 2  
Bac k gr o u n d of t he St u d y  .......................................................................................... 2 8  
1. 2. 1  Ge neral Descri pti o n of A L L O B ®  .................................................................... 2 8  
1. 2. 2  A L L O B ®  i n Precli nical St u dies ....................................................................... 2 9  
1. 2. 3  A L L O B ®  i n Cli nical St u dies ........................................................................... 3 1  
1. 2. 4  J ustificati on of d ose  ......................................................................................... 3 1  
1. 3  
Assess me nt of A ntici pate d Be nefits a n d Ris ks  ........................................................ 3 1  
2  
IN V E S TI G A TI O N A L P L A N  ............................................................................................ 3 3  
2. 1  
Ge neral St u d y Desi g n  ............................................................................................... 3 3  
2. 2  
St u d y O bj ecti ves ....................................................................................................... 3 4  
2. 2. 1  Safet y  ............................................................................................................... 3 4  
2. 2. 2  Efficac y  ........................................................................................................... 3 4  
2. 2. 3  Bi o distri b uti o n S u b -st u d y O bjecti ve ............................................................... 3 5  
2. 2. 4  C o nsi derati o n f or Resc ue S ur ger y  ................................................................... 3 6  
2. 3  
Mai n St u d y Pr oce d ures  ............................................................................................ 3 6  
2. 3. 1  Patie nt I nf or mati o n a n d I nf or me d C o nse nt  ..................................................... 3 6  
2. 3. 2  Pr oce d ures  ....................................................................................................... 3 8  
2. 4  
Patie nt E val uati o n ..................................................................................................... 3 8  


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 6 /1 3 6  
 
2. 4. 1  Defi niti o n of Dela ye d -u ni o n i n t he St u d y  ....................................................... 3 8  
2. 4. 2  Cli nical E val uati o n  .......................................................................................... 3 9  
2. 4. 3  Ra di ol o gical E val uati o n –  T U S a n d m R U S  .................................................... 3 9  
2. 5  
Patie nt i ncl usi o n sc he me  .......................................................................................... 4 0  
2. 6  
St u d y P o p ulati o n  ...................................................................................................... 4 0  
2. 6. 1  El i gi bilit y ......................................................................................................... 4 0  
2. 6. 2  I ncl usi o n Criteria ............................................................................................. 4 2  
2. 6. 3  E xcl usi o n Criteria  ............................................................................................ 4 2  
3  
R A T I O N A L F O R T H E S T U D Y D E SI G N  ........................................................................ 4 5  
3. 1  
T y pes a n d Sites of Dela ye d a n d N o n -U ni o n Fract ures  ............................................ 4 5  
3. 2  
Cli nical a n d Ra di ol o gical E val uati o n T o ols  ............................................................. 4 5  
3. 2. 1  Cli nical E val uati o n  .......................................................................................... 4 5  
3. 2. 2  Ra di ol o gical E val uati o n  .................................................................................. 4 8  
3. 2. 3  Rati o nale f or t he C h oice of Cli nical a n d Ra di ol o gical I m pr o ve me nt Le vels  .. 5 0  
4  
D E T AI L E D S C H E D U L E O F  VI SI T S  .............................................................................. 5 1  
4. 1  
Ge neral O ver vie w of Visits a n d Pr oce d ures  ............................................................ 5 1  
4. 2  
Scree ni n g ( Visit # 1)  .................................................................................................. 5 5  
4. 3  
Treat me nt/ A L L O B ®  I m pla ntati o n Visit ( Visit # 2) ................................................... 5 6  
4. 4  
F oll o w -u p Visit # 3 ( 2 wee ks ± 2 da ys)  .................................................................... 5 7  
4. 5  
F oll o w -u p Visit # 4 ( M o nt h 1: 4 wee ks ± 1 wee k)  .................................................... 5 8  
4. 6  
F oll o w -u p Visit # 5 ( M o nt h 3: 1 2 wee ks ± 2 wee ks)  ................................................ 5 8  
4. 7  
F oll o w -u p Visit # 6 ( M o nt h 6: 2 4 wee ks ± 3 wee ks)  ................................................ 5 9  
4. 8  
P ost -St u d y Safet y F oll o w -u p Visits # 6a, # 7 a n d # 8 ( 6, 1 2 & 2 4 ± 1 m o nt hs after e n d 
of st u d y)  ............................................................................................................................. 6 0  
5  
D E T AI L E D D E S C RI P TI O N  O F T H E P R O C E D U R E S  ................................................... 6 2  
5. 1  
Re visi o n Pr oce d ure pri or t o t he Trial  ....................................................................... 6 2  
5. 2  
A L L O B ®  I m pla ntati o n Pr oce d ure ............................................................................ 6 2  
5. 3  
Peri -o perati ve a nti bi otic t hera p y a n d ot her me dicati o n  ............................................ 6 4  
5. 4  
P ost -o perati ve Ma na ge me nt  ..................................................................................... 6 4  
5. 5  
Re visi o n Pr oce d ure d uri n g t he Trial ......................................................................... 6 4  
5. 6  
Resc ue S ur ger y Pr oce d ure  ........................................................................................ 6 4  


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 7 /1 3 6  
 
5. 7  
Bi o distri b uti o n s u b -st u d y ......................................................................................... 6 5  
5. 8  
P ost -st u d y Safet y F oll o w-u p  .................................................................................... 6 5  
6  
IN V E S TI G A TI O N A L P R O D U C T  .................................................................................... 6 7  
6. 1  
I n vesti gati o nal Me dici nal Pr o d uct ............................................................................ 6 7  
6. 2  
P ost -a d mi nistrati o n Sterilit y T esti n g of I M Ps  .......................................................... 6 8  
6. 3  
Trac ki n g, Tracea bilit y, a n d Acc o u nta bilit y of I n vesti gati o nal Me dici nal Pr o d uct  .. 6 9  
7  
S A F E T Y A N D T O L E R A BI L I T Y M E A S U R E M E N T S A N D E N D P OI N T S ................... 7 0  
7. 1  
O ver vie w of Safet y Para meters a n d E n d p oi nts  ........................................................ 7 0  
7. 1. 1  Vital Si g ns  ....................................................................................................... 7 1  
7. 1. 2  P h ysical E xa mi nati o n  ...................................................................................... 7 1  
7. 1. 3  La b orat or y Safet y Meas ure me nts  .................................................................... 7 1  
7. 2  
Ot her Safet y Meas ure me nts  ..................................................................................... 7 4  
7. 2. 1  W o me n wit h c hil d beari n g p ote ntial  ................................................................ 7 4  
7. 2. 2  A d diti o nal safet y e xa mi nati o ns a n d pr oce d ures  .............................................. 7 4  
8  
A D V E R S E E V E N T S A N D S E RI O U S A D V E R S E E V E N T S  .......................................... 7 5  
8. 1  
Defi niti o ns  ................................................................................................................ 7 5  
8. 1. 1  A d verse E ve nt ( A E) a n d Seri o us A d verse E ve nt ( S A E)  ................................. 7 5  
8. 1. 2  Ca usal relati o ns hi p wit h t he I n vesti gati o nal Me dici nal Pr o d uct  ..................... 7 7  
8. 1. 3  A d verse Dr u g Reacti o n ( A D R)  ....................................................................... 7 9  
8. 1. 4  Seri o us A d verse Reacti o n ( S A R)  .................................................................... 7 9  
8. 1. 5  Seri o us A d verse Safet y/ Q ualit y E ve nt ( S A S Q E)  ............................................ 7 9  
8. 2  
Re p orti n g of A d verse E ve nts  ................................................................................... 7 9  
8. 2. 1  O bser vati o n peri o d f or t he occ urre nce of A Es a n d S A Es  ............................... 8 0  
8. 2. 2  S u m mar y  of P ossi ble Ris ks relate d t o t he Pr oce d ures  .................................... 8 1  
8. 2. 3  S u m mar y of A d verse Dr u g Reacti o ns a n d P ossi ble Ris ks relate d t o t he Pr o d uct 
a n d/ or t o t he Pr oce d ures  ............................................................................................. 8 2  
8. 2. 4  Assess me nt of t he Safet y M o nit ori n g C o m mittee  ........................................... 8 2  
8. 3  
Re p orti n g of Safet y Iss ues  ........................................................................................ 8 3  
8. 3. 1  Safet y Data N otificati o n, Re p orti n g, a n d M o nit ori n g  ..................................... 8 3  
8. 3. 2  A n n ual Safet y Re p orts –  De vel o p me nt Safet y U p date re p orts ( D S U Rs)  ....... 8 6  
8. 3. 3  Safet y Data M o nit ori n g  ................................................................................... 8 7  


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 8 /1 3 6  
 
8. 3. 4  Data Safet y M o nit ori n g B oar d  ........................................................................ 8 7  
8. 4  
Ma na ge me nt of Safet y Iss u e  .................................................................................... 8 7  
8. 4. 1  Pr oce d ure i n case of Pre g na nc y  ....................................................................... 8 7  
8. 4. 2  E mer ge nc y Pr oce d ures  .................................................................................... 8 8  
8. 5  
L o n g -T er m P har mac o vi gila nce S yste m  ................................................................... 8 9  
9  
P R E M A T U R E R E M O V A L F R O M T H E S T U D Y  ........................................................... 9 0  
9. 1  
Reas o ns f or Earl y Disc o nti n uati o n  ........................................................................... 9 0  
9. 2  
Pr oce d ure f or Earl y Disc o nti n uati o n  ........................................................................ 9 1  
9. 3  
Re place me nt of S u bj ects  .......................................................................................... 9 1  
9. 4  
S us pe nsi o n of t he Trial  ............................................................................................. 9 2  
1 0  
S T A TI S TI C A L C O N SI D E R A TI O N S A N D M E T H O D S O F A N A L Y SI S  ...................... 9 3  
1 0. 1  A nal ysis P o p ulati o ns  ............................................................................................... 9 3  
1 0. 2  Efficac y E n d p oi nts  .................................................................................................. 9 3  
1 0. 3  Ot her Efficac y E n d p oi nts  ........................................................................................ 9 4  
1 0. 4  Safet y  ...................................................................................................................... 9 5  
1 0. 5  Statistical A nal ysis  .................................................................................................. 9 5  
1 0. 5. 1  Ge neralit y  ...................................................................................................... 9 5  
1 0. 5. 2  De m o gra p hics a n d patie nts c haracteristics  .................................................... 9 6  
1 0. 5. 3  Pr ot oc ol de viati o ns  ........................................................................................ 9 7  
1 0. 5. 4  I m pla ntati o n pr oce d ure.................................................................................. 9 8  
1 0. 5. 5  E xte nt of e x p os ure  ......................................................................................... 9 9  
1 0. 5. 6  Efficac y a nal ysis  ........................................................................................... 9 9  
1 0. 5. 7  Safet y a nal ysis  ............................................................................................. 1 0 0  
1 0. 5. 8  I nteri m data a nal ysis .................................................................................... 1 0 2  
1 0. 5. 9  P ost -treat me nt data a nal ysis ........................................................................ 1 0 4  
1 0. 6  Ra n d o misati o n  ...................................................................................................... 1 0 4  
1 0. 7  Sa m ple size esti mati o n  .......................................................................................... 1 0 4  
1 0. 8  Ha n dli n g of missi n g val ues  ................................................................................... 1 0 4  
1 0. 9  Safet y F oll o w -u p  ................................................................................................... 1 0 5  
1 0. 1 0  I nteri m A nal ysis .................................................................................................. 1 0 5  


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 9 /1 3 6  
 
1 1  
S T U D Y M A N A G E M E N T  .............................................................................................. 1 0 6  
1 1. 1  M o nit ori n g  ............................................................................................................ 1 0 6  
1 1. 2  S o urce D oc u me nts  ................................................................................................ 1 0 7  
1 1. 3  S o urce Data Verificati o n  ....................................................................................... 1 0 9  
1 1. 4  C o m pleti o n of Case Re p ort F or ms, Si g ni n g, a n d Fili n g  ....................................... 1 0 9  
1 1. 5  Data Ma na ge me nt  ................................................................................................. 1 1 0  
1 1. 6  A u dits a n d I ns pecti o ns  .......................................................................................... 1 1 0  
1 1. 7  Access t o S o urce Data  .......................................................................................... 1 1 1  
1 1. 8  Trai ni n g of Staff  .................................................................................................... 1 1 1  
1 1. 9  C ha n ges t o t he Pr ot oc ol  ........................................................................................ 1 1 2  
1 2  
A D MI NI S T R A TI V E, L E G A L, A N D E T HI C A L A S P E C T S  ......................................... 1 1 4  
1 2. 1  Et hical Pri nci ples a n d C o n d uct of t he Trial  .......................................................... 1 1 4  
1 2. 2  Healt h A ut h orities a n d I n de pe n de nt Et hics C o m mittees/ I nstit uti o nal Re vie w B oar d
 
1 1 8  
1 2. 3  S u bj ect Data Pr otecti o n a n d C o nfi de ntialit y  ......................................................... 1 1 9  
1 2. 4  I ns ura nce ............................................................................................................... 1 2 0  
1 2. 5  Fi na nci al as pects ................................................................................................... 1 2 1  
1 2. 6  Arc hi vi n g at t he E n d of t he St u d y  ......................................................................... 1 2 1  
1 3  
R E P O R TI N G A N D P U B LI C A TI O N S P O LI C Y  ............................................................ 1 2 3  
1 3. 1  Cli nical St u d y Re p ort  ............................................................................................ 1 2 3  
1 3. 2  P u blicati o ns a n d P osters  ....................................................................................... 1 2 3  
1 4  
R E F E R E N C E S  ................................................................................................................ 1 2 6  
1 5  
A N N E X E S  ....................................................................................................................... 1 3 2  
1 5. 2  A N N E X 
1: 
VI S U A L 
A N A L O G U E 
S C A L E 
O F 
G L O B A L 
DI S E A S E 
E V A L U A TI O N  ............................................................................................................... 1 3 3  
1 5. 3  A N N E X 2: VI S U A L A N A L O G U E S C A L E O F P AI N  ........................................ 1 3 4  
1 5. 3. 1  Pai n at rest  ................................................................................................... 1 3 4  
1 5. 3. 2  Pai n d uri n g acti vities  ................................................................................... 1 3 4  
1 5. 3. 3  Pai n at pal pati o n ( perf or me d b y t he I n vesti gat or or t he n urse)  ................... 1 3 4  
1 5. 4  A N N E X 3: W EI G H T B E A RI N G S C O R E  ........................................................... 1 3 5  
1 5. 5  A N N E X 4: R A DI O L O GI C A L E V A L U A TI O N: M O DI FI E D R U S / T U S  .......... 1 3 6  


C O N FI D E N TI A L 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 0 /1 3 6  
S T U D Y S Y N O P SI S 
E u dr a C T N u m ber: 2 0 1 2 -0 0 5 3 3 3 -3 6  
Pr ot oc ol N u m ber:  0 0 0 0 0 5/ B T  
Pr ot oc ol C o de : A L L O B -D U 1  
S p o ns or or S p o ns or's re prese nt ati ve i n t he E ur o pe a n U ni o n  
B o ne T h era p e utics S. A., G osselies, Bel gi u m  
P h ase of De vel o p me nt 
Pil ot  P hase I /IIa St u d y  
Pl a n ne d St u d y Peri o d  
T otal recr uit me nt peri o d: u ntil ma xi m u m 3 2  patie nts ha ve bee n tr eate d  
T otal st u d y f oll o w-u p p eri o d: 6 m o nt hs 
O pe n p ost-st u d y f oll o w- u p: 2 4 m o nt hs after t he e n d of t he st u d y 
O bjecti ves  
T o e val uate t he safet y a n d effic ac y of A L L O B ® , a pr o prietar y p o p ul ati o n of all o ge neic 
oste o blastic cells, i n t he treat me nt of del a ye d -u ni o n fract ures of l o n g b o n es, gi v e n as si n gle 
perc uta n e o us a d mi nistrati o n directl y i nt o t he del a ye d -u ni o n site.  
Pl a n ne d N u m ber of S u bjects: 
Ma xi m u m 3 5 e nr olle d patie nts f or ma xi m u m 3 2 treate d patie nts (ass u mi n g 1 0 % dr o p-o ut) . A 
mi ni m u m of 1 6 c o m plete d patie nts is re q uire d f or t he I nt eri m A nal ysis.   
Me dic al C o n diti o n, P ati e nt Selecti o n a n d I ncl usi o n Criteri a  
Me n a n d w o me n, a ge d 1 8 t o 8 0  year s ol d, dia g n ose d wit h a n o n-i nfecte d dela ye d-u ni o n fract ur e 
of a l o n g b o n e (fe m ur, ti bia, fi b ula, h u mer us, ul n a  a n d ra di us) of mi ni m u m 3  ( ± 2 wee ks) a n d 
ma xi m u m 7  m o nt hs  ( ± 2 wee ks) at t he ti me of i ncl usi o n. 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 1 /1 3 6  
 
Test pr oce d ure, pr o d uct, d ose a n d m o de of a d mi nistr ati o n  
A L L O B ® is a n all o ge neic oste o blastic cell pr o d uct falli n g u n der t he E M A classificati o n 
E M A/ 4 8 6 2 4 6/ 2 0 1 1  as tiss ue e n gi neere d A d va nce d T hera p y M e dici nal Pr o d ucts ( A T M P).  
A L L O B ® will be gi ve n p erc uta n e o usl y  as a si n gle a d mi nistrati o n i nt o t he dela ye d -u ni o n site 
usi n g a tre p hi ne. T h e v ol u me a d mi nist ere d is base d o n t he siz e of t he dela ye d -u ni o n ga p a n d 
deter mi ne d as f oll o w:    
Fract ure i nterli ne < 0. 5 c m: 2  ml of s us pe nsi o n s ol uti o n  
Fract ure i nterli ne ≥ 0. 5 –  ≤ 1 c m: 3  ml of s us pe nsi o n s ol uti o n  
Fract ure i nterli ne >  1 –  ≤ 2 . 5 c m: 4 ml of s us pe nsi o n s ol uti o n 
I n case i m pla ntati o n usi n g 2 s ur gic al sites is j u d ge d best a p pr oac h b y t he i n vesti gat or, a t otal 
of u p t o 4 ml ma y be a d mi nistere d.  
Det aile d visit sc he d ule  
After i nf or me d c o nse nt is o btai ne d, f ulfil me nt of st u d y i ncl usi o n a n d e x cl usi o n criteria will be 
perf or me d at Visit # 1 , w hic h will ta ke u p t o 8 wee ks t o c o m plete . Visit # 2 is sc he d ule d t o ta ke 
place after c o m pleti o n of Visit  # 1 f or bas eli ne cli ni cal  assess me nts a n d A L L O B ®  i m pla ntati o n 
(t he bas eli ne of t he ra di ol o gical assess me nts is Visit # 1). At Visit # 2, all patie nts will be 
h os pitaliz e d f or 2 4 or 4 8 h o urs after i m pla ntati o n , acc or di n g t o t he j u d g me nt of t he 
I n v esti gat or.  
Patie nts will be f oll o we d d uri n g 6 m o nt hs, at 2 wee ks, 1, 3, a n d 6 m o nt hs  ( Visit # 3 t o Visit 
# 6) .  
 
  
 
 
D ur ati o n of tre at me nt  
T his is a si n gle d ose a d mi nistrati o n st u d y.  


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 2 /1 3 6  
 
P ati e nt I ncl usi o n Sc he me:  
In or der t o ma xi m ise patie nt safet y, f or t he first 1 6 patie nts  treate d, p atie nt recr uit me nt will 
pr ocee d ste p wise b y bl o c ks of 4. F ull first 2 wee ks safet y d ata of t he first bl oc k of 4 treate d 
patie nts will be a n al ys e d bef ore t he first patie nt of t he sec o n d bl oc k of 4 is treate d. First 4 8 
h o urs safet y dat a of  t he s ec o n d bl oc k of 4 tr eate d patie nts will be a nal yse d bef ore treat me nt  of 
t he first patie nt of t he ne xt bl oc k. T his latter sc he me will be re peate d u ntil 1 6 patie nts ha ve 
bee n  tr eate d. T his  re vi e w of re p orte d S A E p ote nti all y relate d t o t he In vesti gati o na l M e dici nal 
P r o d uct (I M P), a n d es p eciall y t h os e relate d t o i m m u n ol o gical reacti o ns (se v ere A d verse E ve nt 
of S pecial C o nsi derati o n ( A E S C )), will be d o ne b y t he Safet y M o nit ori n g C o m mittee ( S M C).  
St u d y E n d p oi nts a n d Criteri a f or E v al u ati o n  
S afety Criteri a  
I n a d diti o n t o sta n dar d p har mac o vi gila nce re q uir e me nts, partic ular atte nti o n will be gi ve n t o 
A E s u g g esti n g i m m u ne -me diate d  reacti o ns, s uc h as: ge n eral disc o mf ort, u n easi ness, ill feeli n g, 
pai n or s w elli n g i n t he i m pla nte d area, fe v er a n d a n y i nfla m mat or y reacti o ns, fl u-li ke 
s y m pt o ms (e. g., c hills, b o d y ac hes, s h ort n ess of breat h , c uta ne o us ras h es… ). All se vere A Es 
p ote ntiall y relate d t o  t h e I M P a n d i n p artic ular t h ose p ote ntiall y relate d t o t he all o ge nei c 
reacti o ns will be ma n a ge d b y t he S M C  w h o will a nal ys e a n d re p ort t hes e e ve nts i n a ti mel y 
ma n ner c o nsiste nt wit h t he safet y of  p atie nt  recr uit me nt sc he me. 
Effic acy Criteri a  
T he f oll o wi n g cli nical a n d ra di ol o gic al criteria will be use d:  
- Cli nical: Gl o bal disease e val uati o n ( G D E) sc ore as assesse d b y t he patie nt a n d I n vesti gat or 
usi n g a Vis u al A nal o g ue Scale  ( V A S); Pai n usi n g a V A S ; Wei g ht -b eari n g sc ore usi n g a 
Li kert Scale  
- Ra di ol o gical h eali n g pr o gressi o n as assesse d b y C T  sca n a n d b y c o n v e nti o nal X -ra y usi n g 
t he T o m o gra p hi c U ni o n Sc ore ( T U S) a n d m o difie d R a di ol o gical U ni o n S c ore (m R U S ), 
res pecti vel y 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 3 /1 3 6  
 
 
 
 
Ev al u ati o n Ti me P oi nts  
Efficac y a n d safet y e n d p oi nts wi ll be deter mi ne d at eac h sc h e d ule d visit o ver t he 6 -m o nt h 
f oll o w-u p peri o d (at 2 wee ks, 1, 3  a n d 6  m o nt hs) . 
T he i nteri m re p ort a n d t he decisi o n f or c o nti n uati o n  will be esta blis he d o n t he first 1 6 
assessable patie nts after 6  m o nt hs of f oll o w -u p a n d  t he fi nal Cli nical St u d y Re p ort ( C S R) will 
be esta blis he d at 6 m o nt hs  (e n d of st u d y) after treat me nt f or all  patie nts , as a p plica ble. 
 
 
 
I nteri m A n al ysis  
A Data Safet y M o nit ori n g B o ar d ( D S M B) will be esta blis he d t o a nal yse a n d re p ort t he safet y 
a n d t he efficac y data w he n 6 -m o nt h p ost -treat me nt res ults fr o m t he first 1 6 assessa ble patie nts 
will be a vaila ble. T his B oar d will rec o m me n d w het her t o c o nti n ue, m o dif y or st o p t he st u d y. 
If s uccess is less t ha n 3 0 % or hi g h er t ha n 7 0 %, patie nt  recr uit me nt will be st o p pe d.  If t h e 
D S M B rec o m me n d ati o n is c o nti n uati o n ( wit h or wit h o ut c ha n ges) of t he st u d y, patie nt 
recr uit me nt will c o nti n ue u ntil 3 2 patie nts ha ve bee n treate d. 
St atistic al A n al ysi s 
Statistical met h o ds will be e x ha usti vel y d escri b e d i n a Statistical  A nal ysis Pla n ( S A P), w hic h 
will c o nstit ute t he o nl y refere nce d oc u me nt. T he S A P will be re vie we d, a p pr o ve d, a n d si g ne d 
pri or t o data base l o c k at t he latest.  
T he safet y p o p ulati o n will b e c o nsi dere d as t he pri mar y c o h ort f or a n al ysis of efficac y. It will 
c o m prise all treat e d p atie nts.  
Effic acy E n d p oi nts:  
T he efficac y of A L L O B ®  will be e v al uate d at 6  m o nt hs . T he s uccess will be base d o n t h e 
perce nt a ge of treate d pati e nts ( A L L O B ® ) n ot faili n g u n der treat me nt. A treate d patie nt will be 
c o nsi dere d as faile d if, at t he e n d of t he st u d y ( 6  m o nt hs):  


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 4 /1 3 6  
 
- T he patie nt ha d re q uire d a resc u e s ur ger y or   
- T he G l o bal D isease E val uati o n sc ore as percei ve d b y t he patie nt has n ot i m pr o ve d b y at 
least 2 5 % a n d t he T U S  as assesse d  b y C T sca n h as n ot i ncrease d b y at least 2  p oi nts.  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
All safet y a nal yses will b e c o n d u cte d o n t he safe t y p o p ulati o n a n d t a b ulate d. F or eac h A E a n d 
S A Es re p orte d, t he n u m b er a n d perce nta ge of p atie nts will be ta b ulate d bas e d o n s yste m or ga n 
class a n d preferre d t er m. Si milar ta b ulati o ns will be perf or me d b y se v erit y, relati o ns hi p t o t he 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 5 /1 3 6  
 
st u d y pr o d uct/ pr oce d ure, acti o n ta ke n a n d o utc o m e. T he fre q u e nc y of A Es a n d S A Es will be 
assesse d usi n g a 9 5 % C o nfi de nce I nter val.   
M ore details will be gi ve n i n t he S A P.  
Et hic al c o nsi der ati o ns  
T his st u d y will be c o n d ucte d i n acc or da n ce wit h a p plica ble la ws a n d re g ulati o ns i ncl u di n g, b ut 
n ot li mite d t o, t he I nter nati o nal C o nfere n ce o n Har m o nisati o n (I C H) G ui deli ne f or G o o d 
Cli nical Practice ( G C P) a n d t he et hical pri nci ples t hat ha ve t heir ori gi ns  i n t he Decl arati o n of 
Helsi n ki.  T he Instit uti o nal R e vie w B oar d (I R B)/ In de p e n de nt E t hics C o m mittee (I E C) m ust 
re vie w a n d a p pr o ve t he pr ot oc ol a n d t he Inf or me d C o nse nt F or m  (I C F) b ef ore a n y p atie nts  are 
e nr olle d.  Bef ore a n y pr ot oc ol -re q uire d pr oce d ures are perf or me d, t he s u bject m ust si g n a n d 
date t he I R B/I E C -a p pr o ve d IC F.  
D ate a n d Versi o n of t he St u d y Pr ot oc ol:  0 2  Fe b 2 0 1 7, V 0 5  
 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 6 /1 3 6  
 
LI S T O F T A B L E S 
T a ble 1: Det aile d Sc he d ule of Visits a n d Pr oce d ures d uri n g t he St u d y ............................ 5 2  
T a ble 2: Det aile d Sc he d ule of Visits & Pr o ce d ures d uri n g t he S afet y P ost- St u d y F oll o w-
u p  ............................................................................................................................................. 5 3 
T a ble 3: Det aile d sc he d ule of Visits a n d Pr oce d ures d uri n g t he Bi o distri b uti o n s u b-st u d y
 .................................................................................................................................................. 5 4 
T a ble 4: C h ar acteristics of t he I n vesti g ati o n al Me dici n al Pr o d uct ................................... 6 7  
T a ble 5: A d mi nistr ati o n of t he Test Pr o d uct ....................................................................... 6 8  
T a ble 6: O ver vie w of S afet y P ar a meters a n d Ti me p oi nts .................................................. 7 0  
T a ble 7: O ver vie w of Bl o o d C ollecti o n ................................................................................. 7 2  
T a ble 8: Cl assific ati o n of A d verse E ve nts ............................................................................ 7 6  
T a ble 9: O bser v ati o n Peri o d f or t he Occ urre nce of A Es a n d S A Es .................................. 8 0  
T a ble 1 0: S u m m ar y of P ossi ble Ris ks rel ate d t o t he Pr oce d ures ...................................... 8 1  
T a ble 1 1: S u m m ar y of O bser ve d A d verse E ve nts ( A E) a n d Seri o us A d verse E ve nts ( S A E) 
p ossi bl y rel ate d t o St u d y Tre at me nt (i.e., P R E O B ® a n d/ or t he I m pl a nt ati o n Pr o ce d ure)
 .................................................................................................................................................. 8 2 
 
 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 7 /1 3 6  
 
LI S T O F A B B R E VI A TI O N S 
A D R  
A d verse Dr u g Reacti o n  
A E  
A d verse E v e nt  
A E S C  
A d verse E v e nt of S pecial C o nsi derati o n  
A S T 
( S G O T) 
As partate A mi n o  T ra nsferase (als o k n o w n as:  
S er u m G l uta mic-O x al oacetic T ra nsa mi nase) 
A L T 
( S G P T) 
Ala ni ne a mi n otra nsf eras e (als o k n o w n as:  
S er u m G l uta mic-P yr u vi c T ra nsa mi nase) 
A T M P  
A d va nce d T h era p y Me di ci nal Pr o d uct  
B MI  
B o d y Mass I n d e x  
B P  
Bl o o d Press ure  
C As  
C o m pete nt A ut h orities  
C A T  
C o m mittee f or A d va nce d T hera pies  ( E M A) 
C B M P  
Cell -Base d M e dici nal Pr o d ucts  
C H M P  
C o m mittee f or Me dici nal Pr o d uct f or H u ma n Us e  ( E M A) 
CI  
C o nfi de nce I nter val  
C M V  
C yt o m e gal o vir us  
C P M P  
C o m mittee f or Pr o prietar y Me dici n al Pr o d ucts  ( E M A) 
C R A  
Cli nical Researc h Ass o ciate  
C R F/e C R F  
Case Re p ort F or m/electr o nic Case Re p ort F or m  
C R O  
C o ntract Researc h Or ga nizati o n  
C S R  
Cli nical St u d y Re p ort  
C T  
C o m p ute d T o m o gra p h y  
C T A  
Cli nical Trial A p plicati o n  
C U  
Cli nical U nit  
D C F  
Data Clarific ati o n F or m  
D S M B  
Data Safet y M o nit ori n g B oar d  
D M P  
Data Ma na ge me nt Pla n  


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 8 /1 3 6  
 
D U  
Dela ye d -u ni o n  
E B V  
E pstei n -Bar Vir us  
E C  
E ur o pea n C o m missi o n  
E Cs  
Et hics C o m mittees  
E M A  
E ur o pea n Me dici nes A ge nc y  
E P Cs  
E n d ot helial Pr o ge nit or C ells  
E U  
E ur o pea n U ni o n  
E u dra C T  
E ur o pea n Cli nical Trials Data base  
F A  
F ull A nal ysis  
G C P  
G o o d Cli nical Practice  
G L P  
G o o d La b orat or y Practice  
G M P  
G o o d Ma n ufact uri n g Practice  
Gr.  
G ra m  
H B V  
He patitis B Vir us  
H C V  
He patitis C Vir us  
H H V 6  
H u ma n Her pes Vir us T y pe 6  
HI V  
H u ma n I m m u n o deficie nc y Vir us  
H S V -1  
Her pes Si m ple x Vir us T y p e 1  
H T L V -1  
H u ma n T -l y m p h otr o pi c Vir us T y p e 1 
I A T A 
I nter nati o nal Air Tra ns p ortati o n Ass ociati o n  
I C/ E C 
I n cl usi o n a n d E x cl usi o n Criteria 
I C F 
I nf or me d C o nse nt F or m 
I C H 
I nter nati o nal C o nfere nce o n Har m o nizati o n 
I E C 
I n d e pe n de nt Et hics C o m mittee 
I M P 
I n v esti gati o nal Me dici nal Pr o d uct 
I M P D 
I n v esti gati o nal Me dici nal Pr o d uct D ossier 
I R B 
I nstit uti o nal Re vie w B oar d 
I R B 
I nstit uti o nal Re vie w B oar d 
L L O Q  
L o w er Li mit of Q ua ntificati o n  


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 9 /1 3 6  
 
L M S  
Least Mea n S q uare  
L O C F  
Me d D R A  
Last O bs er vati o n Carrie d F or war d  
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
M N C  
M P  
m R U S  
M o n o n uclear Cell  
Ma na gi n g P h ysicia n  
M o difie d Ra di o gra p hic U ni o n Sc ore  
M S C  
Mese nc h y mal Str o mal Cell  
N U  
N o n -U ni o n  
O E C D  
Or ga nisati o n f or E c o n o mic C o -O perati o n a n d De v el o p me nt  
PI L  
Patie nt I nf or me d Letter  
P K  
P har mac o ki netic  
P P  
Per Pr ot oc ol  
S A  
Safet y A nal ysis  
S A E  
Seri o us A d verse E v e nt  
S A P  
Statistical  A nal ysis Pla n  
S A R  
Seri o us A d verse Reacti o n  
S A S Q E  
Seri o us A d verse Safet y/ Q ualit y E ve nt   
S D V  
S o urce Data Verifi cati o n  
S M C  
Safet y M o nit ori n g C o m mittee  
S O P  
Sta n dar d O perati n g Pr oce d ure  
S S O  
St u d y Safet y Officer  
S U S A R  
S us pecte d U ne x pecte d S eri o us A d verse Reacti o n  
T U S  
T o m o gra p hic U ni o n Sc ore  
V A S  
Vis ual A nal o g ue Scale  
W H O  
W orl d Healt h Or ga niz ati o n  
W M A  
W orl d Me dical Ass ociati o n  
 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 2 0 /1 3 6  
 
 D E FI NI TI O N S O F T E R M S 
- 
A d verse D r u g Re acti o n:  a n y u nt o war d a n d u ni nt e n de d res p o nses t o a n i n vesti gati o nal 
me dici nal pr o d uct relat e d t o a n y d ose a d mi nistere d ( ha vi n g a reas o n a ble ca us al 
relati o ns hi p t o t he pr o d uct, t he ter m “reas o n a ble ca usal relati o ns hi p” mea ni n g t hat t here 
is e vi de nce or ar g u m e nts t o s u g gest a ca us al relati o ns hi p). U ne x pecte d A D R is a n 
a d verse reacti o n w h ose nat ure, se v erit y, s p ecificit y, or o utc o me is n ot c o nsiste nt wit h 
t he a p plica ble pr o d u ct i nf or mati o n (e. g., I n v esti gat or’s Br oc h ure). 
- 
A d verse E ve nt:  a n y u nt o war d me dical occ urre nce i n a patie nt or cli nical i n vesti gati o n 
s u bject w h o has bee n a d mi nistere d a p har mace utical pr o d uct a n d/ or a n y i n vesti gati o nal 
me dici nal pr o d uct a n d w hic h d oes n ot necess aril y ha ve a ca usal relati o ns hi p wit h t his 
treat me nt. A n A E ca n t h eref ore be a n y u nfa v o ura ble a n d u ni nte n de d si g ns (i ncl u di n g 
a n y a b n or mal la b orat or y fi n di n gs), s y m pt o ms, or disease te m p orall y ass o ciate d wit h t he 
use of a me dici n al pr o d u ct, wit h o ut a n y j u d g me nt a b o ut ca usalit y  
- 
A d verse E ve nt of S peci al C o nsi der ati o n : i n t his st u d y, a d v erse e ve nt w hi c h has bee n 
i de ntifie d as p ote ntiall y relate d t o all o ge neic reacti o n 
- 
A L L O B ® : is a pr o prietar y all o ge neic tiss ue e n gi neere d pr o d uct (i.e., a n a d va nce d 
t hera p y me di ci nal pr o d uct A T M P, falli n g u n d er t he sc o p e of t he E ur o pea n Re g ulati o n 
1 3 9 4/ 2 0 0 7/ E C a n d t he Directi ve 2 0 0 1/ 8 3/ E C), c o nsisti n g i n all o ge nic oste o blastic cells 
( A L L O B ® cells), ma n ufact ure d b y B o ne T h era pe utics S. A. 
- 
Assess a ble p atie nt:  a patie nt w h o c o m plete d all sc he d ule d visits u p t o last sc he d ule d 
visit (i ncl usi ve) or a patie nt w h o has bee n scree n e d ( V # 1), treate d ( V # 2) a n d w h o at 
least has c o m plete d t he f oll o w- u p visit V # 5 or V # 6. 
- 
C o m plete d p atie nt : a patie nt w h o c o m plete d all sc he d ule d visits u p t o last sc he d ule d 
visit (i ncl usi ve)  
- 
C o ntr ac t Rese a rc h Or g a niz ati o n ( C R O): a pers o n or a n or ga nizati o n c o ntracte d b y 
t he S p o ns or t o perf or m o ne or m ore of t h e S p o ns or's tri al-relat e d d uties a n d f u ncti o ns  
- 
Disc o nti n ue d or wit h dr a w n p atie nt  is a patie nt w h o has b ee n e nr olle d, scree ne d,  
ran d o mize d or tr eate d b ut has wit h dra w n fr o m t he st u d y bef ore c o m pleti o n of t he last 
sc he d ule d visit 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 2 1 /1 3 6  
 
- 
Distri b uti o n : tra ns p ortati o n a n d deli ver y of tiss ues a n d cells i nte n de d f or h u ma n 
a p plicati o ns  
- 
Del a ye d- u ni o n ( D U): fract ure t hat has n ot u nite d wit hi n a peri o d of ti me t hat w o ul d be 
c o nsi dere d a d e q uate f or b o ne heali n g. I n t his st u d y, dela ye d- u ni o n is defi ne d at t he ti me 
of scree ni n g as (i) a n a bs e nce of heali n g 3 m o nt hs ( ± 2 wee ks) (a n d wit h a ma xi m u m of 
7 m o nt hs) after t he o ns et of fract ure a n d (ii) a n a bse nce of t he pr o gressi o n of heali n g 
o ve r t he last 4 wee ks, as c o nfir me d b y cli nical a n d ra di ol o gical e val u ati o n. 
- 
D at a S afet y M o nit ori n g B o ar d  ( DS M B) : a n i n d e pe n de nt d ata m o nit ori n g c o m mittee 
esta blis he d b y t he S p o ns or t o assess at i nter vals t h e pr o gress of a cli nical tri al, t he safet y 
data, a n d t he critical effi cac y e n d p oi nts, a n d t o rec o m me n d t o t he S p o ns or w het her t o 
c o nti n ue, m o dif y or st o p t he trial.  
- 
Eli gi ble p atie nt:  a s cree ne d patie nt w h o is c o nsi dere d eli gi ble acc or di n g t o selecti o n 
criteria. 
- 
E nr olle d p atie nt:  patie nt w h o has date d a n d si g n e d t he I nf or me d C o nse nt F or m (I C F). 
- 
G o o d Cli nic al Pr acti ce  ( G C P): set of i nter nati o nall y rec o g nize d et hical a n d scie ntific 
re q uire me nts a n d sta n d ar ds as re gar ds t he desi g n, c o n d uct, perf or ma nce, m o nit ori n g, 
a u diti n g, rec or di n g, a n al ys es, a n d re p orti n g of cli nical trials, t hat pr o vi des ass ura nce 
t hat t he data a n d re p ort e d res ults are cre di ble a n d acc urate, a n d t h at t he ri g hts, safet y, 
well- bei n g, a n d c o nfi de ntialit y of trial s u bjects are pr otecte d 
- 
I nter me di ar y Str uct ure Tiss ue Est a blis h me nt: is a n accre dite d tiss ue esta blis h me nt 
w here t h e acti vities of pr ocessi n g, pres er vati o n, st ora ge or distri b uti o n of h u ma n tiss ues 
a n d cells are perf or me d u n der a n a gree me nt wit h a h u ma n tiss ue ba n k ( Bel gia n La w of 
Dece m b er 1 9 t h 2 0 0 9, t he Bel gia n R D 2 of Se pte m b er 2 8t h 2 0 0 9) 
- 
I n vesti g ati n g Site: a n y p u blic or pri vate e ntit y or me dical facilit y w here cli nical trial 
a n d trial-rel ate d acti vities are c o n d u cte d  
- 
I n vesti g ati o n al 
Me dici n al Pr o d uct (I M P): a p har mace utical f or m of a n acti ve 
s u bsta nce or Place b o bei n g teste d or use d as a refere nce i n a cli nical trial . 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 2 2 /1 3 6  
 
- 
I n vesti g at or: a pers o n res p o nsi ble f or t he c o n d u ct of t he cli nical tri al at a trial site. If a 
trial is c o n d ucte d b y a tea m of i n di vi d uals at a trial site, t he i n vesti gat or is t he 
res p o nsi ble lea der of t he tea m a n d ma y be calle d t he pri nci pal i n vesti gat or. 
- 
M a n a gi n g P h ysici a n ( or dele g ate):
 ma na gi n g P h ysicia n of H u ma n Bi ol o gical Material 
i n t he Pr o d ucti o n/ Tiss ue Esta blis h me nt, is a Me dical D oct or res p o nsi ble t o g uara nt y t he 
tracea bilit y, t he q u alit y a n d safet y of t he H u ma n Bi ol o gi cal Material, as well as t he 
q ualit y a n d safet y of all o perati o ns e x ec ute d i n t he Pr o d ucti o n/ Tiss ue Esta blis h me nt.  
He is als o res p o nsi ble f or t he re p orti n g of Seri o us A d verse E ve nt a n d Seri o us A d verse 
Reacti o n relate d t o H u ma n Bi ol o gical Mat erial. His f u ncti o n ca n be d ele gat e d.   
- 
Mese nc h y m al Str o m al Cells: “ plastic-a d here nt” ste m cells, e x pressi n g s pecific s urface 
mar kers, a n d gi vi n g rise t o b o ne, cartila ge, a n d a di p oc yt e cells.  
- 
N o n- u ni o n fr act ure : refers t o a fract ure t hat will n ot u nite wit hi n 6 t o 9 m o nt hs a n d 
ne e ds a d diti o nal s ur gical or n o n-s ur gical i nter v e nti o n  
- 
Oste o bl astic cells:  cells bel o n gi n g t o t he oste o blastic li nea ge ( b o ne f or mi n g cells) 
e nc o m passi n g t he oste o pr o ge nit ors, t he pre- oste o blasts, t he oste o blasts, t h e li ni n g cells 
a n d t he oste oc ytes.  
- 
Oste o pr o ge nit or cells or oste o pr o g e nit ors 
& 
pre- oste o bl asts:  are n ot-f ull y 
differe ntiat e d cells c o m mitte d t o t he oste o blastic li nea ge, i.e., prec urs ors of oste o blast 
dis pla yi n g li mite d pr oliferati o n ca pacit y.  
- 
Pr o cessi n g : all o perati o ns i n v ol ve d i n t he pre parati o n, ma ni p ulati o n, preser vati o n, a n d 
pac ka gi n g of tiss ues or cells i nte n de d f or h u ma n a p plicati o ns 
- 
R a n d o mise d p atie nt : patie nt t o w h o m a ra n d o misati o n n u m ber has bee n all ocate d 
- 
Scree ne d p atie nt : a patie nt w h o has date d a n d si g n e d t he I nf or m e d C o nse nt F or m (I C F) 
(e nr olled patie nt) a n d w h o has perf or me d t he c h ec ki n g of t he s electi o n criteria. 
- 
Scree ni n g f ail ure : a scree ne d p atie nt w h o is n ot eli gi ble f or t h e st u d y aft er c hec ki n g 
t he selecti o n criteria. 
- 
S afet y M o nit ori n g C o m mittee (S M C ): a c o m mittee esta blis he d b y t h e S p o ns or t o 
a nal ys e, f or eac h bl o c k of 4 patie nts fr o m t he first 1 6 patie nts, t he safet y dat a a n d ma ke 
rec o m me n dati o ns w h et her t o c o nti n ue or st o p t he trial.  


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 2 3 /1 3 6  
 
- 
Seri o us A d verse E ve nt ( S A E ): a n y a d verse e v e nt ( A E) or seri o us a d v erse reacti o n 
( S A R) t hat, i n t he vie w of t he i n vesti gat or or s p o ns or, res ults i n a n y of t he f oll o wi n g 
o utc o mes (I C H E 2a): 
Deat h, Life-t hreate ni n g 
A E, I n patie nt h os pitalizati o n or 
pr ol o n gati o n of e xisti n g h os pitalizati o n, Persiste nt or si g nifica nt i nca pacit y or 
s u bsta ntial disr u pti o n of t he a bilit y t o c o n d u ct n or mal life f u ncti o ns, C o n ge nital 
a n o mal y/ birt h defect. M e dical a n d scie ntific j u d ge me nt s h o ul d be e x ercise d i n deci di n g 
w het her e x pe dite d re p orti n g is a p pr o pri ate i n ot her sit uati o ns, s uc h as i m p orta nt me dical 
e ve nts t hat m a y n ot b e i m me diatel y life-t hr eate ni n g or res ult i n deat h or h os pitalizati o n 
b ut ma y j e o par dize t he patie nt or ma y re q uire i nter ve nti o n t o pre ve nt o ne of t he ot her 
o utc o mes liste d i n t he defi niti o n a b o ve.  
- 
Seri o us A d verse Re a cti o n ( S A R ): a n y u nt o war d a n d u ni nte n de d res p o nses t o a n 
i n vestigati o nal me dici nal pr o d uct rel ate d t o a n y d ose a d mi nistere d ( ha vi n g a reas o n a ble 
ca usal relati o ns hi p t o t he pr o d uct), a n d t hat res ults i n deat h, is life-t hr eate ni n g, re q uires 
patie nt h os pitaliz ati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n, res ults i n persiste nt 
or si g nifica nt disa bilit y or i nca pacit y, or is a c o n ge nital a n o mal y or birt h d efect. 
- 
Seri o us A d verse S afet y/ Q u alit y E ve nt ( S A S Q E): a n y a d v erse e v e nt relate d t o t he a n y 
o perati o n d o ne o n t he c ollecte d h u ma n bi ol o gical material u n der t he res p o nsi bilit y of 
t he I nt er me diar y Str uct ure (i.e., direct tr a ns p ort a n d distri b uti o n of t he h u ma n bi ol o gical 
material fr o m t he har vesti n g site t o t he Pr o d ucti o n/ Tiss ue Esta blis h me nt of B o n e 
T hera p e utics S. A.) t h at ma y ca use deat h, be life-t hreate ni n g, ge nerate disa bilit y or 
i nca pacit y t o w or k t o t he patie nt, or t hat ma y ca us e m or bi dit y. 
- 
St or a ge : 
mai nte na nce of t he I M P u n der a p pr o priate c o ntr olle d c o n diti o ns u ntil 
a d mi nistrati o n. 
- 
St u d y S afet y Officer : i n di vi d ual desi g nat e d t o perf or m t he ha n dli n g, n otifi cati o n, a n d 
re p orti n g of safet y iss ues 
- 
S u bject : a n i n di vi d ual w h o partici pates i n t he cli nical trial 
- 
S us pecte d 
U ne x pecte d Seri o us 
A d verse 
Re acti o n ( S U S A R):  seri o us a d verse 
reacti o n, t he nat ure, se v erit y, s pecificit y, or o utc o me of w hic h is n ot c o nsiste nt wit h 
a p plica ble pr o d u ct i nf or mati o n (e. g., t h e I n vesti gat or’s Br oc h ure) 
- 
Tre ate d p atie nt: a patie nt t o w h o m a treat me nt h as bee n a d mi nistere d 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 2 4 /1 3 6  
 
- 
Tiss ue 
B a n k : is t he accre dite d tiss ue esta blis h me nt res p o nsi ble f or d o nati o n, 
pr oc ure m e nt, testi n g a n d releas e of cells a n d 
w here acti vities of pr ocessi n g, 
preser vati o n, st ora ge or distri b uti o n of h u ma n tiss ues a n d cells ca n be u n derta ke n. 
Acc or di n g t o Bel gia n l e gislati o n, it ca n dele gate s o me acti vities t o a n accre dite d 
I nter me diar y Str u ct ure u n der a n a gree me nt b et wee n t he parties ( Bel gi a n La w of 
Dece m b er 1 9t h 2 0 0 9, t he Bel gia n R D 2 of Se pte m ber 2 8t h 2 0 0 9).  


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 2 5 /1 3 6  
 
1  
I N T R O D U C TI O N 
1. 1  
G e ner al B ac k gr o u n d  
1. 1. 1  I m p aire d Fr act ure H e ali n g 
B o ne h as a s u bsta ntial ca pacit y f or re pair a n d re ge n erati o n i n res p o nse t o i nj ur y or s ur gical 
treat me nt. B ot h pr ocess es i n v ol ve a c o m ple x i nte grati o n of cells, gr o wt h fact ors a n d 
e xtracell ular matri x. Re pair si m pl y rest ores t he c o nti n uit y of t he i nj ure d tiss ues wit h o ut 
necessaril y i ncreasi n g b o ne v ol u me, w hile re ge n erati o n i n v ol ves t he differe ntiati o n of ne w cells 
a n d t he f or mati o n of n e w b o ne tiss ue, w hic h res ults i n a n o verall i ncrease i n t he v ol u me of ne w 
s keletal tiss ues. Fract ur e heali n g is a m ultista ge re pair pr ocess t hat i n v ol ves c o m ple x well-
orc hestrat e d ste ps t hat are i nitiate d i n res p o nse t o i nj ur y, res ulti n g e v e nt uall y i n t he re pair a n d 
rest orati o n of f u ncti o n ( Al- A ql et al., 2 0 0 8). 
Fract ures are n o w s uccessf ull y treate d i n t he maj orit y o f p atie nts; ne vert heless a b o ut a t hir d 
re q uires s o me s ur gic al i nter ve nti o n. 
A m o n g t h ose, dela ye d- u ni o ns or n o n- u ni o ns 
ma y 
necessitate n u mer o us o p erati ve pr oce d ures, ca n l ea ve t he patie nt wit h f u ncti o nal deficits, a n d 
are oft e n ass ociat e d wit h pr ol o n ge d m or bi dit y ( Wiss a n d Stets o n, 1 9 9 6). 
F ract ure h eali n g is c o nsi dere d as a d y na mic pr o gressi ve pr ocess. N o wa da ys, i nter ve nti o n is 
us ua ll y i n dicate d b y 3 t o 5 m o nt hs after i nj ur y if m o nt hl y ra di o gra p hic st u dies d o n ot s h o w 
pr o gressi o n of fract ur e h eali n g ( Wiss a nd S tets o n, 1 9 9 6). 
T y pic all y, d ela ye d- u ni o n is a ter m use d f or a fract ure t hat has n ot u nite d wit hi n a peri o d of ti me 
t hat w o ul d be c o nsi dere d a de q uate f or b o n e heali n g. Dela ye d- u ni o n s u g gests t hat u ni o n is sl o w 
b ut will e ve nt uall y occ ur wit h o ut a d diti o nal s ur gi cal or n o n-s ur gical i nter ve nti o n, w hereas n o n-
u ni o n is defi ne d as t he cessati o n of all re p arati ve pr ocess of h eali n g. T here is n o u ni versall y 
acce pte d or vali date d a p pr oac h t o e val u ate t he pr o gressi o n of fract ure heali n g: defi niti o ns of 
dela ye d- u ni o n or n o n- u ni o n c o nti n ue t o be s u bject of vari o us i nter pret ati o ns ( B ha n d ari, 2 0 0 2 ; 
B ha n dari et al., 2 0 1 2). T he disti ncti o n bet wee n d ela ye d- u ni o n a n d n o n- u ni o n is base d o n ti me: 
a fract ur e n ot heale d 3 t o 8 m o nt hs after o nset is d efi ne d as a d ela ye d- u ni o n, w hereas a fract ur e 
n ot heale d 9 m o nt hs after o nset is defi ne d as n o n- u ni o n (re g ulat or y defi niti o n).  


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 2 6 /1 3 6  
 
H o we ver, t he ti mefra me f or heali n g differs acc or di n g t o t he fract ure sites (e. g., f or a ti bial 
dia p h yseal fract ure, bri d gi n g call us a n d cli nical st a bilit y s h o ul d be ac hie ve d b y 4 m o nt hs), t h e 
i nitial c o nfi g urati o n of t h e fract ure a n d t he i n di vi d ual me dical hist or y ( Wiss a n d Stets o n, 1 9 9 6). 
1. 1. 2  Di a g n osis of Del aye d or N o n - u ni o ns a n d F oll o w- u p of t he He ali n g Pr ocess 
T he m ost c o m m o n para meters use d b y s ur ge o ns t o dia g n ose dela ye d- or n o n- u ni o ns are 
ra di ol o gic al (e. g., c ortical c o nti n uit y) a n d cli nical ( e. g., pai n o n wei g ht beari n g) ( B h a n dari, 
2 0 1 2 ; Ha k et al., 2 0 1 4). Ra di ol o gical assess me nts, b y X-ra y or C T sca n, are ma de o n t he u ni o n 
of c ortices ( 3 t o 4) a n d prese nce/ a bse nce of a fract ure li ne. C T sca n has bee n s h o w n t o be m ore 
acc urate t ha n c o n v e nti o nal ra di o gra p h y i n e val uati n g fract ure heali n g of l o n g b o nes 
( Zi m mer m a n n, 2 0 0 7; M ors he d et al., 2 0 0 8). T he ra di ol o gical e v ol uti o n ca n be sc ore d usi n g a 
m o di fie d versi o n of R a di o gra p hi c U ni o n Scale f or Ti bial Fract ur e ( R U S T) ( K o oistra, 2 0 1 0). 
Cli nical assess me nts are ge n erall y bas e d o n pai n, wei g ht- b eari n g, a n d healt h relate d q ualit y of 
life. 
1. 1. 3  I nci de nce of Del ay e d- a n d N o n- U ni o n Fr act ures 
T he i nci de nce of i m paire d heali n g is esti mate d t o ra n ge fr o m 5 t o 1 0 % of all l o n g b o ne fract ures 
( Ei n h or n, 1 9 9 5). I n ci de n ce varies de p e n di n g o n t he t y p e of b o n es, t heir v asc ularisati o n, a n d 
t heir s u bc uta ne o us p ositi o n. 
1. 1. 4  Aeti ol o gy of Del aye d- a n d N o n- U ni o n Fr act ures 
T he de vel o p me nt o f dela ye d/ n o n - u ni o n is m ost cl osel y rel ate d t o t he t y pe a n d de gree of i nj ur y, 
b ut se veral ot her fact ors ma y als o pre dis p ose pati e nts t o dela ye d/ n o n- u ni o n. Ma n y of t h ese are 
relate d t o fract ur e feat ur es, i ncl u di n g t he d e gree of fract ure c o m mi n uti o n, b o ne l oss, a n d s oft 
tiss ue i nj ur y, as well as t he prese nce of o pe n fract ure a n d dis place me nt ( Ellis, 1 9 5 8; Nic oll, 
1 9 6 4 ; B is h o p et al.,  2 0 1 2). I na de q u ate re d ucti o n of a fract ur e lea di n g t o i nsta bilit y or p o or 
i m m o bilizati o n ma y b e a pri me reas o n f or dela ye d- u ni o n a n d n o n- u ni o n. 
S u bse q ue nt c o m plicati o ns, s uc h as i nfecti o n a n d c o m part me nt s y n dr o me, h a ve als o bee n s h o w n 
t o pla y a n i m p orta nt r ol e i n t he occ urre n ce of dela ye d- a n d n o n- u ni o n ( C o urt- Br o w n a n d 
Mc Q uee n, 1 9 8 7 ). T h e patie nt pr ofile als o c o ntri b utes t o its i nci de nce. F or i nsta nce, a ge, 
s m o ki n g a n d alc o h ol c o ns u m pti o n or me dical hist or y s uc h dia betes, a nae mia or peri p heral 


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vasc ular dis eases are well d oc u me nte d t o i ncreas e ris ks of d ela ye d- or n o n- u ni o n ( Sc h mitz , 
1 9 9 9; Gast o n, 2 0 0 7). T he use of n o n-ster oi dal a nti-i nfla m mat or y dr u gs or c ortic oster oi ds ca n 
als o i n hi bit b o ne heali n g ( Gia n n o u dis et al., 2 0 00 ), as well as t he n utriti o nal stat us of t he patie nt 
a n d c o m plia nce wit h t he p ost- o perati ve re gi me ( Gast o n a n d Si m ps o n, 2 0 0 7).  
F i nall y, pr o m pt a n d a p pr o priate treat me nt is nee d e d beca us e iatr o ge ni c i nj ur y t o t he s oft tiss ue 
en vel o pe (i. e., e x cessi ve peri osteal stri p pi n g), distracti o n acr oss t he fract ure site, i na de q uate 
i m m o bilizati o n or fi x ati o n, ca n pr o m ote t he de vel o p me nt of dela ye d/ n o n- u ni o n ( Gast o n a n d 
S i m ps o n, 2 0 0 7). 
1. 1. 5  Tre at me nt of Del aye d Fr act ures 
L o n g b o ne d ela ye d/ n o n- u ni o n fract ur es are treate d wit h de bri de me nt of t he dela ye d/ n o n- u ni o n 
site a n d i nter nal ( or e xter nal) fi x ati o n, wit h or wit h o ut a p plicati o n of a ut o ge n o us or all o ge n eic 
ca ncell o us b o ne graft. N e w treat me nts are a p peari n g: grafti n g of t he fract ure sites t o pr o vi de 
bi ol o gical sti m uli or e xter nall y a p plie d s yste ms s u c h as el ectrical sti m ulati o ns or l o w-i nte nsit y 
p ulse d ultras o u n ds, t he be nefits of w hic h h a ve n ot bee n clearl y esta blis he d ( B usse, 2 0 0 2).  
P re vi o us a nal ysis ha v e s h o w n t hat re d uce d h e ali n g ti mes c o ul d yi el d s u bsta ntial c ost sa vi n gs 
(i ncl u de d f or g o ver n me nt a ge nci es) b y decreasi n g t h e nee d f or sec o n d ar y pr oce d ures a n d 
decreasi n g t he a m o u nt of ti me nee de d b y a w or ker t o g o bac k t o his acti vit y ( Hec k ma n, 1 9 9 7). 
1. 1. 6  B o ne A ut o gr aft  
B o ne a ut o graft still re mai ns t he treat me nt of c h oice f or n o n- u ni o n fract ures, partic ularl y f or 
atr o p hic n o n- u ni o ns, c o m bi ne d or n ot wit h i ntra me d ullar y naili n g, plati n g, a n d e xter nal fi x ati o n 
de vices ( K o nta kis et al., 2 0 0 6; S o ucac os et al., 2 0 0 6; Cr o wle y et al., 2 0 0 7; Ka na karis et al., 
2 0 0 7; Se n a n d Micla u , 2 0 0 7). I n d ee d, a ut ol o g o us b o ne grafti n g prese nts e x celle nt oste o ge nic, 
oste oc o n d ucti ve 
a n d 
oste oi n d ucti ve 
pr o perti es, is 
bi oc o m pati ble, 
a n d 
a v oi ds 
a n y 
i m m u n o ge nicit y c o n cer ns or disease tra ns missi o n ris ks ( Ka na karis et al., 2 0 0 7; Se n a n d Micla u, 
2 0 0 7). 
Alt h o u g h c o nsi dere d as t he G ol d St a n d ar d , o nl y rare p u blicati o ns o n t he efficac y of b o ne 
a ut o graft i n n o n- u ni o n fract ures ca n be f o u n d i n t h e literat ur e.  Ort h o pae dic s ur ge o ns re p ort t hat 
a vera ges of 7 5 % t o 8 5 % of n o n- u ni o ns are s uccessf ull y tr eate d b y b o ne a ut o graft ( base d o n 
cli nical a n d ra di ol o gic al assess me nt). T his ra n ge of efficac y s ee m c o nfir me d b y d ata fr o m 


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c o ntr olle d st u dies c o m pari n g b o n e a ut o graft wit h b o ne m or p h o ge n etic pr otei ns i n n o n- u ni o n 
fract ur es, wit h re p orte d heali n g rates of 7 6 % at 8. 3 m o nt hs, cli nicall y, a n d 7 7 % at 1 0. 9 m o nt hs, 
radi ol o gic all y ( Frie dlae n der et al., 2 0 0 1; R o n ga et al., 2 0 0 6).  
S i de-effects of b o ne a ut o graft are m uc h lar gel y d oc u me nte d a n d t he si de effects ass ociate d t o 
t his pr oce d ure are c o nsi dera ble ( S o ucac os et al., 2 0 0 6; S e n et al., 2 0 0 7; Pies ke et al., 2 0 0 9):  
a. Ma j or c o m plicati o ns i n at least 1 0 % of patie nts s uc h as dee p i nfecti o n, oste o m yelitis, 
hae mat o ma, ne ur ol o gic i nj ur y, vas c ular i nj ur y, iatr o ge nic wi n g/ SI j oi nt i nj ur y, cr oss 
c o nta mi nati o n, a b d o mi n o-l u m bar her niati o n et c … 
b.  Mi n o r c o m plicati o ns s uc h as s u perfi cial i nfecti o n ( 3 9 %), s u perficial ser o ma, s mall 
hae mat o ma, persiste nt s h ort ter m ( 4 0 %) or l o n g-ter m ( 1 9 %) pai n, e x cessi ve bl o o d l oss, 
pel vic i nsta bilit y, c os metic defects, etc … 
I n t he Frie dla e n der et al. ( 2 0 0 1) st u d y c o m pari n g b o ne a ut o graft wit h Osi graft® , oste o m yelitis 
was re p orte d at t he fract ure site i n 2 1 % of patie nts f oll o wi n g treat me nt wit h b o ne a ut o graft, a n d 
m ore t ha n 2 0 % of patie nts treate d wit h a ut o graft ha d c hr o nic d o n or site pai n f oll o wi n g t he 
pr oce d ure. C hr o nic pai n at t he har vest site was re p orte d i n 4 1 % of patie nts at 6 m o nt hs p ost-
s ur ger y a n d i n 3 3 % at 1 year. Fi nall y, i n rare circ u msta nces, b o ne a ut o graft har vesti n g has bee n 
relate d t o a n u nsta bl e pel vic ri n g a n d t o ile u m fract ures ( N oci ni et al., 2 0 0 3; Oa kle y et al., 
2 0 0 7). 
1. 2  
B ac k gr o u n d of t h e St u d y 
1. 2. 1  Ge ner al Des cri pti o n of A L L O B ®  
A L L O B ®  is t he re gistere d tra de na me f or B o n e T hera pe utics’ h u ma n all o ge n eic cell base d 
me dici nal pr o d uct. T he acti ve s u bsta nce of A L L O B ®  is h u ma n all o ge neic oste o blastic cells. Its 
i mpla ntati o n is i nte n de d t o pr o d uce ne w b o ne at t he b o ne defect site of affecte d patie nts a n d t o 
re-esta blis h a h ealt h y b o ne e n vir o n me nt. 
A L L O B ®  is d eri ve d fr o m b o ne marr o w mes e nc h y mal str o mal cells of h ealt h y a d ult v ol u nteers. 
Fr o m a b o ne marr o w as pirate (fr o m t he h ealt h y d o n or’s iliac crest u n der l ocal a n aest hesia), 
mese nc h y mal str o mal cells are ex viv o c ult ure d u n der strictl y c o ntr olle d c o n diti o ns t o ge nerat e 
A L L O B ®  cells. T he ma n ufact uri n g pr ocess is c o n d ucte d i n c o m plia nce wit h G M P a n d f oll o ws 


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pr oce d ures t hat e ns ure ase ptic ma n ufact uri n g pr ocess, f ull tracea bilit y, a n d q ualit y c o ntr ol. 
A L L O B ®  cells are n ot ge neticall y m o difie d. A L L O B®  is n ot a c o m bi ne d pr o d uct as t he s ole 
acti ve s u bsta nce is A L L O B ®  cells i n s us pe nsi o n. 
A L L O B ®  cell i de ntit y a n d p ote nc y are c haracterize d b y t he n e gati vit y f or he mat o p oietic cell 
mar kers, t he 
p ositi vit y f or 
mese nc h y m al str o mal cell 
mar kers, t he 
p ositi vit y f or 
a d hesi o n/ oste o blastic cell mar kers, e x pressi o n of b o ne-rel ate d ge nes, a bse nce of i m m u n o ge nic 
p he n ot y p e, a bs e nce of t u m o uri ge nic c h aracteristics, b o ne matri x f or mati o n a n d mi neralizati o n 
pr o pe rties. 
A d mi nistrati o n of A L L O B ®  is d o ne usi n g a mi ni mall y i n vasi ve tec h ni q ue. T he pr o d uct is 
a d mi nistere d wit h a s mall dia meter tre p hi ne b y perc uta ne o us i m pla ntati o n t hr o u g h a s mall s ki n 
i ncisi o n, directl y i nt o t he b o ne defect site. 
F or m ore i nf or m ati o n c o ncer ni n g t he descri pti o n of A L L O B ® , pleas e refer t o t he I n vesti gat or’s 
Br oc h ure. 
1. 2. 2  A L L O B ®  i n Precli nic al St u dies 
N o n-cli nical i n viv o a n d i n vitr o st u dies ha ve bee n c o n d ucte d t o ass ess t he p har mac o d y n a mics, 
safet y p har mac ol o g y, bi o distri b uti o n, t o xicit y, t u m o uri ge nicit y a n d i m m u n ot o xicit y of 
A L L O B ® .  
Wit h res pect t o pri mar y p har mac o d y n a mics, A L L O B
®  b o ne f or mati o n ca pacit y was assesse d 
i n a 
 m o del a n d i n a 
 defect m o del. I n b ot h m o dels, 
ra di ol o gic al a n d hist ol o gical a nal ys es c o nfir me d pr o d ucti o n of ne w b o ne after A L L O B ®  cells 
a d mi nistrati o n.  
Safet y p h ar mac ol o g y was i n vesti gate d i n a  
 fract ure m o use m o del after A L L O B ®  l ocal 
ad mi nistrati o n. Safet y para meters i ncl u di n g cli nical o bser vati o n, b o d y wei g ht f oll o w- u p a n d 
la b orat or y p h ysi ol o gical para m eters (e. g., h ae mat ol o g y a n d bl o o d c he mical c h e mistr y 
para meters) were o bser ve d u ntil 6 wee ks p ost-a d mi nistrati o n. N o te st ite ms relate d cli nical si g n 
a n d n o test ite ms relate d l a b orat or y a n o mal y were o bser ve d. C o m plete necr o ps y was perf or me d 
a n d n o macr os c o pic test ite m relate d fi n di n g was o bser ve d. 
T he  mi grati o n of A L L O B®  cells after a d mi nistrati o n at t he b o ne defect site was assesse d i n t he 
 fract ure m o use m o del. Ra di ola belle d cells were a d mi nistere d i n t he fract ur e d site a n d 


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t heir bi o distri b uti o n was assesse d wit h hi g h-res ol uti o n w h ole- b o d y q ua ntitati ve sci nti gra p h y 
( S P E C T/ C T i ma gi n g). At t he differe nt ti me p oi nts, t he maj orit y of resi d ual ra di oacti vit y was 
retai ne d at t he fract ure (a d mi nistrati o n) site s u g gesti n g t hat A L L O B®  cells prefere ntiall y 
e n graft e d at t he fract ur e site a n d di d n ot mi grate a n d h o me t o t he vit al or ga ns ( heart, l u n gs, 
brai n, ki d ne y, s plee n, li v er). T he ra di ola belli n g bi o distri b uti o n st u d y res ults were c o nsiste nt 
wit h a 6- w ee k P C R bi o distri b uti o n st u d y aft er l o cal a d mi nistrati o n of A L L O B ®  at t h e fract ur e 
site i n fe m oral fract ure m o use m o del. After e ut ha nasia, or ga ns were e x cise d a n d pr ocesse d f or 
a nal ysis. Trace le v els of h u ma n D N A were tra nsi e ntl y d etecte d i n heart a n d l u n g i n 1 5 % t o 5 0 % 
of i njecte d mice d uri n g t he first 2 4 h o urs; after 2 4 h o urs, n o h u ma n D N A was detecte d i n a n y 
ot her or ga ns t ha n b o n es.  
A 2 4- wee k l o n g-ter m G L P t o xicit y st u d y was c o n d ucte d i n mice after i. v. a d mi nistrati o n of 
hi g h d oses of A L L O B ®  ( > 5 0-f ol d t he h u ma n d ose i n or der t o pr o vi de a c o mf orta ble s afet y 
mar gi n). D uri n g t he 2 4- w ee k o bser vati o n peri o d, A L L O B ®  a d mi nistrati o n di d n ot ca use e x cess 
m or bi dit y or m ort alit y, a n d t he hae mat ol o gical a n d uri ne a n al yses, t he macr osc o pi c ( d uri n g 
ne cr o ps y) a n d micr osc o pic e x a mi nati o ns faile d t o e vi de nce a n y test ite m rel ate d a n o malies.  
In vitr o st u dies h a ve d e m o nstrate d t hat A L L O B ®  cells ha ve a li mite d re plicati o n ca p acit y a n d 
t hat A L L O B®  cells ha ve n o t u m o ural p he n ot y pe as cells were u na ble t o gr o w u nattac he d t o a 
s urface. I n vi v o t u m o uri ge nesis st u dies (P h. E ur.  c o m plia nt) were c o n d ucte d i n mice t o c o nfir m 
t hat A L L O B®  d oes n ot i n d uce t u m o urs. At 3 a n d 1 2 wee ks p ost-i njecti o n, macr osc o pic a n d 
micr osc o pic e x a mi nati o ns faile d t o re veal a n y e vi de nce of t u m o ur f or mati o n a n d/ or or ga n 
i n vasi o n ( n = 2 0).  
I n or der t o ass ess i m m u n o ge ni c pr o perties of A L L O B® , i m m u n ot o xicit y st u dies ha ve bee n 
c o n d ucte d i n acc or da nce wit h t he I C H S 8 “I m m u n ot o xicit y St u dies f or H u ma n p har mace utical” 
g ui deli ne. I n t hat res pect, peri p heral bl o o d m o n o n uclear cells ( P B M C) fr o m differe nt u nrelate d 
v ol u nteers (reci pie nt P B M C) a n d A L L O B ®  cells were c o-c ult ure d. T h e A L L O B® / P B M C c o-
c ult ures di d n ot t o elicit l y m p h oc ytic pr oliferati o n i n > 8 0 % of cas es ( n = 5 4). I n all e x peri me nts, 
pr o-i nfla m mat or y c yt o ki nes pr o d ucti o n (e. g., I N F-γ a n d T N F-a) were meas ure d o n s u per nata nts 
fr o m A L L O B® / P B M C c o-c ult ures. N o pr o d ucti o n of I N F-γ a n d T N F- α was meas ure d i n 
p ositi ve c o-c ult ures, s u g gesti n g t hat p ositi ve c o-c ult ures or res ulte d i n i nc o m plete i m m u ne 
res p o nse or w ere u nrelat e d t o a n i m m u ne reacti o n. 


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Besi des t hes e i m m u n o pri vile ge d c haracteristics, A L L O B ®  als o dis pla y i m m u n os u p pressi ve/ 
i m m u n o m o d ulat or y pr o perties a gai nst acti vate d l y m p h oc ytes i n a d os e- de p e n de nt ma n ner.  
1. 2. 3  A L L O B ®  i n Cli nic al St u dies 
T he safet y a n d effic ac y of A L L O B ®  is c urre ntl y e val uate d i n p h ase IIa cli nical st u dies i n 
dela ye d- u ni o n fract ure, s pi nal i nter b o d y f usi o n a n d resc ue i nter b o d y f usi o n. 
1. 2. 4  J ustific ati o n of d ose 
Precli nical st u dies o n b o ne f or mati o n a n d b o ne re pair m o dels i n mice h a ve de m o nstrate d t h e 
effic ac y of A L L O B ®  at t he d oses u p t o 5 0. 1 06 cells/ ml. T o bala nce b et wee n efficac y a n d safet y, 
t he c o nce ntr ati o n selecte d f or t he cli nical trial is 2 5. 1 06/ ml, si nce at t he ma xi m u m i njecte d 
v ol u me ( of 4 ml), t his c o nce ntrati o n still prese nts a safet y mar gi n of o ver 9 0 x.  
1. 3  
Asse ss me nt of A ntici p ate d Be nefits a n d Ris ks 
L o n g b o ne d ela ye d- u ni o n fract ur es are treate d wit h de bri de me nt of t he del a ye d- u ni o n site  a n d 
i nter nal ( or e xter nal) fi x ati o n, wit h or wit h o ut a p plicati o n of all o/a ut o ge n o us b o ne graft. 
Alt h o u g h t he e x act pat h o p h ysi ol o gical mec ha nis m of dela ye d- u ni o n is n ot k n o w n, dela ye d-
u ni o n fract ures m a y b e nefit fr o m re d y n a misati o n a n d/ or a u g me ntati o n t o sti m ulate b o ne 
f or mati o n, a n d he nce will be nefit fr o m t he a d diti o n of a n oste oc o n d u cti ve or oste oi n d ucti ve 
sti m ul us ( Wiss et al., 1 9 9 6). T his ma y be c o ntri b ute d b y t he l ocal i m pla ntati o n of ne w e x -vi v o 
c ult ure d cells wit h oste o ge nic p ote ntial 
w hic h c o ul d re place t he defecti ve or 
missi n g 
oste o blastic cells a n d re- esta blis h a healt h y b o ne e n vir o n me nt. I n vitr o a n d i n vi v o e x peri me nts 
ha ve s h o we d t hat A L L O B ®  cells ha ve t he a bilit y t o a d here, s y nt hesize a n d mi neralize ne w b o ne 
matr i x wit h o ut o bser va ble t o xicit y. I n a d diti o n, bi o distri b uti o n st u dies ha ve de m o nstrate d t hat 
after l ocal a d mi nistrati o n (at fract ure site), A L L O B ®  cells d o n ot mi grate i n n o n-tar get or ga ns 
( heart, l u n gs, brai n, li ver, s plee n, a n d ki d ne ys).  T his s u p p orts t he p ote ntial be nefits of t he use 
of A L L O B ® i n t he i n dicati o n of dela ye d- u ni o n fract ure. 
A L L O B ®  M a n uf act uri n g  
B o ne m arr o w starti n g material is har veste d fr o m h ealt h y v ol u nteer d o n ors s electe d o n me dical 
hist or y, p h ysi cal e x a mi nati o n, la b orat or y para meters a n d ( ne gati ve viral) ser ol o g y acc or di n g t o 
E ur o pea n dir ecti ves a n d nati o nal re g ulati o ns, a n d ra w materials e nteri n g t he ma n ufact uri n g 


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pr ocess ( m e di u m, fact ors...) are teste d f or sterilit y, e n d ot o xi ns a n d m yc o plas mas. A L L O B ®  is 
ma n ufact ur e d u n d er stri ct G M P a n d ase ptic c o n diti o ns.  At t he e n d of ma n ufact uri n g, A L L O B ®  
is c o ntr olle d (rele ase tests) f or q ualit y (i de ntit y, p ote nc y a n d a bs e nce of i m m u n o ge nicit y) a n d 
mi cr o bi ol o g y (sterilit y, e n d ot o xi ns, m yc o plas mas). 
A L L O B ®  T oxicity a n d I m m u n ot oxicity 
L o n g-t er m t o xicit y st u di es ha ve s h o w n t hat A L L O B ®  cells e v e n w he n a d mi nistere d at hi g h 
d oses ( o ver 5 0-f ol d t he ma xi mal pr o p ose d cli nical d ose) di d n ot ca use a n y e x cess m or bi dit y or 
m orta lit y, di d n ot i n d uce a n y or ga n t o xicit y or di d n ot ca use ect o pic b o ne f or mati o n. St u dies 
ha ve als o faile d t o s h o w t u m o ural ris ks at u p t o 3 0 0 ti mes t he h u ma n t hera pe utic d ose). 
S i milarl y, b ase d o n precli nical st u dies, A L L O B®  is n ot e x pecte d t o i n d uce i m m u n o ge nic or 
i nfla m mat or y res p o nses.  
P atie nt Be nefit 
I n or der t o mi ni mise t he ris k of patie nt-relate d tr eat me nt fail ure d uri n g t his trial, patie nts will 
be e nr olle d base d o n a strictl y c o ntr olle d me dical criteria i ncl u di n g classificati o n of t he disease, 
p ote ntial c o m plia nce wit h t he st u d y pr ot oc ol a n d f oll o w- u p as well as ta ki n g i nt o acc o u nt 
c o nc o mita nt disease a n d/ or treat me nt n ot c o m pati ble 
wit h t he 
A L L O B ®  treat me nt. 
A d diti o nall y, patie nts will be teste d f or a nti- H L A a nti b o dies a n d ot her a ut o-i m m u nit y mar kers 
i n or der t o m o nit or t he de vel o p me nt of i m m u ne reacti o n a gai nst A L L O B®  or t he occ urre nce of 
all oreacti o n. 
If a v aila ble tr eat me nts ( b o ne a ut o graft) h a ve s h o w n 7 6 % a n d 6 2 % of ra di ol o gical heali n g a n d 
7 7 % a n d 8 1 % cli nical heali n g after 9 m o nt hs res p ecti vel y, t hese be n efits are c o u nter b ala nce d 
b y a lar ge n u m ber of seri o us c o m plicati o ns ( Frie dla n der et al., 2 0 0 1; N oci ni et al., 2 0 0 3; Oa kle y 
et al., 2 0 0 7).  T he mi ni mall y i n vasi ve i m pla ntati o n a p pr oac h of A L L O B ®  i nte n ds t o a v oi d t he 
nee d f or o p e n s ur ger y, a n d he nce t he relate d c o m plicati o ns. I n t his pil ot st u d y, t h e test treat me nt 
A L L O B ® will be pr o vi de d 
 a n d a d mi nistere d t o patie nts as a si n gle 
perc uta n e o us a d mi nistrati o n u n der a naest hesia at t he i n vesti gati n g sites. 
I n c o ncl usi o n, ta ki n g i nt o acc o u nt t hes e preca uti o ns, t he be nefit/ris k rati o of A L L O B®  s u p p orts 
t he i nitiati o n of its cli nical de vel o p me nt i n dela ye d- u ni o n fract ures. 
 
 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 3 3 /1 3 6  
 
2  
I N V E S TI G A TI O N A L P L A N 
2. 1  
G e ner al St u d y Desi g n 
T he prese nt st u d y is a pr os pecti ve, m ultice ntre, o pe n, n o n-c o ntr olle d st u d y t o assess t he safet y 
an d efficac y of all o ge nei c oste o blastic cells ( A L L O B ® ) i m pla ntati o n i n n o n-i nfecte d dela ye d-
u ni o n fract ur es.    
After si g ni n g t he I nf or m e d C onse nt F or m (I C F), e nr olle d patie nts will e nt er a n u p t o 8 wee ks 
scree ni n g peri o d. Eli gi ble patie nts (acc or di n g t o t he eli gi bilit y criteria) will be treate d b y a 
si n gle A L L O B ®  i m pla ntati o n i nt o t he dela ye d- u ni o n site. O nce treate d, patie nts will be 
f oll o wed u p d uri n g 6 m o nt hs wit h p ost-treat me nt assess me nts perf or me d: at 2 wee ks, 1, 3 a n d 
6 m o nt hs, res pecti vel y. D uri n g f oll o w- u p, n o n-res p o n di n g patie nts (see bel o w a n d secti o n 
3. 2. 3 ) c oul d be c o nsi dere d as dr o p- o ut a n d u n der g o a resc ue s ur ger y, acc or di n g t o t he j u d g me nt 
of t he I n vesti gat or.  
 
 
 
E x peri me ntal desi g n  
P r os pecti ve, m ultice ntre, o pe n, n o n -c o ntr olle d P hase I/IIa st u d y 
D urati o n of s t u d y 
6 m o nt hs of f oll o w -u p   
Dela ye d -u ni o n sites  
Fe m ur, ti bia, fi b ula, h u mer us , ul na, ra di us  
Treat me nt  
A L L O B ®   
Pr oce d ure  
Im pla ntati o n perf or me d u n der a naest hesia  
St u d y Ti me p oi nts  
2 wee ks, 1  m o nt h, 3 m o nt hs  a n d 6 m o nt hs  after treat me nt  
Self -c o ntai ne d st u d y 
Data c ollecti o n: Case Re p ort F or m ( C R F) 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 3 4 /1 3 6  
 
2. 2  
St u d y O bjecti ves 
T he pri mar y o bjecti ve is t o assess t he safet y a n d efficac y of A L L O B ®  si n gle perc uta ne o us 
i m pla ntati o n i n heali n g d ela ye d- u ni o n fract ures at t he e n d of t he st u d y peri o d ( M o nt h 6).  
T his als o i ncl u des a safet y a n d effic ac y i nt eri m a nal ysis w he n t h e 1 6 first assessa bl e patie nts 
will ha ve reac he d t he 6 m o nt h f oll o w- u p visit.  
 
 
 
 
 
2. 2. 1  S afety 
Fr o m Visit # 1 t o t he e n d of t he mai n st u d y p eri o d at M o nt h 6, s u bjects will be s yste maticall y 
assesse d f or t h e p ote ntial occ urre nce of a n y A E or S A E, relate d t o t he pr o d uct or relate d t o t he 
pr oce d ure, usi n g patie nt o pe n q uesti o n naires, p h ysical e x a mi nati o n, (i ncl u di n g vital si g ns), a n d 
la b orat or y me as ure me nts.  
2. 2. 2  Effic acy 
T he efficac y of A L L O B ®  will be e v al uate d at 6 m o nt hs a n d base d o n t he perce nt a ge of treate d 
pa tie nts n ot faili n g u n der treat me nt.  
A patie nt will be c o nsi dere d as faile d u n der a treat me nt if, at t he e n d of t he st u d y p eri o d ( at 
M o nt h 6):  
- 
T he patie nt ha d a resc u e s ur ger y  
Or  
- 
T he Gl o bal Disease E v al uati o n sc ore ( V A S) as percei ve d b y t he p atie nt has n ot 
i m pr o ve d b y at least 2 5 % a n d  t he T U S as ass esse d b y C T s ca n has n ot i n creas e d b y at 
least 2 p oi nts ( vers us bas eli ne). 
T he i nteri m a nal ysis will be perf or me d o n sa me e n d p oi nts.  


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 3 5 /1 3 6  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 3 6 /1 3 6  
 
2. 2. 4  C o nsi der ati o n f or Resc ue S ur gery 
D uri n g t he st u d y f oll o w- u p, if j u d ge d necessar y, t he I n vesti gat ors will ha v e t he p ossi bilit y t o 
wit h dra w t he patie nt fr o m t he st u d y f or a resc u e treat me nt s uc h as a b o ne a ut o graft or a n y ot her 
a ppr o priate s ur gical or n o n-s ur gical treat me nt. I n t his case, a n earl y disc o nti n uati o n visit will 
be sc he d ule d. Reas o ns f or resc u e s ur ger y will be d oc u me nte d. 
2. 3  
M ai n St u d y Pr oce d ures 
2. 3. 1  P atie nt I nf or m ati o n a n d I nf or me d C o nse nt 
Bef ore a n y st u d y-relat e d pr oce d ure, t he Pri nci pal I n vesti gat or ( or a me m ber of t he i n vesti gati n g 
tea m, desi g nat e d b y t h e Pri nci pal I n vesti gat or) 
will gi ve detaile d a n d c o m pre he nsi ve 
i nf or mati o n re gar di n g all as pects of t he trial t o t he patie nt ( or, w he n t h e patie nt is n ot ca pa ble 
of gi vi n g i nf or me d c o nse nt, his/ her le gal re prese ntati ve), i ncl u di n g n ot a bl y t he f oll o wi n g 
p oi nts: 
 P ur p ose, o bjecti ves, a n d nat ure of t he tri al (i ncl u di n g all perf or me d pr oce d ures) 
 C o n diti o ns u n der w hic h t he trial are c o n d ucte d 
 C o nse q ue nces a n d si g nifi ca nce of t he trial 
 E x pecte d be nefits 
 I n c o n ve nie n ces a n d ris ks 
 Tests perf or m e d 
 Ri g ht t o recei ve t he res ults of t he tests perf or me d  
 Ri g hts of t he p atie nt t o p h ysi cal, 
me nt al, a n d s ocial i nte grit y, di g nit y, pri v ac y, 
c o nfi de ntialit y, a n d pr ot ecti o n of his pers o nal d ata a n d me dical rec or ds, i n acc or da nce 
wit h t he D eclarati o n of Helsi n ki o n Et hical Pri nci ples f or Me dical Researc h i n v ol vi n g 
H u ma n S u bjects, a d o pte d b y t h e Ge neral Asse m bl y of t he W orl d Me dical Ass ociati o n 
( 1 9 9 6), wit h a me n d me nts, a n d a n y ot her a p pli ca ble C o m m u nit y a n d nati o nal la ws, 
re g ulati o ns, g ui da n ce, g ui deli nes, a n d pri nci ples (see refere nce d o c u me nts i n Secti o n 1 2 ) 
 Me dical c o nfi d e ntialit y - rec or di n g a n d pr otecti o n of patie nt data 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 3 7 /1 3 6  
 
 Access a n d s cr uti n y of pers o nal data a n d i nf or mati o n d uri n g i ns pecti o n b y t he C o m pete nt 
A ut h orities a n d a n y ot her pr o perl y a ut h orize d pers o ns, pr o vi de d t hat s uc h i nf or mati o n is 
treate d as stri ctl y c o nfi de ntial a n d is n ot ma de p u blicl y a v aila ble 
 Ri g ht t o ref use t o partici pate or wit h dra w fr o m t he cli nical trial, at a n y ti me, wit h o ut a n y 
res ulti n g d etri me nt, p e nalt y or l oss of b e nefits t o w hic h t he patie nt is ot her wise e ntitle d, 
n ota bl y i n ter ms of me di cal care, f oll o w- u p, a n d p atie nt- p h ysi cia n rel ati o ns hi p 
 Pr o visi o n ma de f or i ns ur a nce or i n de m nit y t o c o v er t he lia bilit y of b ot h t h e S p o ns or a n d 
I n v esti gat or (i n cl u di n g all me m bers of t he i n vesti gati n g t ea m a n d a n y ot her partici p a nts 
t o t he trial) 
T his detaile d i nf or m ati o n will be gi ve n i n b ot h oral a n d writte n f or ms ( S u bject I nf or mati o n 
S heet a n d I nf or me d C o nse nt F or m (I C F)), i n a p pr o priate a n d clear ma n ner, w or d e d i n t he 
patie nt’s m ot her t o n g ue, usi n g n o n-te c h nical a n d practical l a n g ua ge a n d ter ms t hat are easil y 
u n derst o o d b y t he patie nt ( or his/ her le gal re pres e ntati ve). T he i nf or mati o n pr o vi de d will n ot 
i ncl u de a n y t er m or se nte nce t hat a p pears t o wai ve a n y of t he p atie nt's le gal ri g hts, or a p pears 
t o release t he I n vesti gat or, I nstit uti o n/I n vesti gati n g Site, S p o ns or, re prese ntati ves of t he 
S p o ns or, a n d/ or t he M o nit or fr o m lia bilit y f or n e gli ge n ce. 
T he patie nt ( or his/ her le gal re prese nt ati ve) will t he n be pr o vi de d s ufficie nt ti me (as nee de d) 
a n d o p p ort u nit y t o i n q uire a b o ut details a n d as k a n y q uesti o ns a b o ut t he trial t o t he Pri nci pal 
I n v esti gat or ( or t he pers o n w h o c o n d ucts t he I nf or me d C o nse nt disc ussi o n), a n d t o deci de 
w het her or n ot t o partici pate t o t he trial. All q uesti o ns a b o ut t he tri al will be a ns were d t o t he 
satisfacti o n of t he patie nt ( or his/ her le gal r e prese ntati ve). 
If t he patie nt ( or her/ his le gal re pres e ntati ve) a grees t o partici pate, he/s he will be i n vite d t o dat e 
a n d si g n t he I C F. T he Pri nci pal I n v esti gat or ( or t he pers o n w h o c o n d ucte d t h e I nf or me d C o nse nt 
disc ussi o n) will als o si g n a n d date t he d o c u me nt o n t he sa me da y.  
O ne ori gi nal c o p y of t h e I C F si g ne d b y t he patie nt ( or her/ his le gal re prese ntati ve) a n d t he 
Pri nci pal I n vesti gat or ( or t he pers o n w h o c o n d ucte d t he I nf or me d C o nse nt disc ussi o n) will be 
gi ve n t o t h e patie nt ( or his/ her le gal re prese ntati ve), t he ot her ori gi nal d ul y si g ne d c o p y will be 
ke pt i n t he I n v esti gat or’s Site File at t he I n vesti gati n g Site. 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 3 8 /1 3 6  
 
T he Pri nci pal I n v esti gat or will t he n c o m plete a n d si g n t he Case Re p ort F or m ( Scree ni n g a n d 
I n cl usi o n Visit pa ges), t h ere b y attesti n g a n d rec or di n g t hat si g ne d I C F has bee n o btai ne d fr o m 
t he patie nt.  
T he  st u d y p artici pa nt will be i n vite d t o date a n d si g n a n y s u bs e q ue nt versi o n of t he I C F, as 
a p pr o ve d b y t h e I E C. T he Pri nci pal I n vesti gat or ( or t he pers o n w h o c o n d ucte d t he I nf or me d 
C o nse nt disc ussi o n) will als o si g n a n d d ate t he d o c u me nt o n t he sa me da y.  
2. 3. 2  Pr oce d ures  
2. 3. 2. 1  A L L O B ® I m pl a nt ati o n Pr oce d ure 
Patie nts will u n der g o u n der a naest hesia (e. g., ge n eral, l oc o-re gi o n al or l ocal as c h ose n b y t he 
I n v esti gat ors) t he i m pla ntati o n of A L L O B®  wit h a tre p hi ne i nt o t he d ela ye d- u ni o n site (si n gle 
a d mi nistrati o n). 
H o we ver, w he n necessar y as per I n v esti gat or’s j u d ge m e nt, t he i m pla ntati o n of A L L O B ®  i nt o 
t he dela ye d- u ni o n site ca n be perf or me d usi n g t w o s ur gical a p pr oac hes.  
2. 3. 2. 2  Resc ue S ur ger y Pr oce d ure 
W he n j u d ge d necessar y, t he Pri nci pal I n v esti gat or ca n d eci de t o perf or m a resc ue s ur ger y. T he 
pa tie nt ca n b e wit h dra w n fr o m t he st u d y f or a resc ue s ur gical (e. g., b o n e a ut o graft, all o graft...) 
or n o n-s ur gical treat me nt acc or di n g t o t he sta n d ar d- of-care pr oce d ure of t h e i n vesti gati n g site. 
Re as o n f or resc ue s ur ger y, t y pe a n d date will be rec or de d. 
2. 4  
P ati e nt E v al u ati o n 
2. 4. 1  Defi niti o n of Del aye d- u ni o n i n t he St u dy 
I n t his st u d y, a d ela ye d- u ni o n fract ur e is defi ne d at t he ti me of scree ni n g as (i) a n a bse n ce of 
heali n g 3 m o nt hs ( wit h a ma xi m u m of 7 m o nt hs) ± 2 wee ks after t he o nset of fract ure a n d (ii) 
a n a bse nce of t he pr o gressi o n of heali n g o ver t he last 4 wee ks, as c o nfir me d b y cli nical a n d 
ra di ol o gic al e val u ati o n. 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 3 9 /1 3 6  
 
2. 4. 2  Cli nic al Ev al u ati o n 
I n or der t o a v oi d bias, cli nical e val uati o n s h o ul d be t he first pr oce d ure d uri n g a st u d y visit 
bef ore disc ussi n g wit h t h e I n v esti gat or or t he St u d y N urse/ C o or di nat or. I n d ee d, t he patie nt h as 
t o c o m plete t he q uesti o n naires al o ne wit h o ut a n y o utsi de i nter ve nti o n ( Br ya nt a n d Fer na n d es, 
2 0 1 1). 
T he f oll o wi n g cli nical assess me nt will be e val uate d: 
- Gl o bal Disease E val uati o n usi n g a Vis ual A nal o g ue Scale (see d etails i n secti o n 3. 2. 1  a n d 
A n ne x 1 ): t he Gl o bal Disease E val uati o n V A S is a 1 0 0 m m le n gt h h oriz o ntal li ne w here 0 
mea ns best p ossi ble healt h stat us (“ ver y well”) a n d 1 0 0 t he w orst p ossi ble healt h stat us 
(“e xtre mel y b a d”). Patie nts m ust mar k a n “ X” o n t he scale t o i n dicate t heir ge n eral healt h 
stat us o ver t he last wee k. Pri nci pal I n vesti gat or ( or t he st u d y n urse) m ust mar k a n “ X” o n 
t he scale t o i n dicate t he ge n eral healt h stat us of t he patie nt as percei ve d at t he ti me of t he 
visit.  
- Pai n usi n g a Vis ual A n al o g ue Scale (see details i n A n ne x 2):  t he Pai n V A S is a 1 0 0 m m 
le n gt h h oriz o ntal li ne wit h e n d p oi nts la belle d “ n o pai n” ( 0) a n d “e xtre me pai n” ( 1 0 0). 
Patie nts m ust mar k a n “ X” o n t he scale t o i n dicate t heir pai n o ver t he last wee k. I n t his st u d y, 
pa i n will be e val u ate d b y t he patie nt at rest, d uri n g acti vit y a n d at p al pati o n ( perf or me d b y 
t he I n v esti gat or or t he st u d y n urs e). 
- Wei g ht- Beari n g usi n g a Li kert scale (see details i n A n ne x 3 ): i n t his st u d y, f u ncti o nalit y o n 
t he affecte d li m b will be assesse d usi n g wei g ht- beari n g.  I n t his test, t he patie nt will be as ke d 
t o place o nl y as m uc h w ei g ht as h e/s he feels c o mf orta ble (as t olerate d) o n t he i nj ure d li m b 
( base d o n pai n feeli n g) st a n di n g. T his s pecific cate g or y all o ws a differe ntial sc ori n g relate d 
t o pai n feeli n g.  
2. 4. 3  R a di ol o gic al Ev al u ati o n –  T U S a n d m R U S  
I n t his st u d y, t he m o difie d Ra di o gra p hic U ni o n Sc ore ( m R U S) a n d T o m o gra p hic U ni o n Sc ore 
( T U S) will be assesse d b ot h o n c o n ve nti o nal X-ra y a n d o n C T s ca n, res pecti vel y. C T sca n is 
m ore se nsiti ve, a n d t hree- di me nsi o nal rec o nstr ucti o n will all o w t o ha ve a m ore gl o bal vie w of 
t he fract ure a n d t o i m pr o ve t h e assess me nt (see details i n secti o n 3. 2. 2  a n d A n ne x 4).   


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 4 0 /1 3 6  
 
2. 5  
P ati e nt i ncl usi o n sc he me 
Wit h t he o bjecti ve of ma xi m u m 3 2 patie nts treate d i n t he st u d y, a n d ta ki n g i nt o acc o u nt 1 0 % 
dr o p - o ut, 3 5 patie nts will be e nr olle d .   
F or t he first 1 6 patie nts, t he patie nt recr uit me nt will pr ocee d ste p wise b y bl oc ks of 4. F ull first 
2 wee ks safet y d ata of t he first bl oc k of 4 patie nts will be a n al ys e d b ef ore t h e first p atie nt of t he 
sec o n d bl oc k of 4 patie nts is treate d. First 4 8 h o urs safet y data of t h e sec o n d bl oc k of 4 patie nts 
will be a nal yse d bef ore treati n g t he first patie nt of t he ne xt bl oc k. T his latter sc he me will be 
re peat e d u ntil t he first 1 6 patie nts ha ve bee n treate d. 
A Data Safet y M o nit ori n g B o ar d ( D S M B ) will be esta blis he d t o assess t he safet y a n d efficac y 
w he n 6- m o nt h p ost treat me nt res ults f or t he first 1 6 assessa ble p atie nts will be a vaila ble (i. e., 
i nteri m a nal ysis). T his B oar d will rec o m me n d t o t he S p o ns or w het her t o c o nti n ue, m o dif y or 
st o p t he trial. T he st u d y ca n be pre m at urel y st o p pe d:  
- F or safet y c o n cer ns  
- F or f utilit y if less t ha n 4 s uccesses are o bs er ve d  
- F or efficac y if 1 2 or m ore s uccess es are o bser ve d  
A d diti o nal patie nts ca n ot her wise be tr eate d i n or d er t o reac h a t otal of 3 2 p atie nts.  
2. 6  
S t u d y P o p ul ati o n 
2. 6. 1  Eli gi bility 
Pri or t o patie nt i ncl usi o n a n d b aseli ne assess me nt b y t h e I n vesti gat or, a scree ni n g peri o d is 
pla n ne d t o all o w verifi cati o n of patie nt eli gi bilit y.  
Patie nts will be selecte d base d o n t he eli gi bilit y criteria liste d i n secti o n 2. 6 .  
D ur ati o n of del aye d- u ni o n  
As t he trial i n v ol ves pati e nts dia g n os e d wit h dela ye d- u ni o n fract ures of a l o n g b o n e (see 2. 4. 1 ) 
at t he ti me of i ncl usi o n, a n d as t he ti me bet wee n s cree ni n g a n d i m pla ntati o n c o ul d ta ke u p t o 8 
we e ks, d ela ye d- u ni o n patie nts c o ul d be scree ne d ( Visit # 1) as fr o m a fract ure d urati o n of 3 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 4 1 /1 3 6  
 
m o nt hs ± 2 wee ks t o a ma xi m u m of 7 m o nt hs ± 2 wee ks.  Patie nts will be treate d u p t o 8 m o nt hs 
+  2 wee ks after fract ure occ urre nce. 
Re visi o n of oste osy nt hesis m ateri al  
Oste os y nt hesis re visi o n is all o we d pri or t o patie nt e ntr y i nt o t he st u d y: 
o  W it h a 
mi ni m u m of 2 
m o nt hs bet wee n re visi o n/s ur ger y a n d s cree ni n g f or 
re visi o n/s ur ger y perf or m e d at t he fract ur e site 
o  W it h a 
mi ni m u m of 4 
wee ks 
bet wee n re visi o n/s ur ger y a n d s cree ni n g f or 
re visi o n/s ur ger y o utsi de t he fract ure site. 
B ef ore i m pla ntati o n, t he a bse nce of si g ns of ra di ol o gical heali n g ( d ue t o t he oste os y nt hesis 
re visi o n perf or me d bef ore t he st u d y) will be c o nfir me d b y t h e I n d e pe n de nt Ra di ol o gist. T his 
will be d o ne b y c o m p ari n g t h e i ma ges fr o m c o n v e nti o nal X- Ra y (a n d/ or C T sca n) perf or me d 
at Visit # 1 wit h t he X- Ra y (a n d/ or C T sca n) p erf or me d bef ore t he st u d y (a mi ni m u m of 4 wee ks 
be t wee n t he i ma ges is re q uire d).  
 
P atie nt I nf or m ati o n 
A part fr o m i ncl usi o n a n d e x cl usi o n criteria detaile d i n secti o n 2. 6. 2  a n d 2. 6. 3 , t he f oll o wi n g 
cli nical i nf or mati o n a n d data will als o be c ollect e d a n d rec or de d: 
- 
Past a n d c urre nt rele v a nt me dical (a n d s ur gi cal) hist or y  


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 4 2 /1 3 6  
 
- 
Alc o h ol c o ns u m pti o n (i ncl u di n g t he n u m ber of dri n ks per da y) 
- 
S m o ki n g ha bits (i ncl u di n g t he n u m ber of ci garettes, ci gars, a n d/ or pi pes p er da y) 
Patie nts will n ot be selecte d acc or di n g t o t heir ge n der, si nce t here are n o k n o w n or e x pecte d 
g e n d er differe nces i n p h ar mac o ki netics, efficac y, a n d/ or safet y pr ofile of t he test pr o d uct, n o 
s u b gr o u p a nal ysis wit h se x as a varia ble is pla n ne d (ra n d o m se x distri b uti o n).  
2. 6. 2  I ncl usi o n Criteri a 
All s u bjects m ust satisf y A L L t h e f oll o wi n g criteri a at st u d y e ntr y: 
- Patie nt a ge d 1 8 t o 8 0 years i ncl usi ve 
- Patie nt dia g n ose d wit h a n o n-i nfecte d d ela ye d- u ni o n fract ur e of a l o n g b o n e (fe m ur, ti bia, 
fi b ula, h u mer us, ul na, ra di us) of mi ni m u m 3 m o nt hs  a n d ma xi m u m 7 m o nt hs ( ± 2 
wee ks) wit h o ut si g ns of h eali n g o v er t he last 4 wee ks at t he ti me of scree ni n g  
- M o difie d Ra di o gra p hic U ni o n Sc ore ( m R U S) 1  < 1 0  
- Gl o bal Disease E val uati o n Sc ore as assesse d b y t h e patie nt ≥ 2 0 m m o n a Vis ual A nal o g ue 
Scale  
- Patie nt ( or patie nt’s le gall y acce pta ble re prese ntati ve) ca p a ble t o pr o vi de a writte n, date d, 
a n d si g ne d i nf or me d c o nse nt pri or t o a n y st u d y pr oce d ure.  
2. 6. 3  Excl usi o n Criteri a 
T he f oll o wi n g criteria s h o ul d be c hec ke d at t he ti me of st u d y e ntr y. If A N Y e x cl usi o n criteri o n 
a p plies, t he patie nt m ust n ot be i ncl u de d i n t he st u d y:  
C urre nt sy m pt o ms a n d/ or si g ns rel ate d t o t he dise ase u n der st u dy 
- Fract ure i nterli ne > 2. 5 c m, as defi ne d b y t he I n d e pe n de nt R a di ol o gist  
- I ns ufficie nt r e d ucti o n of t he fract ure 
                                                 
1 I n case t he m R U S is n ot assessa ble, t he T o m o gra p hic U ni o n Sc ore ( T U S) c o ul d be use d i nstea d (j u d ge d b y t he 
I n de p e n de nt Rea der) 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 4 3 /1 3 6  
 
- I ns ufficie nt fract ur e sta bilit y defi ne d as oste ol ysis at t he le vel of t he nails/scre ws a n d/ or 
defect a n d/ or m o bilit y of t he oste os y nt hesis material at p h ysic al e x a mi nati o n, as assesse d 
b y t he I n vesti gat or 
- Oste os y nt hesis materi al re visi o n or s ur ger y (i) p erf or me d less t ha n 2 m o nt hs fr o m t he 
scree ni n g visit at t he fract ure site or  (ii) p erf or m e d less t ha n 4 wee ks fr o m t he scree ni n g 
visi t at dista nce of t he fract ure site.  
- Acti ve b o ne i nfecti o n (at site) 
- Fe m oral n ec k fract ure, if t he fe m ur is t he tar get b o ne of t he st u d y 
- M ultif ocal fract ure  ( e. g. , m ore t ha n o ne fract ure site o n t he st u die d b o ne) 
- S y m pt o matic dela ye d/ n o n- u ni o n fract ur e o n t he nei g h b o uri n g b o ne , as j u d ge d b y t h e 
I n v esti gat or 
- Se vere ner ve da ma ge a n d/ or ne ur o pat hic/ ne ur o p at hic-li ke pai n at fract ur e site, t hat ma y 
i nterfere wit h assess me nt d uri n g t he st u d y, as a p preciate d b y t he I n vesti gat or 
- Se vere te n d o n l esi o n (e. g., r u pt ure or e nt hes o pat h y) at fract ure site, t h at ma y i nterfere wit h 
assess me nt d uri n g t he st u d y, as a p preciate d b y t he I n v esti gat or 
C urre nt or previ o us di a g n oses, si g ns a n d/ or sy m pt o ms 
- P ositi ve ser ol o g y f or HI V ( d efi ne d as p ositi ve A nti -H I V 1 a n d/ or 2 a n d/ or p ositi ve P C R) 
- Acti ve he patitis B ( d efi n e d as p ositi ve H Bs A g a n d/ or p ositi ve P C R )  
- Acti ve he patitis C ( defi n e d as p ositi ve A nti- H C V a n d/ or p ositi ve P C R)  
- Gl o bal se psis 
- Re nal i m pair me nt, defi ne d as ser u m creati ni ne > 2 m g/ dl or 1 7 6 µ m ol/ L 
- He patic i m pair me nt, defi ne d as ala ni ne a mi n otra nsferas e or as partate a mi n otra nsferase ≥ 3 
ti mes t he u p per n or mal li mit  
- P o orl y c o ntr olle d dia b etes mellit us ( defi ne d as H b A 1 C > 8 %) 
- K n o w n aller g y t o ge nta mici n 
- Hist or y of h y pers e nsiti vit y t o h u ma n bi ol o gi cal material i ncl u di n g bl o o d a n d bl o o d deri ve d 
pr o d ucts, d oc u me nte d cli nicall y or b y l a b orat or y t ests 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 4 4 /1 3 6  
 
- C urre nt or past hist or y of s oli d or hae mat ol o gi cal ne o plasia 
- Hist or y of or ga n or b o n e marr o w tra ns pl a ntati o n 
- Acti ve a ut o-i m m u ne disease (e. g., s cler o d er mia, Sj ö gre n s y n dr o me, l u p us,...) 
- A n y c o n c o mita nt disease t hat c o ul d i nterfere wit h t he e val uati o n of effi cac y, as j u d ge d b y 
t he I n v esti gat or, i ncl u di n g b ut n ot li mite d t o l ocal or meta b olic b o ne dise ases  
- Lif e e x pecta nc y less t h a n 6 m o nt hs 
C urre nt or previ o us tre at me nt 
- Patie nts w h o ha ve pre vi o usl y bee n treat e d wit h A L L O B ®  
- Partici pati o n i n a n ot her cli nical st u d y i n v ol vi n g a p har mac ol o gical treat me nt wit hi n 3 
m o nt hs pri or t o scree ni n g 
- C urre nt ( or wit hi n 1 m o nt h of scree ni n g) treat me nt wit h calcit o ni n, ral o xife n, teri parati de, 
a n d/ or str o nti u m rale nate  
- C urre nt ( or wit hi n 6 m o nt hs of scree ni n g) illicit dr u g a b us e (as p er l ocal la w) 
S afety  as pects c o n cer ni n g fe m ale s u bjects of c hil d be ari n g p ote nti al 
- Pre g n a nc y 
- Breast-fee di n g 
- W o ma n n ot willi n g or a ble t o use a relia ble c o ntr ace pti ve met h o d f or at least 6 wee ks pri or 
t o scree ni n g a n d d uri n g t he w h ole st u d y peri o d. Relia ble c o ntrace pti ve m et h o ds i ncl u de 
orall y a d mi nistere d h or m o nal c o ntrace pti ves, s ur gical i nter ve nti o n (e. g., t u bal li gati o n) , 
a n d i ntra uteri ne d e vice (I U D) 
- W o ma n wit h p ositi ve uri ne pre g na n c y tests at Visits # 1 a n d/ or # 2 
Ot he r excl usi o n criteri a 
- B o d y Mass I n d e x ( B MI) of 3 5 k g/ m 2 or greater 
- U na ble t o u n der g o ge neral a naest hesi a or a s ur gi cal i nter ve nti o n 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 4 5 /1 3 6  
 
3  
R A TI O N A L F O R T H E S T U D Y D E SI G N 
3. 1  
T y pes a n d Sites of Del a ye d a n d N o n- U ni o n Fr act ures  
I n t his st u d y, patie nts wit h dela ye d- u ni o n fract ures of l o n g b o nes will be e nr olle d. All l o n g 
b o ne s ha v e a l o n git u di nal a xis c o nsisti n g of a b o d y or s haft (t he dia p h ysis) a n d a n e x pa n de d 
p orti o n (t he e pi p h ysis) at eac h e n d t hat is us uall y artic ular. Acc or di n g t o t h e A O classificati o n 
b y M üller ( 1 9 9 0), f o ur differe nt gr o u ps of fract ures are si milarl y disti n g uis h e d f or all l o n g b o nes 
an d t he te n de nc y of e v ol vi n g t o war ds n o n- u ni o ns a p pears t o be gr ossl y si milar a m o n g t he m 
( Cal ori et al., 2 0 0 7).   
T o a v oi d e val uati o n bias, patie nts wit h m ultif ocal fract ur es will be e x cl u de d fr o m t he st u d y. I n 
s uch cases, it will be diffic ult t o e val uate t he treate d fract ur es i n de pe n de ntl y fr o m t he ot h er 
u ntreate d fract ure. 
3. 2  
Cli n ic al a n d R a di ol o gic al E v al u ati o n T o ols 
3. 2. 1  Cli nic al Ev al u ati o n 
T o assess fract ur e heali n g, ort h o pae di c s ur ge o ns perf or m b ot h a cli nical a n d a ra di ol o gical 
e val uati o n ( Me gas, 2 0 0 5; C orrales et al., 2 0 0 8). Cli nical criteria use d t o assess fract ure u ni o n 
are t he a bs e nce of p ai n or te n der ness d uri n g wei g ht beari n g, t he a bse nce of pai n or te n der ness 
o n pal pati o n a n d t he a bilit y t o bear wei g ht ( C orrales et al., 2 0 0 8). T his cli nical assess me nt is 
us uall y c o m bi ne d wit h ra di ol o gic al e x a mi nati o ns i ncl u di n g plai n ra di o gra p hic meas ures s uc h 
as c ortical c o nti n uit y, prese nce of fract ure li ne a n d call us f or mati o n ( C orrales et al., 2 0 0 8). 
Vis u al A n al o g ue Sc ales 
T he us ual t o ol t o assess pai n is t he Vis ual A nal o g ue Scale ( V A S). T his o ne- di me nsi o nal t o ol 
all o ws relia ble assess me nt of s y m pt o ms ( Brei vic k et al. , 2 0 0 8). A V A S is a meas ure me nt 
i nstr u me nt de dicate d t o t he e val uati o n of c haract eristics, attit u des or s y m pt o ms t hat is belie ve d 
t o ra n ge acr oss a c o nti n u u m of val ues a n d ca n n ot easil y b e directl y meas ure d (e. g., pai n or 
gl o bal healt h stat us i n t his partic ular st u d y). I n V A S, t he s y m pt o m t hat a patie nt feels ra n ges 
acr oss a c o nti n u u m fr o m n o s y m pt o m ( 0 m m) t o e xtre me s y m pt o m ( 1 0 0 m m) o n a h oriz o ntal 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 4 6 /1 3 6  
 
li ne of 1 0 0 m m i n le n gt h. T he p atie nt mar ks o n t he li ne t h e p oi nt t hat he/s he feels re pres e nts 
his/ her perce pti o n of his/ her c urre nt stat us of s y m pt o m. T he V A S sc ore is deter mi ne d b y 
mea s uri n g i n milli metres fr o m t he left ha n d e n d of t he li ne t o t he p oi nt t hat t he patie nt mar ks. 
P ai n ( V A S) 
I n p ai n V A S, t he pai n t hat a patie nt feels ra n ges acr oss a c o nti n u u m fr o m n o ne ( 0 m m) t o 
e xtre me ( 1 0 0 m m) o n a h oriz o ntal li ne of 1 0 0 m m i n le n gt h (see A n ne x 2).  T his V A S has bee n 
s h o w n t o all o w relia ble assess me nt of p ai n b ot h at rest, d uri n g acti vities a n d at p al pati o n 
( Brei vi k et al., 2 0 0 8). T he patie nts wit h V A S pai n sc ores of 3 0 m m or less w o ul d be cate g orise d 
as ha vi n g mil d pai n, t h ose wit h sc ores of 7 0 m m or m ore are cate g orise d as ha vi n g s e vere pai n, 
a n d t h ose fr o m 3 1 t o 6 9 m m, m o derate p ai n ( Kell y, 2 0 0 1). T h e ti me fra me o ver w hic h t he 
patie nts s h o ul d c o nsi der t he se verit y of t heir p ai n is t he last 2 4 h o urs ( Brei vi k et al., 2 0 0 8). I n 
t his st u d y, p ai n will be assesse d at rest, d uri n g acti vit y a n d at p al pati o n. 
Meas ure me nt of t he i nte nsit y of pai n a n d d eter mi nati o n of t he e xte nt t o w hic h pai n affects a n 
i n di vi d ual is n ot si m ple as pai n is a c o m ple x a n d m ulti di me nsi o nal p he n o me n o n. I n d ee d, pai n 
ca n be ge nerate d b y differe nt me c ha nis ms i ncl u di n g tiss ue isc h e mia, m uscle c o ntr acti o n, a n d 
direct tiss ue da ma ge fr o m tra u ma. I n a d diti o n, t he peri p heral a n d ce ntral ner v o us s yst e ms n ot 
o nl y passi vel y carr y t h e n ocice pti ve si g nal f or c o g niti ve pr ocessi n g b ut als o acti vel y m o dif y it 
al o n g t he wa y. I nt er pretati o n of t his si g nal i ncl u des ps yc h ol o gical, p h ysi ol o gic al, e m oti o nal 
a n d be ha vi o ural di me nsi o ns. Beca use of t hes e c haracteristics, t he perce pti o n of a n d t he 
res p o nse t o pai n ca n var y greatl y ( Ke n dall et al., 1 9 9 6; K n o x, 1 9 9 6).  
T he data deri ve d fr o m t his meas ure m e nt ca n be a n al yse d usi n g para metric statistical tec h ni q ues 
( Kell y, 2 0 0 1). A mi ni mal cli nicall y si g nifica nt differe n ce ( mi ni mall y i m p orta nt differe nce 
MI D) i n Pai n as meas ure d b y V A S sc ore h as bee n deter mi ne d a n d is ge nerall y re p orte d t o ra n ge 
bet wee n 9 t o 1 5 m m ( Kell y, 1 9 9 8, 2 0 0 1; P o pe et al., 2 0 0 9; K w o k a n d P o pe, 2 0 1 0; Ge or ge a n d 
P o pe, 2 0 1 1).  
T o ta ke i nt o acc o u nt t his varia bilit y, ot her q uesti o n naires are a vaila ble t o o btai n a better 
o ver vie w of t h e gl o bal disease a n d h ealt h q ualit y of life, s uc h as t h e S h ort- F or m healt h s ur ve y 
S F -3 6 q uesti o n naire, t h e Healt h Assess me nt Q uesti o n naire ( H A Q), Os westr y Disa bilit y I n de x 
( O DI), Wei g ht- Beari n g s c ore (f or m ore i nsta n ces, see S hearer a n d M ors he d, 2 0 1 1).  


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 4 7 /1 3 6  
 
Assessi n g t he gl o bal disease e v al uati o n e na ble t o a v oi d s o me bias ass o ciate d wit h t he 
e val uati o n of pai n or t he f u ncti o n of t he fract ure d site. I n d ee d, a n ot her fract ur e near b y t he tar get 
fract ur e, m ulti ple fract ur es at t he sa me site,  n er ve da ma ges or pre vi o us s ur gical i nter ve nti o ns 
ma y n e gati vel y i m pact t he patie nt a bilit y t o disti n g uis h bet w ee n p ai n fr o m t h ose c ollateral 
s y m pt o ms a n d pai n ca use d at t he treate d fract ur e site.  
Gl o b al Dis e ase Ev al u ati o n ( V A S) 
Res p o nse ( ge n eral disease i m pr o ve me nt) t o treat me nt ca n b e assesse d b y a Gl o b al Diseas e 
E val uati o n sc ore ( vis ual a nal o g ue scale), w hic h is c o m m o nl y use d f or j oi nt diseases ( Fels o n et 
al.,  1 9 9 7). T he patie nt’s gl o bal assess m e nt of disease acti vit y is a sta n dar dize d a n d vali date d 
meas ure  of dise ase (acti vit y) stat us de vel o pe d b y t he A meri ca n C olle ge of R he u mat ol o g y i n 
or der t o pr o vi de a si m pl e, ge n eric meas ure of h ealt h f or cli nical a p praisal a n d res p o nse t o 
treat me nt ( A C R, V ol. 5 7, N 2, 2 0 0 7; E M A, C P M/ E W P/ 4 2 2/ 0 4, 2 0 0 6).  
T he  Gl o bal Disease E val uati o n V A S defi n es t he ge neral healt h p atie nt stat us c orres p o n di n g at 
t he Q uesti o n “ H o w d o y o u feel ( o n a sc ore of 0 – 1 0 0 m m w here 0 m m is as g o o d as y o u ca n 
feel a n d 1 0 0 m m e xtre mel y ba d) o ver t he last wee k re gar di n g y o ur diseas e (i.e., dela ye d- u ni o n 
fract ur e), pl ease i n dicate b y a n “ X” ( bet wee n 0 m m t o 1 0 0 m m) y o ur ge n eral healt h stat us o n 
t he h oriz o ntal scale li ne ”. T his i nf or mati o n is use d as a q u a ntitati ve meas ure of healt h as j u d ge d 
b y t he i n di vi d ual res p o n de nts. T he patie nt is as ke d t o si m pl y mar k a n “ X” o n t he scale t o 
i n dicate his/ her healt h t o da y (s ee A n ne x 1). T he V A S sc ore is deter mi ne d b y meas uri n g i n 
milli metres fr o m t he left ha n d e n d of t he li ne t o t h e p oi nt t hat t he patie nt mar ks. 
T he data d eri ve d fr o m t his meas ure me nt ca n b e a nal yse d, as f or pai n, usi n g para metric 
statistical tec h ni q ues ( Kell y, 2 0 0 1). H o we v er, cli nical a n d statistical si g nifica nce are n ot 
necessaril y t h e sa me, a n d t he cli nical i m pact o n t he patie nt a n d o n t h e m e dical practice is a 
cr ucial fact or. T heref ore, a mi ni mal cli nicall y si g nifica nt differe nce ( mi ni mall y i m p orta nt 
differe n ce MI D ) i n Gl o bal Disease E val uati o n as meas ure d b y V A S sc ore has als o bee n 
deter mi ne d a n d is ge n erall y re p orte d t o ra n ge bet wee n 8 t o 1 2 m m  ( K w o k a n d P o pe, 2 0 1 0; 
Ge or ge a n d P o pe, 2 0 1 1).  
 
 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 4 8 /1 3 6  
 
Wei g ht- Be ari n g Sc ore 
T he f u ncti o nal e v al uati o n usi n g wei g ht beari n g li mits or restricti o ns is base d o n a s e mi-
q ua ntitati ve sc ore o n t he f oll o wi n g cate g ories (e. g., U ni v ersit y of Pitts b ur g h, M e dical Ce nter 
i nf o f or patie nts, 2 0 0 4): 
- N o n wei g ht beari n g (s c ore of 0): n o wei g ht o n i nj ure d ar m/ le g i n all o we d. W hile t he patie nt 
sta n d or wal k he/s he m ust h ol d i nj ure d le g/ar m off t he fl o or/ta ble. 
- T oe-t o uc h or fi n ger-t o u c h wei g ht b eari n g or t o u c h d o w n wei g ht beari n g (sc ore of 1): w he n 
t he patie nt sta n d or wal k, he/s he ma y o nl y t o uc h t h e fl o or/ta ble f or b ala nce. N o b o d y wei g ht 
ca n be pla ce d o n t he le g/ ar m.  
- Partial wei g ht beari n g (s c ore of 2): t he patie nt ma y place s o me of his/ her b o d y wei g ht o n 
t he i nj ure d le g/ar m w h e n he/s he sta n d or wal k. 
- F ull wei g ht beari n g (sc ore of 3)  
T his sc ori n g ca n be d o ne “ u nrestricte d ” or “as t olerate d”. I n t he latter, t he patie nt ca n place o nl y 
as m uc h wei g ht as he/s h e feels c o mf orta ble o n t h e i nj ure d li m b ( base d o n pai n feeli n g). T h e 
patie nt places less wei g ht o n t he affecte d li m b if he/s he feels pai n. T his s pecific cate g or y all o ws 
a differe ntial sc ori n g relate d t o pai n feeli n g (see A n ne x 3 ). T here is n o wei g ht- beari n g 
assess me nt base d o n a vis ual a nal o g ue scale.  
U nf ort u natel y, wei g ht beari n g sc ori n g d oes n ot all o w t he use of vali date d assess me nt t o ols, a n d 
t he c urre nt e xisti n g sc ori n g met h o d ca n n ot a v oi d r o o m f or s u bjecti ve p atie nt a n d p h ysi cia n 
i nter pretati o n. 
 
 
3. 2. 2  R a di ol o gic al Ev al u ati o n 
Dia g n osis a n d treat me nt e val uati o n ( heali n g) of i m paire d fract ur e heali n g is base d o n cli nical 
s y m pt o ms as well as o n ra di ol o gic al si g ns a p p eari n g d uri n g t he c o urse of treat me nt. T he 
ra di ol o gic al si g ns de p e n d o n t he t y pe of del a ye d- u ni o ns b ut ge n erall y i n cl u de d t he a bse nce or 
prese nce of bri d gi n g bet wee n t he b o ne fra g me nts, persiste nce or n ot of fract ure li nes, a bse nce 
or pr ese n ce of b o n e call us ( Me gas, 2 0 0 5).  


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 4 9 /1 3 6  
 
Base d o n a s yste matic re vie w of p u blis he d cli nical o utc o mes pertai ni n g t o l o n g b o n e fract ure 
heali n g, t he m ost c o m m o n ra di o gra p hic d efi niti o ns of fract ure heali n g i n st u dies a p pear t o be a 
bri d gi n g of t he fract ur e site b y call us, tra b ec ula e, or b o ne ( 5 3 % of t he st u dies), bri d gi n g of t h e 
fract ur e site at 3 c ortices ( 2 7 % of t he st u dies), a n d o bliterati o n of t h e fract ure li ne or c ortical 
c o nti n uit y ( 1 8 % of t h e st u dies) ( C orral es et al., 2 0 0 8). 
M ore  rece ntl y, i n a n atte m pt t o i m pr o ve t he relia bilit y of ra di o gra p hi c ass ess me nt of heali n g, 
st u dies ha ve e x pl ore d a n o vel ra di o gra p hi c assess me nt f or ti bial s haft fract ures, t he 
Ra di o gra p hic U ni o n Scale f or Ti bial Fract ures ( R U S T). R U S T was d e vel o pe d as a sta n d ar d 
meas ure me nt of fract ur e heali n g i n p atie nts wit h ti bial fract ur es ( W hela n et al., 2 0 0 2; K o oistra 
et al., 2 0 1 0; W hela n et al., 2 0 1 0). T he R U S T assesses t he prese nce of bri d gi n g call us a n d of a 
fract ur e li ne o n eac h of f o ur c ortices (see n o n a nteri or, p osteri or, me dial, a n d lateral vie ws). 
Eac h of t he f o ur c ortices is e val uate d acc or di n g t o a ra n ge fr o m 1 t o 3. T he i n di vi d ual sc ores 
are a d d e d t o pr o vi de a n o verall t otal ra n gi n g fr o m 4 ( n o ne of t he c ortices bri d ge d) t o 1 2 ( bri d ge d 
at all f o ur c ortices wit h n o prese n ce of t he fract ure li ne) (see A n ne x 4 ). T h e T o m o gra p hic U ni o n 
Sc ore ( T U S) a n d m o difie d Ra di ol o gic al U ni o n Sc ore ( m R U S) are bei n g us e d i n t his st u d y (fr o m 
2 t o 1 6) i n or der t o ta ke i nt o acc o u nt t he cas e w he n t he fract ure li ne is a bse nt o n at least 2 vie ws 
of t he sca n after a rece nt fract ur e ( Sc ore 0), a n d t h e case w he n call us is t otall y a bse nt o n eac h 
vie w of t he sca n after b o ne re parati o n ( Sc ore 4).  
T he de v el o p me nt of t he R U S T hi g hli g hts t he first atte m pt at creati n g a v ali date d s yste m f or 
deter mi ni n g h eali n g i n ti bial fract ur es a n d ma y s er ve as a n e x a m ple f or t he de vel o p me nt of 
ot her sc ori n g s yste ms, p artic ularl y t h ose i n w hic h har d ware or casti n g material ma y o bsc ure 
vis ualizati o n o n X-ra y ( A x elra d a n d Ei n h or n, 2 0 1 1; Va n na b o uat h o n g et al., 2 0 1 1). T his sc ori n g 
s yste m has de m o nstrate d hi g her i nter-rater relia bilit y w he n c o m pare d wit h s ur ge o n’s ge n eral 
i m pressi o n ( W hela n et al., 2 0 1 0).  I n a n atte m pt t o i m pr o ve t he relia bilit y of ra di o gra p hi c 
assess me nt of heali n g as well as t he sta n dar dizati o n of t he o bser vati o ns, a n d base d o n t he 
literat ure re vie w ( C orrales et al., 2 0 0 8), t he ra di ol o gical e val uati o n of fract ure heali n g will be 
d o ne acc or di n g t o a m o difie d versi o n of t he R U S T (i.e., m R U S a n d T U S) i n t his st u d y. 
Ge nerall y, m R U S is perf or me d o n X-ra ys, b ut ca n be d o ne o n b ot h X-ra y a n d C T sca n ( T U S). 
I n t h e pres e nt st u d y, T U S o n C T sca n has b ee n c h ose n as a pri mar y e n d p oi nt, beca use C T sca n 
is a m ore se nsiti ve met h o d, a n d t he t hree- di me nsi o nal rec o nstr ucti o n will all o w t o get a m ore 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 5 0 /1 3 6  
 
gl o bal vie w of t he fract ur e a n d will i m pr o ve t he assess me nt. N u mer o us st u dies ha ve e x p o u n de d 
t he be nefits of c o m p ute d t o m o gra p h y i n pr o vi di n g a m ore acc urate assess me nt of heali n g a n d 
a hi g her c orrelati o n wit h fract ur e ri gi dit y ( M ors he d et al. , 2 0 0 8). O ne st u d y s h o we d g o o d 
relia bilit y a n d dia g n ostic acc urac y of C T f or ti bi al n o n- u ni o n fract ures ( ka p pa = 0. 6 7, p < 
0. 0 0 0 1; se nsiti vit y = 1 0 0 %, s pecificit y = 6 2 %), v ers us plai n ra di o gra p h y ( ka p pa = 0. 1 4, p = 
0. 3 6; se nsiti vit y = 5 4 %, s pecificit y = 6 2 %) ( B hattac har y ya et al., 2 0 0 6). 
I n t his pil ot p hase I/IIa st u d y, t he pri mar y tar get f or TU S  as assesse d b y C T sca n will be a n 
i m pr o ve me nt of at least 2 p oi nts at M o nt h 6, as a n i m pr o ve me nt b y t w o p oi nts of TU S  mea ns: 
- 
T here is a t otal c o ns oli dati o n of o ne c ortices, or 
- 
T here is a b o n e u ni o n o n t w o c ortices (e ve n if t he fract ur e i nterli ne is still visi ble), or 
- 
T he disa p peara nce of t he fract ur e i nterli nes o n t w o c ortices i n b o ne u ni o n. 
3. 2. 3  R ati o n ale f or t he C h oice of Cli nic al a n d  R a di ol o gic al I m pr ove me nt Levels  
I n t heir d ail y practice, ort h o pae dic s ur ge o ns ta ke t he decisi o n of a ne w s ur gical i nter ve nti o n if 
si g ns of b ot h cli nical a n d ra di ol o gi cal i m pr o ve m e nts are o bser ve d (i.e., si g ns of fa v o ura ble 
e v ol uti o n). T his is beca use cli nical a n d ra di ol o gical i m pr o ve me nts are n ot al wa ys c orrel ate d. 
T his has bee n o bser ve d i n ot her st u dies w here s o me patie nts s h o we d si g nifica nt cli nical 
i m pr o ve me nt wit h li mite d ra di ol o gical i m pr o ve m e nt or vice versa.  I n t he prese nt st u d y, t he 
sa me strate g y of a c o m bi ne d cli nical a n d ra di ol o gical e val uati o n will hel p deter mi ni n g if a 
resc ue s ur ger y will be re q uire d or n ot.  
Base d o n t h e efficac y of t he treat me nt, I n v esti gat ors will ha ve t he o p p ort u nit y t o s witc h t o 
resc ue s ur ger y fr o m M o nt h 3 if t he patie nt has n ot i m pr o ve d b y at least 1 5 % his/ her gl o bal 
disease e val uati o n sc ore ( V A S) as percei ve d b y t he patie nt a n d his/ her T U S or m R U S (as 
a vaila ble) h as n ot i m pr o ve d b y at least 1 p oi nt. 
T he  le vels of i m pr o ve me nts ha ve bee n calc ulate d as base d o n ot her si milar i m paire d fract ure 
heali n g trials (e. g., P R E O B ® o n n o n- u ni o n fract ure) a n d ta ke i nt o acc o u nt sta n dar d de viati o n 
a n d patie nt varia bilit y.   


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol   
A L L O B -D U 1 _  C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 5 1 /1 3 6  
 
4  
D E T AI L E D S C H E D U L E O F VI SI T S  
4. 1  
G e ner al O ver vie w of Visits a n d Pr oce d ures 
St u d y Fl o w C hart 
A n o ver vie w of t h e st u d y assess me nts a n d pr oce d ures is gi ve n i n t h e Fl o w C hart bel o w. St u d y 
pr oce d ures are descri be d se parat el y f or t he A L L O B ® st u d y, t he 
 a n d t h e 
 i n Ta ble 1, 
. 
 
 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 5 2 /1 3 6  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 5 3 /1 3 6  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 5 4 /1 3 6  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 5 5 /1 3 6  
 
 
4. 2  
Scree ni n g ( Visit # 1) 
Bef ore a n y st u d y-relate d pr oce d ure, t he Pri nci pal I n vesti gat or ( or a me m ber of t he i n v esti gati n g 
tea m, desi g nat e d b y t h e I n v esti gat or) will gi v e, b ot h i n oral a n d writte n, detaile d a n d 
co m pre he nsi ve i nf or m ati o n re gar di n g all as pects of t he trial t o t he patie nt (i ncl u di n g t he Patie nt 
I nf or mati o n Letter a n d I nf or me d C o nse nt F or m). T he scree ni n g peri o d will last u p t o 8 wee ks.  
Visi t # 1 will i ncl u de t he f oll o wi n g pr oce d ures t o be perf or me d after I C F h as bee n si g ne d: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 5 6 /1 3 6  
 
 
 
 
 
Tre at me nt/ A L L O B ®  I m pl a nt ati o n Visit ( Visit # 2) 
B ef ore A L L O B ®  i m pla nt ati o n, t he f oll o wi n g pr oce d ures will be perf or me d: 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 5 7 /1 3 6  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
  
 
  
  
  
  
  
  
  
 
 
 
 
 
 
4. 4  
F oll o w- u p Visit # 3 ( 2 wee ks ± 2 d a ys) 
D uri n g t his visit, t he f oll o wi n g pr oce d ures will be perf or me d: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 5 8 /1 3 6  
 
 
 
 
4. 5  
F oll o w- u p Visit # 4 ( M o nt h 1: 4 wee ks ± 1 w ee k) 
D uri n g t his visit, t he f oll o wi n g pr oce d ures will be perf or me d: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4. 6  
F oll o w- u p Visit # 5 ( M o nt h 3: 1 2 wee ks ± 2 w ee ks) 
T he f oll o wi n g pr oce d ures will be perf or me d: 
 
 
 
 
 
 
 
 
 
 
 
 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 5 9 /1 3 6  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
4. 7  
F oll o w- u p Visit # 6 ( M o nt h 6: 2 4 wee ks ± 3 w ee ks) 
T he f oll o wi n g pr oce d ures will be perf or me d: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 6 0 /1 3 6  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
4. 8  
 
 
 
 
  
 
 
 
 
 
 
 
 
 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 6 1 /1 3 6  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 6 2 /1 3 6  
 
 
5  
D E T AI L E D D E S C RI P TI O N O F T H E P R O C E D U R E S  
5. 1  
Re visi o n Pr o ce d ure pri or t o t he Tri al 
Oste os y nt hesis re visi o n or s ur ger y of t he d ela ye d- u ni o n u n der st u d y is all o we d pri or t o e ntr y 
i nt o t he st u d y:  
- If t here is a mi ni m u m of 2 m o nt hs bet wee n t he re visi o n/s ur ger y a n d t he s cree ni n g if t he 
re visi o n/s ur ger y has b ee n perf or me d at t he fract ur e site  
- If t here is a mi ni m u m of 4 wee ks bet w ee n t h e re visi o n/s ur ger y a n d t he s cree ni n g if t he 
re visi o n/s ur ger y has b ee n perf or me d o utsi de t h e fract ure site. 
At scree ni n g ( Visit # 1), t he a bse nce of si g ns of ra di ol o gical heali n g ( d ue t o t he oste os y nt h esis 
re visi o n perf or me d bef ore t he st u d y) will be c o nfir me d b y t h e I n de p e n de nt Ra di ol o gist. T his 
will be d o ne b y c o m pari n g c o n ve nti o nal X -Ra y (a n d / or C T sca n) perf or m e d at scree ni n g V isit 
# 1  wit h t he X -R a y (a n d / or C T sca n) perf or m e d be f ore t he st u d y ( mi n. ti me of 4 wee ks) .  
U p o n t he I n de pe n d e nt Ra di ol o gist or t he Pri nci p al I n v esti gat or’s j u d ge m e nt as nee de d (e. g., 
a bse nce or p o or q ualit y of pre-st u d y i ma ges, pre-st u d y i ma ges w h ose dates are t o cl ose fr o m 
t he dates of t he fract ures …), a s ec o n d s et of X-ra y ca n b e p erf or me d d uri n g s cree ni n g peri o d 
(i.e., 4 wee ks aft er t h e first set of X-ra ys), i n or der t o assess t h e e v ol uti o n of t he fract ur e: 
a bse nce of fract ure heali n g o v er t h e last 4 wee ks at ti me of i ncl usi o n (i ncl usi o n criteri o n, s ecti o n 
2. 6. 2 ). 
H o w e ver, all eff orts m ust be d o ne t o c ollect t he i m a ges perf or me d at t he ti me of re visi o n. 
5. 2  
A L L O B ®  I m pl a nt ati o n Pr o ce d ure 
I n t he o p erati n g r o o m, t he C-ar m fl u or osc o pe ( or e q ui vale nt) will be dra p e d wit h a sterile slee v e 
a n d p ositi o ne d o ver t he d ela ye d- u ni o n re gi o n t o all o w a n a nt er o- p osteri or vi e w a n d l ateral vie w 
of t he lesi o n. U n der a naest hesia, a 5 t o 1 0 m m i ncisi o n is t he n ma de laterall y t hr o u g h t he s ki n 
a n d t he fas cia at t he le v el of t he dela ye d- u ni o n site. 
 
 
 
 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 6 3 /1 3 6  
 
 
 
 
 
 
 
 
. T he i njecti o n of t he s us pe nsi o n is perf or me d sl o wl y f or 
a p pr o xi matel y 1 t o 2 mi n utes. Fi nall y t he tre p hi ne is was he d wit h a ri nse s ol uti o n ( Na Cl 0. 9 %) 
t o e ns ure t hat t he e ntire s us pe nsi o n has b ee n i nject e d i nt o t he dela ye d- u ni o n lesi o n. T he s yri n ge 
is t he n re m o ve d 
. T he 
 
 (e. g., Gelf o a m® , U pj o h n, U S A) is p us he d t hr o u g h t he 
e xter nal tre p hi ne t o all o w cl otti n g a n d cl osi n g of t h e h ole ma de b y t h e tre p hi ne. T he tre p hi ne is 
re m o ve d a n d stitc hes are a p plie d t o cl ose t he s ki n. 
I m pl a nt ati o n tre p hi ne (exter n al a n d i nter n al tre p hi nes) 
 
If j u d ge d necessar y, t he I M P A L L O B®  (i.e., sa me s yri n ge) ca n be a d mi nistere d i nt o t he 
dela ye d- u ni o n site fr o m t w o differe nt s ur gical a p pr oac hes, usi n g t he s a me pr oce d ure.  


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 6 4 /1 3 6  
 
 
5. 3  
Peri- o per ati ve a nti bi otic t her a p y a n d ot her me dic ati o n 
All patie nts will recei ve a si n gle i ntra ve n o us i nf usi o n of cefaz oli n ( 2 g) or a n y sta n d ar d- of-care 
a nti bi otic t hera p y us e d at t he i n vesti gati n g site at i n d ucti o n. Besi des, dr u gs use d d uri n g 
a naest hesia will n ot be s yste maticall y rec or de d i n t he C R F, e x ce pt if a n A d verse E ve nt s h o ul d 
ha ve occ urre d. 
Patie nts will be h os pitalize d f or 2 4 or 4 8 h o urs, u p o n I n v esti gat or’s j u d ge me nt (
 
). If patie nts are 
h os pi taliz e d f or 2 4 h o urs, t he y m ust ret ur n t o t he I n vesti gati n g Site f or t he Visit # 2 – 4 8 h p ost-
i mpla ntati o n visit. 
5. 4  
P ost- o per ati v e M a n a ge me nt 
F oll o wi n g t he i m pla ntati o n pr oce d ure a n d t he h os pital sta y, i m m o bilizati o n a n d u nl oa di n g of 
t he treate d b o n e will be re q ueste d a n d all patie nts will re mai n n on - wei g ht- beari n g o n t he 
o perate d li m b as l o n g as j u d ge d necessar y b y  t h e I n v esti gat or. Pr o gressi v e m o bilizati o n a n d 
l oa d beari n g will be all o we d t hereafter.  
 (at Visit # 3). 
5. 5  
Re visi o n Pr o ce d ure d uri n g t he Tri al 
Si m ple oste os y nt hesis re visi o n ( defi ne d as sec o n d i nter ve nti o n a n y w here b ut at t he fract ur e 
site) ca n be perf or me d i n case of oste os y nt hesis material i nsta bilit y as fr o m M o nt h 3 after 
treat me nt.  
5. 6  
Re sc ue S ur ger y Pr oce d ure  
Resc ue s ur ger y ( w he n j u d ge d n ecess ar y, as fr o m M o nt h 3 after treat me nt) will be perf or me d 
acc or di n g t o sta n d ar d- of- care pr oce d ure of t he i n v esti gati n g site. 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 6 5 /1 3 6  
 
 
5. 7  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 6 6 /1 3 6  
 
 
 
 
 
 
 
 
 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 6 7 /1 3 6  
 
 
6  
I N V E S TI G A TI O N A L P R O D U C T  
6. 1  
I nvesti g ati o n al Me dici n al Pr o d uct 
T a ble 4 : C h ar acteristics of t he I nvesti g ati o n al Me dici n al Pr o d uct  
 
A L L O B ®  
C B M P  
all o ge neic b o ne marr o w -deri ve d oste o blastic cells  
Cell ular C o nce ntrati o n  
 cells/ ml  
V ol u me  
 ml 
C o ntai ner  
 
Batc h n u m ber(s)  
Pr o vi de d o n t he la bel  
E x pir y date  
Pr o vi de d o n t he la bel  
Ma n ufact urer  
B o ne T hera pe utics S. A.  
Tra de na me  
A L L O B ®  
St ora ge re q uire me nts  
 
Tre at m e nt a d mi nistere d 
T he A L L O B ®  d ose t o be use d i n t his st u d y will de pe n d u p o n t he siz e of fract ure i nterli ne a n d 
t he s ur gical a p pr oac h (fr o m 
 at a c o nce ntrati o n of  
 cells/ ml). T heref ore, 
A L L O B ®  v ol u me will be deter mi ne d o n a case- b y case basis. 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 6 8 /1 3 6  
 
 
T a ble 5 : A d mi nistr ati o n of t he Test Pr o d uct  
 
A L L O B ®  Pr o d uct Pr oce d ure  
Pr o d uct  
A L L O B ®  
Pr oce d ure/ R o ute of 
a d mi nistrati o n 
Perc uta ne o us a d mi nistrati o n via a tre p hi ne  
Si n gle d ose  
 cells/ ml (
 de pe n di n g o n t he dela ye d-u ni o n 
size) 
D osa ge sc he d ule  
1 si n gle d ose per s u bject at i m pla ntati o n  visit ( # 2) 
Re gar di n g t he pac k a gi n g, la belli n g, s hi p me nt of t he I n vesti gati o nal Me dici nal Pr o d uct (I M P), 
Sta n dar d O perati n g Pr oce d ures, i ncl u di n g ste p- b y -ste p i nstr ucti o ns a n d detaile d descri pti o ns, 
will be pr o vi de d t o t he Pri nci pal I n v esti gat or bef ore t he be gi n ni n g of t he trial. C o m plete 
i nf or mati o n will be pr o vi de d i n t he St u d y Pr oce d ure Ma n u al a n d trai ni n g of t he healt hcare 
pr ofessi o nals i n v ol ve d will als o be c o n d ucte d d uri n g t he Site I nitiati o n Visits a n d at t he 
I n v esti gat or’s Me eti n g. 
6. 2  
 
 
 
 
 
 
 
  
 
 
 
 
  
  
  
  
  
  
 
  
  
  
 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 6 9 /1 3 6  
 
 
 
 
 
  
6. 3  
T r ac ki n g, Tr ace a bilit y, a n d Acc o u nt a bilit y of I n vesti g ati o n al Me dici n al Pr o d uct 
A trac ki n g s yste m all o wi n g c o m plete tr acea bilit y of b ot h t he Starti n g M aterials (e. g., b o n e 
marr o w) a n d I M P (i.e., A L L O B ® ) at all sta ges will be esta blis he d a n d mai ntai ne d ( b y S p o ns or, 
Ma n ufact ur er, Ma na gi n g P h ysicia n of t he “I nter me diar y Str uct ur e”, I n vesti gat or a n d C R O). 
T his trac ki n g s yste m w o ul d e ns ure t hat: 
 T he Starti n g Materials a n d I M P are trac k e d a n d trace d d uri n g t he w h ole pr ocess, fr o m t he 
eli gi bilit y a n d sel ecti o n of t he d o n or, t hr o u g h t he d o nati o n, pr oc ure me nt, testi n g, 
pr ocessi n g, st ora ge, pres er vati o n, la belli n g, pac ka gi n g, release, tra ns p ort, distri b uti o n, a n d 
deli ver y, t o t he i m pla ntati o n t o t he patie nt, eac h pr oce d ure a n d ste p bei n g des cri be d i n 
Sta n dar d O perati n g Pr oce d ures, a n d s yste maticall y c ollect e d, verifie d, a n d rec or de d usi n g 
s pecific F or ms a n d Recei pts (a n d i n t he C R F). 
 Pr o d ucti o n data of eac h b atc h are acc uratel y trac k e d a n d rec or de d. 
 T he re is als o a n acc urate s yste m i n place t o n otif y, re p ort, i n vesti gat e, re gister, a n d tra ns mit 
i nf or mati o n a b o ut a n y S eri o us A d verse Safet y/ Q ualit y E v e nts w hic h m a y i nfl u e nce t he 
q ualit y a n d safet y of t he pr o d uct, a n d w hic h ma y be attri b ute d t o t he pr oc ure me nt of starti n g 
material, testi n g, pr ocessi n g, st ora ge, pres er vati o n, d eli ver y, a n d distri b uti o n (see detaile d 
descri pti o n i n S ecti o n 8 ). 
In a d diti o n, it s h o ul d be n ote d t hat all use d s yri n ges ( wit h o ut nee dles) will be ke pt a n d st ore d 
i n eac h i n vesti gati n g site u ntil m o nit or’s verificati o n visits, a n d destr o ye d after t he m o nit ori n g 
visit o n site a n d o nce t he acc o u nta bilit y is p erf or me d. 
F i nall y, data a n d rec or ds re q uir e d f or f ull tr acea bilit y will be k e pt b y t h e S p o ns or, Ma na gi n g 
P h ysicia n of t he I nter me diar y Str uct ur e, Ma n ufact urer, a n d I n v esti gat or f or a mi ni m u m of 3 0 
years after cli nical use. 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 7 0 /1 3 6  
 
 
7  
S A F E T Y A N D T O L E R A BI LI T Y M E A S U R E M E N T S A N D E N D P OI N T S 
7. 1  
O ver vie w of S afet y P ar a meters a n d E n d p oi nts 
T he safet y a n d t olera bilit y of t h e test pr o d uct ( A L L O B ® ) will be s yste m aticall y i n vesti gate d 
t hr o u g h o ut t he st u d y p eri o d. Patie nts will be e val uate d at eac h f oll o w- u p visit f or t he p ote ntial 
occ urre nce of a n y A E or S A E, relate d t o eit her t he pr o d uct or t he st u d y pr oce d ures. Defi niti o ns 
of A E/ S A E are i n Secti o n 8. 
F or t h e first 1 6 patie nts, recr uit me nt will pr ocee d ste p wise b y bl oc ks of 4. F ull first 2 wee ks 
safet y data of t h e first bl oc k of 4 patie nts will be a nal ys e d bef ore t he first patie nt of t he sec o n d 
bl oc k will be treate d. First 4 8 h o urs safet y data of t he sec o n d bl oc k of 4 patie nts will be a nal yse d 
bef ore tr eati n g t he first p atie nt of t he ne xt bl oc k. T his latter sc he me will be re peate d u ntil t he 
1 6 t h patie nt has bee n treate d.  
Ta ble 6 bel o w s h o ws h o w t he safet y e n d p oi nts of t his st u d y relate t o t he st u d y o bj ecti ves. 
Asse ss me nts a n d meas ur e me nts will be carrie d o ut at t he ti mes s pecifie d i n t he st u d y Fl o w 
C hart (see a b o ve). 
T a ble 6 : Overvie w of S afety P ar a meters a n d Ti me p oi nts  
V ari a bles  
Ti me P oi nts  
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 7 1 /1 3 6  
 
 
7. 1. 1  Vit al Si g ns 
Bl o o d press ure ( B P) will be assesse d i n all patie nts o n site b y sta n d ar dise d c uff meas ure me nts. 
Prefera bl y, t h e sa me p ers o n will d o all t he meas ure me nts o n t he sa me patie nt. 
R es ults of meas ure m e nts s h o ul d o nl y b e re p orte d as A E if, i n t h e I n vesti gat or’s o pi ni o n, it is 
o utsi de of “e x pecte d val u es or v ariati o ns”. Als o t he y m ust be c o nsi dere d as S A E if it f ulfils t he 
S A E defi niti o n.  
He art r ate  will be meas ure d o nce, i n beats per mi n utes ( b p m) after t he patie nt has bee n i n a 
resti n g stat e (seate d) f or at least 5 mi n utes. Heart rate will be c o u nte d f or 3 0 s ec o n ds, m ulti plie d 
b y 2 a n d rec or de d i n b p m. 
T he  B o dy te m per at ure  a n d Res pir at ory r ate  will als o be s yst e maticall y meas ure d. 
7. 1. 2  P hysic al Ex a mi n ati o n 
P h ysic al e x a mi n ati o n , i ncl u di n g assess me nt of ge n eral a p peara nce, s ki n, hea d, a n d nec k 
(i ncl u di n g e yes, ears, n ose, a n d t hr oat), l y m p h n o des, t h yr oi d, m usc ul os keletal/e xtre mities, 
car di o vas c ular s yste m, l u n gs, a b d o m e n, a n d ne ur ol o gical stat us as well as t he fract ure d li m b 
a n d t he a d mi nistrati o n site will be perf or me d prefera bl y b y t he sa me pers o n ( Pri nci pal 
In v esti gat or). 
Hei g ht  ( wit h o ut s h oes) will be meas ure d i n ce nti metres (c m). Wei g ht ( wit h o ut s h oes) will be 
meas ure d i n kil o gra ms usi n g a scale. Hist orical patie nt i nf or mati o n a n d/ or p atie nts re p orts m ust 
n ot be use d.  
B o d y M ass I n de x  ( B MI) will be calc ulate d as f oll o ws: Wei g ht ( K g)/ Hei g ht2 ( m) = B MI. 
7. 1. 3  L a b or at ory S afety Me as ure me nts 
T he bl o o d c ollecte d f or bi oc he mistr y, hae mat ol o g y, a n d ser ol o gical testi n g will be d o ne at t h e 
I n v esti gat or’s la b orat ories.  
T he  t otal a m o u nt of bl o o d c ollecte d 
 
 d uri n g t he w h ole st u d y is e x pecte d n ot t o e x cee d 3 0 0 ml.  


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 7 2 /1 3 6  
 
 
T a ble 7 : Overvie w of Bl o o d C ollecti o n  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ser ol o g y 
 
 
 
 
  
 
F or t his a nal ysis, 9 ml of bl o o d will be c ollecte d a n d t he a nal ysis will be perf or me d at t he l ocal 
la b orat or y. 
 
S afet y  
La b orat or y tests will be perf or me d 
 
 
  


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 7 3 /1 3 6  
 
 
T he f oll o wi n g p ara m eters will be a nal ys e d as safet y meas ure me nts:  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
F or t hese a nal yses, 1 1 ml of bl o o d will be c ollecte d at eac h visit.  
T hese a n al ys es will be perf or me d at t he l o cal la b orat or y.  
Ot her ex pl or at ory A n alys es: 
  
I n or der t o ass ess t he effects of treat me nt 
 
  
  
 
  
 
 
  
 
 
  
  
 
 
  
F or t hese a n al ys es, 2 9 ml of peri p heral bl o o d will be c ollecte d i n 4 differe nt bl o o d c ollecti o n 
t u bes ( 3 × 9 ml a n d 1 × 2 ml) 
  
                                                 
 
 
 
 
 
 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 7 4 /1 3 6  
 
 
7. 2  
Ot her S afet y Me as ure me nts 
7. 2. 1  W o me n wit h c hil d be ari n g p ote nti al 
W o me n wit h c hil d beari n g p ote ntial m ust use a relia ble met h o d of c o ntrace pti o n f or at least 6 
wee ks pri or t o st u d y i n cl usi o n (scree ni n g visit) a n d d uri n g t he w h ole st u d y peri o d. Relia ble 
c o ntrace pti ve 
met h o ds i ncl u de orall y a d mi nistere d h or m o nal c o ntrace pti ves, s ur gical 
i nter ve nti o n (e. g., t u bal li gati o n), a n d i ntra uteri n e de vice (I U D). 
M ore o ver, w o me n wit h c hil d beari n g p ote ntial will s yst e maticall y u n der g o uri ne pre g na nc y 
testi n g at eac h visit perf or me d at t he I n vesti gati n g site (fr o m Scree ni n g u p t o m o nt h 6). 
P re g n a nc y test kits will be pr o vi de d b y t he S p o ns or, perf or me d o n site acc or di n g t o 
ma n ufact ur er’s i nstr ucti o ns, a n d res ults will be rec or de d i n t he C R F. 
7. 2. 2  A d diti o n al s afety ex a mi n ati o ns a n d pr oce d ures 
If a n y u n clear cli nical e ve nt, i ncl u di n g s y m pt o ms, si g ns, or ot her o bser vati o ns or a b n or malities, 
s h o ul d occ ur, t he I n vesti gat or, or a n y ot her p h ysici a n i n c har ge, ma y p erf or m a d diti o nal cli nical 
e x a mi nati o ns a n d pr oce d ures ( ot her t ha n o utli ne d i n t his pr ot oc ol), i ncl u di n g a n y cli nical, 
la b orat or y, i ma gi n g a n d/ or tec h nical testi n g, i n or der t o clarif y a n d esta blis h t he aeti ol o g y a n d 
dia g n osis of t his cli nical e ve nt. 
X-ra y of t h e t h ora x a n d li ver Ultra S o u n d will be perf or me d at 6 m o nt hs after treat me nt 
 
i n or der t o c o nfir m a bse n ce of a n y ect o pic mi ner alizati o n. 
 
 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 7 5 /1 3 6  
 
 
8  
A D V E R S E E V E N T S A N D S E RI O U S A D V E R S E E V E N T S 
8. 1  
De fi niti o ns 
8. 1. 1  A dverse Eve nt ( A E) a n d Seri o us A dverse Eve nt ( S A E) 
 A n a d vers e e v e nt ( A E) is a n y u nt o w ar d me dical occ urre nce i n a patie nt or cli nical 
i n vesti gati o n s u bject w h o has bee n a d mi nistere d a p har mace utical pr o d uct a n d/ or a n y 
i n vesti gati o nal me di ci nal pr o d uct a n d w hi c h d oes n ot necessaril y ha v e a ca usal 
relati o ns hi p wit h t his treat me nt. A n A E ca n t heref ore b e a n y u nfa v o ura ble a n d 
u ni nte n de d si g ns (i ncl u di n g a n y a b n or mal la b orat or y fi n di n gs), s y m pt o ms, or dise ase 
te m p orall y ass ociate d wit h t he use of a me dici nal pr o d uct, wit h o ut a n y j u d g me nt a b o ut 
ca usalit y. 
 All A Es will be re p orte d fr o m t he ti me a si g ne d a n d date d I C F is o btai ne d u ntil 
c o m pleti o n of t he s u bject’s last visit.  
 E ve nts relat e d t o pr e-e xisti n g c o n diti o ns s h o ul d be re p orte d as A E, u p o n I n vesti gat or’s 
j u d ge me nt, j ustifie d b y a n i ncreas e i n fre q u e nc y or i nte nsit y of si g ns or s y m pt o ms.  
 A d verse e ve nts will be gra de d wit h res pect t o i nte nsit y a n d classifie d as eit her seri o us 
or n o n-seri o us acc or di n g t o t he W orl d Healt h Or ga nisati o n Classificati o n 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 7 6 /1 3 6  
 
 
T a ble 8 : Cl assific ati o n of A dverse Eve nts  
I nte nsity 
Mil d  
S o me a ware ness of s y m pt o ms or si g ns t hat d oes n ot i nterfere 
wit h t he patie nt’s us ual acti vities or is tra nsie nt, easil y 
t olerate d a n d res ol ve d wit h o ut treat me nt a n d wit h n o se q uelae 
 
M o der ate  
S y m pt o ms or si g ns ca usi n g e n o u g h disc o mf ort t o i nterfere 
wit h t he patie nt’s us ual acti vities, a n d/ or re q uires s y m pt o matic 
treat me nt 
 
Severe  
I nca pacitati n g e ve nt, i ncl u di n g s y m pt o ms or si g ns, ca usi n g 
se vere disc o mf ort a n d i na bilit y t o w or k or t o perf or m us ual 
acti vities, a n d re q uires treat me nt  
Seri o us ness  
Seri o us ( S A E)  
A n y u nt o war d me dical occ urre nce t hat at a n y d ose:  
–  
Res ults i n deat h, or  
–  
Is life-t hreate ni n g, or 
–  
Re q uires s u bject h os pitalizati o n or pr ol o n gati o n of e xisti n g 
h os pitalizati o n, or  
–  
Res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y, or  
–  
Is a c o n ge nital a n o mal y / birt h defect 
–  
Is me dicall y i m p orta nt (see n ote 3) 
 
 
N o n -seri o us 
A n y ot her a d verse e ve nt  
 
N otes  
1. T he ter m "life-t hr eate ni n g" i n t he defi niti o n of S A E refers t o a n e ve nt i n w hic h t he patie nt is 
at i m me diate ris k of deat h at t he ti me of t he e ve nt; it d oes n ot refer t o a n e ve nt, w hic h 
h y p ot hetic all y mi g ht ha v e ca use d d eat h if it was m ore se vere or ha d c o nti n ue d u ntreate d. T h e 
ter m "life-t hr eate ni n g" d oes n ot i m pl y a p ossi ble f ut ure c o urse w hic h mi g ht or mi g ht n ot ha ve 
ha p pe ne d, b ut was pre ve nte d d ue t o a d e q uate p h ysicia n's acti o n. F or e x a m ple, a si m ple b acteri al 
w o u n d i nfecti o n ca n p ote ntiall y lea d t o ga n gre ne, se psis, a n d e v e nt uall y d eat h; w hile se psis is 
us uall y re gar de d as a S A E beca use of k n o w n hi g h m ortalit y, t he pri mar y w o u n d i nfecti o n itself 
is us uall y n ot re gar de d as a S A E. I n a nal o g y, a n e wl y dia g n ose d mali g na nt disease is us uall y 
re gar de d as a S A E b eca use mali g na nt dise ases us uall y ha v e a hi g h m ortalit y rat e a n d are 
t heref ore life-t hreate ni n g. 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 7 7 /1 3 6  
 
 
2.  T o e ns ure n o c o nf usi o n or mis u n dersta n di n g of t he differe nce bet w ee n t he ter ms "seri o us" 
a n d "se v ere", w hic h are n ot s y n o n y m o us, t he f oll o wi n g clarificati o n is pr o vi de d: t he ter m 
"se v ere" is ofte n use d t o descri be t he i nte nsit y (se verit y) of a s pecific e ve nt (as i n mil d, 
m o derate, or se v ere m y o car dial i nfarcti o n); t he e v e nt itself h o we ver ma y b e of relati vel y mi n or 
me dical si g nifica n ce (s u c h as se vere hea d ac h e). T his is n ot t he sa me as "seri o us," w hic h is 
base d o n patie nt/e v e nt o utc o me or acti o n criteria us uall y ass ociate d wit h e ve nts t hat p ose a 
t hreat t o t he patie nt's life or f u ncti o ni n g. 
3. I n a d diti o n, e ve nts t hat ma y n ot m eet t he criteria i n dicate d a b o v e, b ut w hi c h t he I n v esti gat or 
fi n ds ver y u n us ual a n d/ or p ote ntiall y seri o us, will be re p orte d as S A E. I n dee d, me dical a n d 
scie ntific j u d g me nts s h o ul d be e x ercise d i n deci di n g w het her re p orti n g is a p pr o priate i n ot her 
sit uati o ns, s uc h as i m p orta nt me dical e ve nts t hat ma y n ot be i m me diatel y life-t hreate ni n g or 
res ult i n deat h or h os pitalizati o n b ut ma y je o par dize t he patie nt or m a y re q uire i nter ve nti o n t o 
pre ve nt o n e of t he ot her o utc o mes liste d i n t he defi niti o n a b o ve. T h ese e ve nts s h o ul d als o 
us uall y be c o nsi dere d as S A Es. E x a m ples of s uc h e ve nts i ncl u de i nte nsi ve treat me nt i n t h e 
E mer ge nc y R o o m or at h o me f or aller gic br o nc h os pas m, bl o o d d ys crasias or c o n v ulsi o ns t hat 
d o n ot res ults i n h os pitalizati o n, a n d/ or de vel o p me nt of dr u g d e pe n d e nc y or dr u g a b use. 
4. S o me me dical e v e nts ma y j e o par dise t he s u bject or ma y re q uir e a n i nter ve nti o n t o pre v e nt 
o ne of t he c haracteristics/c o nse q ue nces descri be d i n t he S A E defi niti o n ( Secti o n 8. 1). S uc h 
e ve nts (referre d as “i m p orta nt me dical e ve nts”) s h o ul d als o be c o nsi dere d as “seri o us ” i n 
acc or da nce wit h t he defi niti o n. 
5. Electi ve pr oce d ures re q uiri n g h os pitalizati o n will n ot be c o nsi dere d as S A Es if t he y were 
pre - pla n n e d pri or t o si g ni n g I C F (as d oc u me nte d i n s o urce d o c u me nts). 
H o we v er, 
c o m plicati o ns or ot her e v e nts t hat ma y o cc ur d uri n g h os pitalizati o n will be c o nsi dere d as A Es 
or S A Es a n d will be ca pt ure d acc or di n gl y. 
8. 1. 2  C a us al rel ati o ns hi p wit h t he I nvesti g ati o n al Me dici n al Pr o d uct  
Ca usalit y s hall be det er mi ne d acc or di n g t o t he d efi niti o n of a n a d verse reacti o n ( Secti o n 8 . 1). 
All a d verse e ve nts j u d ge d b y eit her t he I n v esti gat or or t he S p o ns or as h a vi n g a reas o na ble 
s us pecte d ca us al relati o ns hi p t o a n i n vesti gati o nal me dici nal pr o d uct q ualif y as a d v erse 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 7 8 /1 3 6  
 
 
reacti o ns. T he ca us alit y assess me nt gi ve n b y t he I n vesti gat or s h o ul d n ot be d o w n gra de d b y t he 
S p o ns or. If t h e S p o ns or disa grees wit h t he I n vesti gat or’s ca usalit y assess me nt, b ot h, t he o pi ni o n 
of t he I n vesti gat or a n d t he S p o ns or s h o ul d be pr o vi de d wit h t he re p ort. 
Deter mi nati o n of t he ca usal relati o ns hi p bet wee n a n A E/ S A E a n d t he trial me dicati o n m ust be 
ma de b y t he I n v esti gat or b y a ns w eri n g t he q uesti o n: "Is t he ca usal relati o ns hi p bet wee n t he 
me dici nal pr o d uct a n d t his A E/ S A E reas o na bl y p ossi ble”? o n t he f oll o wi n g basis 
 
Ye s: Certai n  
 
Li kel y  
 
U nli kel y 
 
N o: N ot relate d 
 
U n k n o w n/ N ot assessa bl e 
In d ee d, ca usalit y assess me nt is a cli nical decisi o n base d o n all a vaila ble i nf or mati o n at t he ti me 
of a n d after t he o cc urre nce of t he e ve nt. T he fact ors w hic h ma y be c o nsi dere d w he n e val u ati n g 
t he ca usal r elati o ns hi p of a n A E/ S A E t o t he I M P a d mi nistrati o n i ncl u de t he f oll o wi n gs: 
 
U n derl yi n g, c o nc o mita nt, a n d/ or i nterc urre nt disease(s): eac h re p ort s h o ul d be 
e val uate d i n t he c o nte xt of t he nat ural hist or y a n d c o urse of t he diseas e bei n g treate d 
a n d a n y ot her dise ases t he patie nt ma y ha ve ha d pri or t o, or de vel o pe d d uri n g t he 
c o urse of t he st u d y 
 
C o nc o mita nt me dicati o n or treat me nt: ot her dr u gs t he patie nt is ta ki n g or treat me nt 
t he patie nt is recei vi n g at t he ti me of t he e ve nt s h o ul d be e x a mi ne d t o deter mi ne 
w het her a n y of t he m ma y be rec o g nize d t o ca use t he e ve nt i n q uesti o n 
 
K n o w n res p o nse p atter n f or t his class of dr u g 
 
T he p har mac ol o g y a n d p har mac o ki netic of t he I M P: a bs or pti o n, distri b uti o n, 
meta b olis m, a n d e x creti o n of t he I M P or ot her m e dicati o ns t he patie nt is recei vi n g 
c o u ple d wit h t he p har mac o d y n a mic res p o nses s h o ul d be c o nsi dere d w he n e val uati n g 
a n e ve nt 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 7 9 /1 3 6  
 
 
8. 1. 3  A dverse Dr u g R e acti o n ( A D R) 
A d verse Dr u g Reacti o n ( A D R): a n y u nt o war d a n d u ni nte n de d res p o ns es t o a n i n vesti gati o nal 
me dici nal pr o d uct relate d t o a n y d ose a d mi nistere d ( ha vi n g a reas o n a ble ca usal relati o ns hi p t o 
t he pr o d uct, t he ter m “reas o na bl e ca usal relati o ns hi p” mea ni n g t hat t here is e vi de nce or 
ar g u me nts t o s u g gest a ca usal relati o ns hi p). 
U ne x pecte d A D R: a n a d verse reacti o n w h ose n at ure, se verit y, s pecificit y, or o utc o me is n ot 
c o nsiste nt wit h t he a p plica ble pr o d uct i nf or m ati o n (e. g., I n vesti gat or’s Br oc h ure) 
8. 1. 4  Seri o us A dverse Re acti o n ( S A R) 
Seri o us A d verse Reacti o n ( S A R): a n y u nt o w ar d a n d u ni nte n de d res p o nses t o a n i n vesti gati o nal 
me dici nal pr o d uct relate d t o a n y d ose a d mi nistere d ( ha vi n g a reas o n a ble ca usal relati o ns hi p t o 
t he pr o d uct, t he ter m “reas o na bl e ca usal relati o ns hi p” mea ni n g t hat t here is e vi de nce or 
ar g u me nts t o s u g gest a ca usal relati o ns hi p), a n d t hat res ults i n deat h, is life-t hreate ni n g, re q uires 
patie nt h os pitaliz ati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n, res ults i n persiste nt or 
si g nifica nt disa bilit y or i nca pacit y, or is a c o n ge nital a n o mal y or birt h d efect or is me di call y 
i m p orta nt. 
8. 1. 5  Seri o us A dverse S afety/ Q u ality Eve nt ( S A S Q E) 
A n A d vers e Safet y/ Q ualit y E ve nt ( S A S Q E) is a n y a d verse e ve nt r elate d t o a n y o p erati o n d o ne 
o n t he c ollecte d h u ma n bi ol o gical materi al u n der t he res p o nsi bilit y of t he I nter me diar y 
Str uct ure (i.e., direct tra ns p ort a n d distri b uti o n of t he h u ma n bi ol o gical material fr o m t he 
har vesti n g site t o t he Pr o d ucti o n/ Tiss ue Esta blis h me nt of B o n e T hera pe utics S. A.) t hat ma y 
ca use deat h, be life-t hr eate ni n g, ge n erat e disa bilit y or i nca pacit y t o w or k t o t he patie nt, or t hat 
ma y ca use m or bi dit y. 
8. 2  
Re p orti n g of A d verse E ve nts 
T he occ urre nce of A E/ S A E ( dr u g- or pr oce d ure- or st u d y-relat e d) will be assesse d b y n o n-
directi ve q uesti o ni n g of t he s u bject si nce t h e be gi n ni n g of t he st u d y at t he scree ni n g visit, a n d 
eac h f oll o w- u p visit searc hi n g f or a n y c ha n ges i n healt h stat us (e. g., " Ha v e a n y A d verse e ve nts 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 8 0 /1 3 6  
 
 
or Seri o us a d vers e e v e nts occ urre d si nce t he last visit?"). F urt h er m ore, A E/ S A E v ol u nteere d b y 
t he patie nt d uri n g or bet wee n t he f oll o w- u p visits, or detecte d t hr o u g h o bser vati o n, p h ysic al 
e x a mi nati o n (i ncl u di n g b o d y mass i n de x a n d vital si g ns), la b orat or y testi n g, or ot her cli nical 
pr oce d ures d uri n g t he o bser vati o n peri o d will be d oc u me nte d. Patie nts will be i nstr ucte d t hat 
t he y m ust i m me diatel y re p ort a n y a d verse e ve nts, s u bjecti ve c o m plai nts, or o bjecti ve c ha n ges 
i n t heir well- bei n g t o t he I n v esti gat or or site pers o n nel, re gar dless of t he percei ve d relati o ns hi p 
bet wee n t he e ve nt a n d t h e test pr o d uct. 
If it is deter mi ne d t hat a n A E/ S A E has occ urre d, t he I n v esti gat or s h o ul d o btai n all t he 
i nf or mati o n re q uir e d t o c o m plete t he c orres p o n di n g A E or S A E F or m of t h e C R F, a n d esta blis h 
p ote ntial ca usalit y relati o ns hi p wit h t he pr o d uct or t he s ur gi cal pr oce d ure. 
8. 2. 1  O bserv ati o n peri o d f or t he occ urre nce of A Es a n d S A Es 
T a ble 9 : O bserv ati o n Peri o d f or t he Occ urre nce of A Es a n d S A Es 
Start of St u d y A E/ S A E O bser vati o n Peri o d  
At I C F si g nat ure  
E n d of St u d y A E/ S A E O bser vati o n Peri o d  
6 m o nt hs after I m pla ntati o n 
 
 
 
 
 
 
 
 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 8 1 /1 3 6  
 
 
8. 2. 2  S u m m ary of P ossi ble Risks rel ate d t o t he Pr oce d ures 
T a ble 1 0 : S u m m ary of P ossi ble Risks rel ate d t o t he Pr oce d ures 
 
A E  
S A E ( F at al a n d N o n -F at al)  
A L L O B ®  I m pla ntati o n  
S ur gery  
Pai n at t he i m pla ntati o n site  
L ocal hae mat o ma  
I nfecti o us c o m plicati o ns 
S ur gery  
Hae m orr ha ge  
Se psis  
S h oc k  
I nfecti o us c o m plicati o ns 
 
A n aest hesi a  
Hae mat o ma  
Irritati o n 
I nfecti o n 
Li p ot h y mia   
Paraest hesia   
Tra nsie nt h y p ote nsi o n  
Na usea a n d v o miti n g  
 
A n aest hesi a  
Aller g y  
I nfecti o n 
S yste mic t o xicit y 
Res pirat or y arrest  
Car diac c o m plicati o ns  
M y ocar dial i nfarcti o n  
Car di o p ul m o nar y arrest  
Ve ntric ular tac h ycar dia  
Ne ur ol o gical c o m plicati o ns  
Str o ke  
P ul m o nar y c o m plicati o ns  
I n halati o n p ne u m o nia 
P ul m o nar y e m b olis m  
A na p h ylactic s h oc k  
Bl o o d Sa m pli n g  
Pai n  at t he sa m pli n g site  
L ocal hae mat o ma  
S u perficial vei n t hr o m b osis  
Tra nsie nt h y p ote nsi o n  
S y nc o pe  
 
 
 
 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 8 2 /1 3 6  
 
 
8. 2. 3  S u m m ary of A dvers e Dr u g Re acti o ns a n d P ossi ble Risks rel ate d t o t he Pr o d uct a n d/ or 
t o t he Pr oce d ures 
T here is n o re p orte d A D R wit h A L L O B ®  at t his sta ge. 
H o we ver, P R E O B ® , a n a ut ol o g o us oste o blastic cell pr o d uct, has bee n a d mi nistere d i n h u ma ns 
i n p hase I/IIa a n d II b st u dies. A s u m mar y of o bser ve d a d verse e v e nts p ossi bl y rel ate d t o st u d y 
treat me nt (i.e., P R E O B ® a n d/ or t he i m pla ntati o n pr oce d ure) is liste d i n Ta ble 1 1. 
T a ble  1 1: S u m m ary of O bserve d A dvers e E ve nts ( A E) a n d Seri o us A d verse Eve nts ( S A E) 
p ossi bly rel ate d t o St u dy Tre at me nt (i. e., P R E O B ® a n d/ or t he I m pl a nt ati o n Pr oce d ure) 
N o n -Seri o us A E  
S A E ( N o n -F at al)  
T ot al  
P yre xia  
Pai n  
        P ai n ( ge ner al dis or ders)  
        Pr oce d ur al P ai n  
       M usc ul oskelet al P ai n  
       Art hr al gi a  
       P ai n i n extre mity  
 
Uri nar y rete nti o n  
P ost -pr oce d ural hae mat o ma  
P ost -pr oce d ural blee di n g  
2 7. 0 %  
7. 9 %  
1 7. 5 %  
6. 3 %  
4. 8 %  
3. 2 %  
1. 6 %  
1. 6 %  
1. 6 %  
1. 6 %  
1. 6 %  
T ot al  
S yste mic i nfla m mat or y  
res p o nse s y n dr o me 
 
P a nc yt o pe nia * *  
P yre xia * *  
Altere d stat us of 
c o nsci o us ness * *  
H y p ote nsi o n * *  
3. 2 %  
1. 6 %  
 
 
1. 6 %  
1. 6 %  
1. 6 %  
1. 6 %  
* A Es a n d S A Es were li mite d t o T E A Es a n d S T E A Es a n d re p orte d per Preferre d Ter m ( P T) ( Me d D R A c o di n g), 
al o n g wit h t heir fre q ue n cy of occ urre n ce i n s u bjects. S u bjects were c o u nte d o nce f or e ac h P T. A n A E/ S A E w as 
c o nsi dere d as tre at me nt-e mer ge nt if it occ urre d o n or after t he d ate of t he I M P i m pl a nt ati o n. I n c ase of missi n g 
st art d ate, t he A E w as c o nsi dere d as tre at me nt-e mer ge nt. ** 4 S A Es were re p orte d i n t he s a me p atie nt. 
 
8. 2. 4  Assess me nt of t he S afety M o nit ori n g C o m mittee 
A re vie w of all t he re p ort e d S A E p ote ntiall y relate d t o t he I M P, a n d es peciall y t h ose relate d t o 
i m m u n ol o gical reacti o ns (se vere A E S Cs), will be d o ne b y t he S afet y M o nit ori n g C o m mittee 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 8 3 /1 3 6  
 
 
( S M C) after t he i ncl usi o n of eac h bl oc k of 4 p atie nts u ntil t he i ncl usi o n of t he first 1 6 patie nts. 
T his re vie w will c o ver all S A E p ote ntiall y relat e d t o t he I M P fr o m t he d a y of treat me nt t o t he 
first 1 5 da ys of f oll o w- u p f or t he first bl oc k of 4 p atie nts a n d fr o m t he da y of treat me nt t o t he 
e n d of h os pitaliz ati o n peri o d f or t he sec o n d, t hir d a n d f o urt h bl oc ks of 4 p atie nts.  
T he  mai n c o ncl usi o ns a n d decisi o ns will be c o m m u nicate d t o all I n v esti gat ors 4 8 h o urs after 
eac h meeti n g. A re p ort will s u bse q ue ntl y be pre pare d a n d its s u m mar y s u b mitte d t o t he I E Cs 
a n d C As. T he S M C will be c o m p ose d b y a Safet y C o ns ulta nt a n d o ne me dicall y q ualifie d 
me m ber of t he S p o ns or. T his c o m mittee will deci de w het h er t he st u d y ca n be c o nti n ue d as 
pla n ne d. If t he d ecisi o n is t o st o p or m o dif y t he st u d y, it will be c o m m u nicate d b y t he S p o ns or 
t o t he I n v esti gat ors of all ce ntres wit hi n 4 8 h o urs, t he I E Cs a n d C As. 
Af ter t he re vie w of t he f o urt h bl oc k of 4 patie nts, t he recr uit me nt will c o nti n ue ( u p t o ma xi m u m 
3 2 treate d patie nts) a n d n o m ore safet y c o m mittee will be perf or me d f or all t he s u bse q ue nt 
treate d p atie nts. T he s afet y of all patie nts will be m o nit ore d re g ularl y as d escri be d i n t h e st u d y 
pr ot oc ol a n d d oc u me nte d as a p pr o priat e.   
8. 3  
Re p orti n g of S afet y Iss ues 
I n t he e v e nt of a n A E/ S A E, t he I n v esti gat or will i m me diatel y i nitiate a p pr o priate t hera p y a n d 
ma na ge me nt acc or di n g t o her/ his me dical j u d g m e nt a n d will deci de w het her t o wit h dra w t he 
s u bject fr o m t he st u d y. 
T he s u bject m ust be f oll o we d u p b y a d diti o nal e x a mi nati o ns acc or di n g t o t h e me dical j u d g me nt 
of t he I n vesti gat or, u ntil t he A E/ S A E a n d/ or a b n or mal c o n diti o n is res ol ve d or t he I n vesti gat or 
dee ms f urt her o bser vati o ns or e x a mi nati o ns are n o l o n ger m e dicall y i n dicate d. 
8. 3. 1  
S afety D at a N otific ati o n, Re p orti n g, a n d M o nit ori n g 
8. 3. 1. 1  Re p orti n g of A dverse Eve nts ( A Es) 
All A Es will be rec or de d o n t he a p pr o priate a n d c orres p o n di n g A E F or m of t he C R F b y t he 
I n v esti gat or. All A Es m ust be re p orte d w het her or n ot c o nsi dere d ca usall y relate d t o I M P. F or 
e ver y A E, t he I n vesti gat or will pr o vi de a n assess m e nt of t he se verit y a n d ca usal relati o ns hi p t o 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 8 4 /1 3 6  
 
 
t he I M P a n d d o c u me nt all acti o ns ta ke n wit h re gar d t o t h e I M P, a n d a n y ot her treat me nt 
m o dalities f or t he A E. Treat me nt of a n y a d v erse e v e nt is at t he s ole discreti o n of t he I n v esti gat or 
a n d acc or di n g t o c urre nt g o o d me dical practice. A n y me dicati o n a d mi nistere d f or t he treat me nt 
of a n A E s h o ul d be rec or de d i n t he patie nt’s C R F. 
If t he o utc o me of a n A E is n ot a vaila ble at t he ti me of t he i nitial re p ort or at st u d y e xit 
( pre mat ure or n ot), f oll o w- u p will pr ocee d u ntil o utc o me is k n o w n. All c ollecte d data will be 
rec or de d i n s o urce d oc u me nts. 
8. 3. 1. 2  N otific ati o n a n d re p orti n g of Seri o us A dverse Eve nts ( S A Es)  
E x pe dite d Re p orts – I n divi d u al C ase S afety Re p orts 
In t he e v e nt of a n y S A E relate d or n ot t o trial pr o ce d ure or treat me nt a n d/ or a n y ot her e ve nt or 
rele va nt i nf or mati o n w hic h re q uire a re-e val uati o n of t he be nefit-ris k rati o, occ urri n g fr o m 
Scree ni n g Visit u p t o t he e n d of t he p ost-st u d y o pe n f oll o w- u p peri o d ( 2 4 m o nt hs after t he e n d 
of t he st u d y), t he Pri n ci pal I n vesti gat or will wit hi n 2 4 h o urs of e ve nt occ urre nce o r 
a w are ness :  
1.   N otif y t he St u d y Safet y Officer ( S S O) b y p h o ne: Safet y E ve nts P h o ne N u m ber, 2 4/ 7 
c o ver: 
  
2.  R ec or d it o n t he c orres p o n di n g C R F F or m ( S A E f or m) a n d se n d it b y fa x 
 
 or per e m ail 
 t o t he S S O 
w h o will i m me diatel y i nf or m t he S p o ns or of t he s afet y e v e nt occ urre n ce 
T he C R F will be c o m plet e d ( b y t he PI) t hereafter as s o o n as p ossi ble.  
B riefl y, t he S A E F or m (a n d t he relate d F oll o w- u p F or ms if nee d e d) will i ncl u de t he f oll o wi n g 
i nf or mati o n a n d differe ntiate d assess me nt:  
 S u bject i de ntificati o n:  Patie nt I d e ntificati o n N u m ber, a ge, a n d se x 
 S A E dia g n osis a n d d escri pti o n, start a n d e n d dates, c o nc o mita nt dr u gs a n d hist or y 
 O utc o me (rec o v er y wit h or wit h o ut se q uelae, u nc ha n ge d, i m pr o ve m e nt, w orse ni n g, deat h, 
or ot her) a n d acti o n(s) ta ke n ( n o ne, s u bject disc o nti n uati o n a n d wit h dra wal fr o m t he st u d y, 
c ha n ge i n c o nc o mita nt me dicati o n(s) a n d/ or ne w me dicati o n(s), ot her treat me nt(s) a n d/ or 
t hera pe utic pr oce d ure(s) i.e., i n vasi ve pr oce d ures, s ur ger y, or u n k n o w n) 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 8 5 /1 3 6  
 
 
 Criteria f or seri o us ness ( deat h, life-t hreate ni n g, persiste nt or si g nifica nt disa bilit y or 
i nca pacit y, ne w or pr ol o n ge d h os pitalizati o n, c o n ge nital a b n or malit y or birt h defect, 
i m p orta nt me dical e ve nt), se verit y ( mil d, m o derate, se vere), a n d fre q u e nc y (i nter mitte nt, 
c o nti n u o us, or ot her) 
 Ca usal relati o ns hi p wit h t he I M P (assess me nt of dr u g-e ve nt ca usal relati o ns hi p a n d 
c o nsiste nc y wit h a p plica ble pr o d uct i nf or mati o n, e. g., t he I n v esti gat or’s Br oc h ure a n d 
e val uate d as certai n, li kel y, u nli kel y, u nrel ate d, u n k n o w n or i nassessa ble) 
 Ca usal relati o ns hi p wit h t he trial pr oce d ures, i ncl u di n g bl o o d sa m pli n g a n d t he pr o d uct 
i m pla ntati o n (i m pla ntati o n , s ur ger y, a n aest hesia) 
 Relati o ns hi p wit h t he st u d y disease a n d/ or u n derl yi n g, c o nc o mita nt, a n d/ or i nterc urre nt 
diseases, rel ati o ns hi p wit h c o nc o mita nt me dicati o n or treat me nt, a n d/ or dr u g i nteracti o ns 
 A n y ot her rel e va nt i nf or mati o n 
Base d o n data a n d i nf or mati o n a vaila ble i n b ot h t he S A E F or m a n d i n t he I n vesti gati o n a n d 
C o ncl usi o n Re p ort (see bel o w) (a n d a d diti o nal q ueries, if n ee d e d), t he S S O will n otif y t he 
occ urre nce of S U S A R, S A R, a n d/ or S A E relate d t o t he tri al pr oce d ures t o b ot h E u dra vi gila nce 
data base a n d E Cs (all Me m ber States c o n cer ne d), a n d t o all c o ncer ne d PIs a n d S p o ns or i n 
a gree m e nt wit h all a p plica ble nati o nal le gislati o n. 
T his n otificati o n will be se nt b y t he S S O t o t he E Cs a n d E u dra vi gila nce data bas e, w hile bli n di n g 
will be preser ve d f or b ot h t he PIs a n d S p o ns or. 
S U S A Rs t hat are fatal or life-t hreat e ni n g are rec or de d a n d re p ort e d wit hi n 7 da ys of a ware n ess. 
Ot her S U S A Rs are rec or de d a n d re p orte d wit hi n 1 5 da ys of a ware n ess.  
8. 3. 1. 3  N otific ati o n a n d Re p orti n g of Seri o us A dverse Re acti o n rel ate d t o t he H u m a n 
Bi ol o gic al M ateri al 
I n t he cas e a re p orte d S A E (i ncl u di n g S U S A R a n d S A R) is i de ntifie d b y t h e S p o ns or as bei n g 
p ote ntiall y rel ate d t o t he use of h u ma n bi ol o gical material f or t he ma n ufact uri n g of A L L O B ® , 
t he Ma na gi n g P h ysicia n ( M P) of t he I nter me diar y Str uct ure will be i m me di atel y i nf or me d. T he 
Ma na gi n g P h ysi cia n will i nitiall y re p ort t his S A E p ote ntiall y relate d t o t he use of H u ma n 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 8 6 /1 3 6  
 
 
Bi ol o gic al Material t o t he Bel gia n C A ( Bi o vi gila n ce) a n d t he Tiss ue Ba n k wit h 2 4 h o urs of t he 
eve nt occ urre nce or a ware ness i n li ne wit h t he Bel gia n la w of t he Dece m ber 1 9, 2 0 0 8 o n t he 
use d h u ma n bi ol o gic al material a n d a p plica ble R o yal D ecree. 
T he n, base d o n t he i nf or mati o n a vaila ble i n t he C R F S A E F or m, t he Ma na gi n g P h ysici a n will 
start o n i n vesti gati n g t o c o nfir m if t he safet y e v e nt is relate d t o t he pr oc ure me nt, c ollecti o n, 
testi n g, pr ocessi n g, st or a ge, la b elli n g a n d pac k a gi n g, deli ver y, tra ns p ort, a n d/ or distri b uti o n of 
t he tiss ues a n d cells, a n d/ or t o t he q ualit y a n d safet y of t he Bi ol o gi cal 
Material. T he 
I n v esti gati o n a n d C o ncl usi o n Re p ort ha ve t o b e s u b mitte d t o t he Bel gi u m C A of Bi o vi gila nce 
a n d t he Tiss ue Ba n k wit hi n 5 da ys of a ware ness b y t he M P. I n parallel, i n vesti gati n g c o ncl usi o n 
re p orts are c o m m u nicate d b y t h e M P t o t he S S O ( w h o will n otif y I n vesti gat or, C R A, a n d 
S p o ns or) a n d if a p plica ble c o m plete t he i nf or mati o n t hat has bee n c o m m u nicate d via t he 
E u dra vi gila nce s yste m. 
If a seri o us safet y iss ue is i de ntifie d, eit her u p o n recei pt of a n i n di vi d ual case re p ort or u p o n 
re vie w of a g gre gate d ata, t he S p o ns or will iss ue a c o m m u nicati o n t o all Pri nci pal I n vesti gat ors 
as s o o n as p ossi ble. A safet y iss ue t hat i m pacts u p o n t he c o urse of t he trial, i ncl u di n g s us p e nsi o n 
of t he tri al, safet y-relate d a me n d me nts t o t he St u d y Pr ot o c ol, c h a n ge or u p date of S u bject 
I nf or mati o n S heet a n d I nf or me d C o nse nt F or m or I n vesti gat or’s Br oc h ure, will als o be re p ort e d 
t o t he Pri nci pal I n v esti gat ors (after pri or s u b missi o n a n d a p pr o val b y t he C As a n d E Cs). 
8. 3. 2  
A n n u al S afety Re p orts – Devel o p m e nt S afety U p d ate re p orts ( D S U Rs) 
I n a d diti o n t o t he e x pe dite d re p orti n g, t he S S O will pr o vi de a n n ual de vel o p me nt safet y u p d ate 
re p orts ( D S U R) t o C As, E Cs, a n d S p o ns or, i ncl u di n g all S U S A Rs, S A Rs, a n d/ or S A Es relate d 
t o t he trial pr oce d ures, t o get h er wit h a n o ver vi e w of all ot her S A Es, A Es, a n d S A R t hat ha ve 
occ urre d d uri n g t he re p orti n g peri o d (i n all sites a n d c o u ntries).  
T he D S U R s h o ul d b e s u b mitte d n o later t ha n 6 0 cale n dar d a ys fr o m t he D S U R data l o c k p oi nt; 
base d o n t he date of t he S p o ns or’s first a ut h orisati o n t o c o n d uct t he cli nical st u d y i n a n y c o u ntr y 
i n li ne wit h t he I C H T o pi c E 2 F. 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 8 7 /1 3 6  
 
 
8. 3. 3  
S afety D at a M o nit ori n g 
T he occ urre nce of A Es, S A Es, a n d S A R will be m o nit ore d d uri n g t he w h ol e st u d y peri o d o n a n 
o n- g oi n g b asis b y t he St u d y Safet y Offi cer, t he Ma na gi n g P h ysicia n of t he I nter me diar y 
S tr uct ure, a n d t he S p o ns or. T he S p o ns or will als o recei ve fr o m t he St u d y S afet y Officer a 
re g ular d etaile d u p date d listi n g of all A Es, S A Es, a n d S A R. 
8. 3. 4  
D at a S afety M o nit ori n g B o ar d 
A Data Safet y M o nit ori n g B oar d ( D S M B ) will be esta blis he d t o assess t he safet y data a n d t he 
effic ac y e n d p oi nts w h e n 6- m o nt h p ost treat me nt res ults f or t he first 1 6 ass essa ble patie nts are 
availa ble. T h e safet y a n d effic ac y data of t he s u p ple me ntar y p atie nts e nr oll e d aft er t he first 1 6  
treate d patie nts will be als o a nal ys e d. 
T his b oar d will rec o m me n d t o t he S p o ns or w het her t o c o nti n ue, m o dif y or st o p t he trial base d 
o n: 
- 
t he effic ac y d ata of t he first 1 6 assessa ble patie nts ( pri mar y e n d p oi nts at M o nt h 6) 
- 
all t he a vaila ble safet y data of all t he treat e d patie nts. 
A g ui da nce d oc u me nt ( D S M B  c h art) will b e est a blis he d t o e ns ure pr o per m o nit ori n g of t he 
data. 
8. 4  
M a n a ge me nt of S afet y Iss ue 
8. 4. 1  
Pr oce d ure i n c as e of Pre g n a ncy 
W o me n i ncl u de d i n t he st u d y m ust be p ost- me n o pa usal ( defi n e d as at least 1 2 m o nt hs p ost 
cessati o n of me ns es), s ur gic all y sterile or, f or w o me n wit h c hil d beari n g p ote ntial, usi n g a 
relia ble met h o d of c o ntr ace pti o n f or at least 6 wee ks pri or t o st u d y e ntr y ( Visit # 1) a n d d uri n g 
t he w h ole st u d y p eri o d. W o me n wit h c hil d beari n g p ote nti al will f urt her u n der g o a pre g n a nc y 
test at all st u d y visits, a n d at t he last visit t o t he cli nic i n case of pre mat ure disc o nti n uati o n. 
If a fe male patie nt bec o mes pre g na nt d uri n g t he trial, after t he tr eat me nt wit h A L L O B® , t he 
patie nt m ust i m me diatel y i nf or m t he i n vesti gat or. T hese patie nts will n ot be e x cl u de d a n d will 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 8 8 /1 3 6  
 
 
be f oll o we d- u p as f oresee n b y t he Cli nical St u d y Pr ot oc ol f or safet y, cli nical a n d la b orat or y 
para meters b ut n ot f or ra di ol o gic al e x a mi nati o ns ( C hest X- Ra y, C T -sca n a n d X-ra y of t h e 
fract ur e). 
A n y pre g na n c y will be h a n dle d as a n S A E re gar dl ess t he relati o ns hi p bet w ee n t he I M P a n d t he 
e ve nt. A n y c o m plic ati o n arisi n g d uri n g pre g n a nc y will be rec or de d as a n A E a n d will c o nstit ute 
a S A E if it f ulfils a n y of t he s pecifie d criteria f or a S A E. 
At t he e n d of t h e pre g n a nc y, w het her t hat is f ull-ter m or pre mat ure, i nf or mati o n o n t he stat us 
of t he m ot her a n d c hil d will be f or war de d t o St u d y Safet y Officer. 
If t he o utc o me of pre g n a nc y is: 
 Electi ve a b orti o ns wit h o ut c o m plicati o ns, t he y will be rec or de d, d oc u me nte d a n d 
re p orte d t o t he St u d y Safet y Officer a n d C R O, b ut t he y s h o ul d n ot be ha n dl e d as A Es; 
 A n y s p o nta n e o us 
miscarria ges or a b orti o ns f or 
me dical reas o ns, or c o n ge nital 
a b n or malities or birt h defects, will be rec or de d, d oc u me nte d, re p ort e d, a n d ha n dle d as 
S A Es a n d f ull details will be re q ueste d. 
8. 4. 2  
E mer ge ncy Pr oce d ures 
I n case of S A E or a n y ot her safet y e v e nt or me dical c o ncer n, t he f oll o wi n g c o ntact will be 
a vaila ble ( 2 4/ 7 c o v er) f or c o nti n u o us s u p p ort a n d assista nce ( St u d y Safet y Officer): 
E m er ge ncy a n d S afety Eve nts P h o ne N u m ber: 
 
T he I n v esti gat or is res p o nsi ble f or e ns uri n g t hat pr oce d ures a n d e x pertise are a vaila ble t o c o pe 
wit h me dical e mer ge nci es d uri n g t he st u d y. Eac h patie nt will recei ve a Patie nt St u d y Car d wit h 
t he na me a n d s ur na me a n d t he Patie nt I d e ntificati o n N u m ber, Title a n d E u dra C T N u m ber of 
t he st u d y, t y pe of treat me nt recei ve d ( A d va n ce d T hera p y Me dici nal Pr o d uct (cell pr o d uct), a n d 
Na me of t he S p o ns or. T his car d will als o rec or d t he na me, s ur na me, f ull a d dress, a n d p h o ne 
n u m ber of t he I n vesti gat or, t he a d dress a n d p h o ne n u m ber of t he E mer ge n c y R o o m of t he 
I n v esti gati n g Site, a n d t he E mer ge n c y a n d Safet y E ve nts P h o ne N u m ber ( 2 4/ 7 c o ver). T he ai m 
of t his car d is t o i nf or m a n y p h ysicia n ha vi n g t o deal wit h a patie nt i n a n e mer ge n c y sit uati o n 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 8 9 /1 3 6  
 
 
t hat t he patie nt is i n a cli nical trial a n d t hat he/s h e ca n c o ntact t he trial I n vesti gat or f or m ore 
rele va nt i nf or m ati o n. Patie nts will be i nstr ucte d t o carr y t his car d ar o u n d at a n y ti me d uri n g t h e 
st u d y. 
F or a n y ot her q u esti o ns or st u d y i nf or mati o n, t he f oll o wi n g c o ntact will be a vaila ble ( office 
h o urs 0 8: 0 0 t o 1 7: 0 0) f or c o nti n u o us s u p p ort a n d assista nce: 
H otli ne - P h o ne N u m ber: 
 
H ot li ne - E- m ail: 
 
8. 5  
L o n g- Ter m P h a r m ac o vi gil a nce S yste m  
Fi nall y, d uri n g t he c o urs e of t h e trial, t he S p o ns or pla ns t o d esi g n, de vel o p, a n d s u b mit t o t he 
rele va nt C As, a detaile d strate g y f or l o n g-ter m patie nt f oll o w- u p, u n der P har mac o vi gila nce 
P la n i n li ne wit h t he I C H T o pic E 2 E. 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 9 0 /1 3 6  
 
 
9  
P R E M A T U R E R E M O V A L F R O M T H E S T U D Y 
9. 1  
Re as o ns f or E arl y Disc o nti n u ati o n 
N otificati o n of p atie nt st u d y disc o nti n uati o n (a n d reas o ns f or disc o nti n uati o n) will be 
c o m m u nicate d t o t he S p o ns or b y t he I n vesti gat or as s o o n as p ossi ble. T he I n vesti gat or will 
d oc u me nt t he circ u msta nces f or pre mat ure disc o nti n uati o n i n t he s u bject's Case Re p ort F or m 
as f oll o ws: 
 V i ol ati o n of eli gi bility criteri a 
Patie nts will be wit h dra w n if i nc orrectl y i n cl u de d (i.e., n ot i n c o m plia nce wit h o ne or m ore 
eli gi bilit y criteria). T h e I n vesti gat or m a y c o ntact t he m o nit or i n or der t o disc uss t he p ote ntial 
c o nti n uati o n of wr o n gl y i n cl u de d patie nts if j u d ge d t hat is i n t he i nterest of t he patie nt t o 
c o nti n ue t he st u d y. 
I n a n y case, a n d es peci all y if t he p atie nt is wit h dra w n f or s afet y reas o ns t he e x pla nati o n f or t his 
disc o nti n uati o n d ue t o vi olati o n of eli gi bilit y criteria s h o ul d be d oc u me nte d i n t he patie nt 's 
C R F. 
 A dverse Eve nts / Seri o us A dverse Eve nts 
A n y patie nts ma y be wit h dra w n fr o m t he st u d y at t he I n v esti gat or’s discreti o n i n case of a safet y 
c o ncer n. H o we v er, patie nts ca n be wit h dra w n fr o m t he st u d y f or A Es or S A Es (i ncl u di n g 
n ota bl y cli nical a n d/ or la b orat or y e v e nts) o nl y if t he I n vesti gat or has clearl y d et er mi ne d t hat 
t he patie nt’s wit h dra wal w o ul d re d uce t he s afet y ris ks. I n t his case, t he C R F A E F or m m ust be 
c o m plete d, e x plai ni n g t h e rati o nal e f or wit h dra wal. I n a d diti o n, t he I n vesti gat or s h o ul d e ns ure 
t hat a de q uate me di cal c are a n d ma na ge me nt will be pr o vi de d t o t he patie nt. 
 Wit h dr a w n c o nse nt 
Partici pati o n i n t he st u d y is strictl y v ol u ntar y. A patie nt has t he ri g ht t o wit h dra w fr o m t he st u d y 
at a n y ti me, a n d f or a n y reas o n, wit h o ut prej u dice t o f urt her treat me nt, care, a n d p atie nt-
p h ysicia n relati o ns hi p. U n der t hese circ u msta nces, a n a de q uat e sta n dar d of care will al wa ys be 
a d o pte d b y t he I n v esti gat or. T he reas o n(s) f or wit h dra wi n g c o nse nt will als o be re vie we d wit h 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 9 1 /1 3 6  
 
 
t he patie nt a n d d oc u me nt e d i n s o urce d oc u m e ntati o n a n d t he C R F. Partic ularl y, t he p atie nt m ust 
be caref ull y q uesti o ne d f or t he p ossi ble occ urre nce of a n y A E or S A E. 
 L ac k of c o m pli a nce t o t he pr ot oc ol 
T he S p o ns or has t he ri g ht t o ter mi nate t he st u d y at a n y ti me. 
 L ost t o f oll o w- u p  
I nte nsi v e eff orts will be ma de t o re-c o ntact patie nts w h o d o n ot ret ur n f or sc he d ule d visits i n 
or der t o, at mi ni m u m, deter mi ne healt h stat us a n d t he p ote ntial occ urre nce of A E a n d/ or S A E. 
All eff orts t o re-c o nta ct will be d oc u me nte d i n t he s o urce d o c u me ntati o n a n d t he C R F. 
 L ac k of effic acy 
Earl y disc o nti n uati o n f or lac k of effi cac y will n ot be c o nsi dere d as a n A E b ut as a treat me nt 
fail ure. T h e reas o n of t he lac k of efficac y will be d o c u me nte d i n t he C R F a n d s o urce d o c u me nts.  
 Ot h er re as o ns 
If n o a b o v e- me nti o ne d reas o ns are a p plica ble i n case of earl y disc o nti n uati o n, t he ot her 
reas o n(s) will be clearl y d oc u me nte d a n d e x plai ne d i n t he C R F a n d s o urce d oc u me nts. 
9. 2  
Pr o ce d ure f or E arl y Disc o nti n u ati o n 
I n case of earl y disc o nti n uati o n a n d w he ne ver p ossi ble, I n vesti gat ors will as k patie nts t o 
perf or m  
E xit Visit  as t he Pre mat ure Disc o nti n uati o n Visit. At t he e n d of t he E xit visit, 
t he I n vesti gat or will declare earl y disc o nti n uati o n i n t he C R F. If st u d y p artici pati o n is 
ter mi nate d d ue t o a n A E p ossi bl y relate d t o t he st u d y me dicati o n or trial-rel ate d pr oce d ures, t he 
s u bject will h o we ver be f oll o we d b y a d diti o nal e x a mi nati o ns acc or di n g t o t he me dical j u d g m e nt 
of t he I n vesti gat or u ntil t he A E is res ol ve d or t h e I n vesti gat or dee ms f urt her o bser vati o ns or 
ex a mi nati o ns t o be n o l o n ger me dicall y i n di cate d. All c ollecte d data s h o ul d be rec or de d i n t he 
s o urce d oc u m e nts a n d C R F. 
9. 3  
Re pl ace me nt of S u bjects 
Patie nts wit h dra w n fr o m t he st u d y will n ot be re pl ace d. 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 9 2 /1 3 6  
 
 
9. 4  
S us pe nsi o n of t he Tri al 
O verall, t he st u d y or t he st u d y tr eat me nt ca n be pre mat urel y i nterr u pte d i n certai n 
circ u msta nces. T he S p o ns or ca n st o p or i nterr u pt t he st u d y f or t he f oll o wi n g reas o ns: 
- A L L O B ®  is i neffecti ve  
- A L L O B ®  is effecti ve 
- Safet y iss u es 
- F oll o wi n g a decisi o n of t he C o m pete nt A ut h orities or t he Et hics C o m mittee. 
 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 9 3 /1 3 6  
 
 
1 0  S T A TI S TI C A L C O N SI D E R A TI O N S A N D M E T H O D S O F A N A L Y SI S 
A Statistical A nal ysis Pla n ( S A P) detaili n g statistical met h o ds will be ge nerate d, re vie we d, 
a p pr o ve d, a n d si g n e d b y t he bi ostatisticia n, S p o ns or a n d Pri nci pal I n vesti gat ors, pri or t o first 
data base l oc k, at t he lat est. T his d oc u me nt will be t h e mai n refere n ce as far as statistical 
a nal ys es are c o ncer ne d a n d t heref ore t he descri pti o n pr o vi de d i n t his Pr ot oc ol will n ot be 
e x ha usti ve. 
1 0. 1  A n al ysis P o p ul ati o ns 
T w o a nal ysis sets will be defi ne d: 
- 
T he  safet y p o p ulati o n t hat will i ncl u de all treate d patie nts. ( Treate d p atie nts will be 
defi ne d as p atie nts i m pla nte d wit h A L L O B ® ). As t he st u d y is n ot ra n d o mize d a n d o nl y 
o ne st u d y gr o u p will be st u die d, t he safet y set will be use d als o t o a nal ys e t he w h ole 
effic ac y dat a. 
- 
T he Per- Pr ot oc ol ( P P) effic ac y p o p ulati o n will i ncl u de all patie nts of t he safet y 
p o p ulati o n wit h o ut a n y maj or pr ot oc ol de viati o n. 
T he defi niti o n of t he p o p ulati o ns will be fi nalise d pri or t o data base l oc k. T h e safet y p o p ulati o n 
will be c o nsi dere d as t he pri mar y c o h ort f or t h e a n al ysis of safet y, efficac y, de m o gra p hics, a n d 
ba seli ne c haracteristics. Efficac y varia bles will be a nal ys e d usi n g t he safet y p o p ulati o n. 
P ri mar y criteria a n d c orres p o n di n g v aria bles will be a nal yse d i n t he P P p o p ulati o n.  
T he  patie nts scree n e d will be descri be d i n t he s u m mar y ta ble prese nti n g t he dis p ositi o n of 
patie nts. 
1 0. 2  E ffic ac y E n d p oi nts 
T he effic ac y of A L L O B ®  will be e val uate d at M o nt h 6. T he s uccess of t he st u d y will be base d 
o n t he perce nta ge of treat e d patie nts ( A L L O B ® ) n ot faili n g u n der treat me nt.  
A patie nt will be c o nsi dere d as f aile d u n der tr eat m e nt if, at M o nt h 6: 
- He/s he ha d a resc ue s ur ger y  


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 9 4 /1 3 6  
 
 
Or  
- T he Gl o bal Diseas e E v al uati o n sc ore ( V A S) as percei ve d b y t he patie nt has n ot i m pr o ve d 
b y at least 2 5 % a n d t he TU S  as assesse d b y C T sca n has n ot i ncrease d b y at l east t w o p oi nts 
( vers us bas eli ne). 
A n i nteri m re p ort will be esta blis he d base d o n t he efficac y a n d safet y res ults fr o m t he first 1 6 
assessa ble patie nts at 6 m o nt hs of f oll o w- u p. T he i nteri m re p ort will als o i ncl u de t he safet y a n d 
effic ac y dat a of t he s u p pl e me ntar y patie nts e nr olle d after t he first 1 6 treat e d patie nts. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 9 5 /1 3 6  
 
 
1 0. 4  S afet y 
Safet y will be assesse d usi n g t he f oll o wi n g vari a bles: 
- A Es  
- S A Es  
- Vital si g ns: heart rate a n d bl o o d press ure 
- P h ysical e x a mi nati o n 
- La b orat or y a nal yses ( h ae mat ol o g y a n d bi oc h e mistr y) 
1 0. 5  S t atistic al A n al ysis 
1 0. 5. 1  Ge ner ality 
1 0. 5. 1. 1  Descri ptive st atistics 
C o nti n u o us varia bles will be des cri be d usi n g t h e n u m ber of o bs er ve d val u es, mea n, sta n dar d 
de viati o n ( S D), me dia n, first q uartile, t hir d q uartile, mi ni m u m a n d ma xi m u m val ues, a n d 
n u m ber of missi n g dat a. 
Cate g orical d ata will be prese nte d usi n g c o u nts ( n u m ber a n d n u m ber of n o n- missi n g dat a) a n d 
perce nt a ges ( %). T he n u m ber of missi n g data will als o be prese nte d. T he perce nt a ges will be 
calc ulate d ta ki n g i nt o acc o u nt t he n o n- missi n g dat a. 
N o a dj ust me nt o n ce ntres is pla n ne d. 
1 0. 5. 1. 2  Ty pe 1 err or r ate, si g nific a nce tests 
I n t his st u d y, t w o si de d tests will be perf or me d at a 5 % le vel of si g nifica n ce e x ce pt f or efficac y 
a nal ys es.  
Acc or di n g t o t he Sc h oe nfel d a p pr oac h ( Sc h o e nfel d et al., 1 9 8 0), f or t he efficac y a n al ysis, t he 
t y pe I err or rat e will be i n creas e d fr o m t he us u al 5 % t o t he 1 0 % rat e. I n d ee d, i n t his pil ot si n gle 
ar m “ pr o of of c o n ce pt” st u d y, it is a p pr o priate t o mai ntai n t he p o wer a n d i ncreas e t he t y pe I 
err or rate. T his i ncreases t he ris k of err o ne o usl y c o ncl u di n g t hat t he treat me nt is w ort h y of 
f urt her i n vesti gati o n, b ut d oes n ot i ncrease t he ris k of missi n g a n efficaci o us treat me nt. S o i n 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 9 6 /1 3 6  
 
 
t his p hase II st u d y, si nce t he trial will be f oll o we d b y f urt her testi n gs, a t y p e II err or ma y be 
m ore seri o us t ha n a t y p e I err or. 
1 0. 5. 1. 3  P atie nt  dis p ositi o ns  
All scree ne d a n d eli gi ble patie nts will be acc o u nte d f or. All p ost-i ncl usi o n disc o nti n uati o ns will 
be s u m marise d a n d reas o n f or disc o nti n uati o n. T h e n u m ber of patie nts scree ne d a n d n ot eli gi ble 
will be prese nte d wit h t h e mai n reas o n f or t heir n o n-eli gi bilit y. 
P atie nt dis p ositi o n will be bas e d o n t h e patie nts scree ne d a n d t a b ulate d f or t h e f oll o wi n g 
cate g ories: 
- T o tal n u m ber of patie nts e nr olle d 
- T otal n u m ber of patie nts eli gi ble 
- N u m ber ( perce nt a ge) of patie nts c o m pleti n g t he st u d y 
- N u m ber ( perce nt a ge) of patie nts pre mat urel y disc o nti n ui n g fr o m st u d y 
- Pri mar y reas o n f or pre mat ure disc o nti n uati o n 
- N u m ber of patie nts i n t he safet y p o p ulati o n 
- N u m ber of patie nts i n t he P P  p o p ulati o n 
F or eac h p o p ulati o n, r eas o ns f or e x cl usi o n fr o m t he p o p ulati o n will be caref ull y descri be d.  
1 0. 5. 2  De m o gr a p hics a n d p atie nts c h ar acteristics 
1 0. 5. 2. 1  De m o gr a p hics a n d ot her c h ar acteristics  
Descri pti ve st atistics of de m o gra p hics, a n d ot h er baseli ne c haract eristics as well as me di cal 
hist or y will be pres e nte d f or all eli gi ble patie nts.  
1 0. 5. 2. 2  Vir al ser ol o gy  
Viral ser ol o g y rec or de d at scree ni n g visit will be ta b ulate d. 
1 0. 5. 2. 3  Fr act ure c h ar acteristics  
Descri pti ve a n al ysis will be c o n d ucte d o n t h e Safet y a n d t he Per- Pr ot oc ol p o p ulati o n.  


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 9 7 /1 3 6  
 
 
T he ti me fr o m fract ure t o scree ni n g, t he ti me fr o m dela ye d- u ni o n dia g n osis t o scree ni n g, 
fract ur e d b o ne, fract ure si de, fract ure le vel, w het her t he fract ur e at o nset was o pe n, t y pe of 
fract ur e, ca use of fract ur e, w het her a n y te n d o n or ner ve was da ma ge d at t he fract ur e site a n d 
meas ure of fract ure i nterli ne will be s u m marize d.  
Ti me fr o m oste os y nt hesis t o scree ni n g, t y pe of oste os y nt hesis, ti me fr o m last oste os y nt hesis 
re visi o n t o scree ni n g, a n d t y pe of oste os y nt hesis r e visi o n will als o be prese nte d. 
L ocati o n of nei g h b o uri n g b o n e fract ur e(s), t y pe of oste os y nt h esis o n t he nei g h b o uri n g b o n e, 
w het her nei g h b o uri n g fract ure heale d a n d w het her a dela ye d/ n o n- u ni o n fract ur e is o n t he 
nei g h b o uri n g b o n e will be ta b ulate d.  
1 0. 5. 2. 4  Me dic al hist ory  
Me dical hist or y will be s u m marise d safet y p o p ul ati o n, a n d fre q ue n c y of pat h ol o gies will be 
s u m marise d usi n g descri pti ve statistics. Fre q ue ncies will be gi ve n b y s yst e m or ga n a n d 
preferre d t er m acc or di n g t o t he Me d D R A Dicti o nar y (last a vaila ble versi o n). 
1 0. 5. 2. 5  Previ o us a n d c o nc o mit a nt me dic ati o ns  
Pre vi o us a n d c o nc o mita nt me dicati o ns will be s u m marise d f or t he safet y p o p ulati o n.  
F re q u e nc y of m e dicati o n will be s u m marise d usi n g des cri pti ve statistics: 
- fre q ue n c y of patie nts wit h at least o ne pre vi o us me dicati o n 
- fre q ue n c y of patie nts wit h at least o ne c o n c o mita nt me dicati o n 
Fre q u e nc y will be gi ve n b y A T C ter m acc or di n g t o t he W H O Dr u g Dicti o nar y ( W H O D D) (last 
a vaila ble v ersi o n) us e d f or dr u gs c o di n g. Eac h fre q ue nc y t a ble will be s orte d b y d esce n di n g 
fre q ue n c y of A T C ter m a n d t he n wit hi n eac h A T C b y desce n di n g fre q u e nc y of W H O Dr u g 
na me (all treat me nt gr o u ps).  
1 0. 5. 3  Pr ot oc ol devi ati o ns 
All t he pr ot oc ol de viati o ns will be i d e ntifie d a n d acte d as maj or or mi n or de viati o ns d uri n g a 
data re vie w meeti n g occ urri n g cl ose t o t he data base l oc k.  
T he pr ot oc ol de viati o ns will be as f oll o ws: 
- N o i m pla ntati o n wit h A L L O B ®  


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 9 8 /1 3 6  
 
 
- Vi olati o n of i ncl usi o n/e xcl usi o n criteria 
- At least o ne p ost-i ncl usi o n pr ot oc ol vi olati o n (e. g., ta ki n g of a f or bi d de n treat me nt, n o 
e val uati o n of maj or effic ac y para meters) 
- At least o ne de viati o n wit h res pect t o t he st u d y pr oce d ure 
Fre q u e nc y a n d perce nta ges of pati e nts wit h pr ot oc ol de viati o ns will be ta b ulate d. 
Patie nts prese nti n g maj or de viati o n will be e x cl u de d fr o m t he P P p o p ulati o n. 
1 0. 5. 4  I m pl a nt ati o n pr oce d ure 
T he w h ole pr oce d ures us e d f or A L L O B ® i m pla ntati o n will be s u m marize d descri pti vel y o n t he 
all e nr olle d patie nts.  
T hese pr oce d ures c o ncer n:  
- If t he patie nt w as a ble t o u n der g o t he i m pla ntati o n pr oce d ure; 
- If t he patie nt ha d a n y c h a n ges i n h ealt h occ urre d si nce t he last visit bef ore i m pla ntati o n; 
- If t he I M P was r eleas e d b y t he s p o ns or, t h e p har macist or t he i n vesti gat or; 
- If t he i m pla ntati o n was p erf or me d; 
- t he d urati o n of i m pla ntati o n o perati o n; 
- I n case of a n o n-i m pla ntati o n, t he reas o ns ; 
- T he prescri be d d ose,  
- T he a d mi nistere d d ose a n d t he reas o n if t he prescri be d d ose was n ot t otall y a d mi nistere d;  
- If fl u or osc o p y i ma ges were ta ke n; 
- If t he I M P i m pla ntati o n was perf or me d b y t h e us e of 2 differe nt s ur gical a p pr oac hes a n d if 
yes, t he d escri pti o n of t h e 2 a p pr oac hes;  
- If o perati ve bl o o d l oss wit h t he descri pti o n of t he a m o u nt; 
- T y pe of a n aest hesia;  
- A n y rele va nt p eri- pr oce d ural e ve nts.  


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 9 9 /1 3 6  
 
 
D uri n g t h e 2 4 h o urs p ost-a d mi nistrati o n f oll o w- u p, n u m ber of patie nts ha vi n g e x perie nce d 
A E/ S A E or ha vi n g d o ne a n y c ha n ges i n t he c o nc o mita nt me dicati o ns will be descri b e d.  
1 0. 5. 5  Exte nt of ex p os ure 
E xte nt of e x p os ure will be s u m mari se d b y d escri pti ve statistics f or t he d urati o n of treat me nt, 
calc ulate d i n da ys as f oll o ws: 
D ur ati o n of tre at me nt = ( D ate of l ast visit or d ate of resc ue s ur gery – D ate of A L L O B  
i m pl a ntati o n) 
T he e xte nt of e x p os ure s u m mar y will be prese nte d f or t he safet y a n d P P p o p ulati o ns. 
1 0. 5. 6  Effic acy a n alysis 
1 0. 5. 6. 1  Pri m ary effic acy criteri a 
T he pri mar y efficac y crit eria will be a nal yse d i n t h e safet y p o p ulati o n a n d i n t he P P p o p ulati o n, 
t he safet y p o p ulati o n c orres p o n di n g t o t he m ai n efficac y p o p ulati o n. 
P erce nta ge of res p o n der patie nts will be calc ulate d as t he p erce nta ge of p atie nts w h o will n ot 
be c o nsi dere d as f aile d u n der treat me nt at M o nt h 6.   
A pa tie nt will be c o nsi dere d as f aile d u n der a treat me nt if, at M o nt h 6: 
- He/s he ha d a resc ue s ur ger y  
Or   
- T he Gl o bal Diseas e E v al uati o n sc ore ( V A S) as percei ve d b y t he patie nt has n ot i m pr o ve d 
b y at least 2 5 % a n d  t he T U S as assesse d b y C T sca n has n ot i ncrease d b y at l east t w o p oi nts 
( vers us bas eli ne). 
 
 
 
 
 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 0 0 /1 3 6  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 0. 5. 7  S afety a n alysis 
Safet y will be a nal yse d i n t he safet y p o p ulati o n, wit h all ce ntres p o ole d. T he statistical a nal ysis 
will be mai nl y des cri pti ve. F or q ualitati ve varia bl es, 9 5 % CI of perce nta ges will be c o m p ute d , 
a n d f or q ua ntitati ve v aria bles, 9 5 % CI of mea ns will be c o m p ute d. 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 0 1 /1 3 6  
 
 
1 0. 5. 7. 1  A Es a n d S A Es 
A Es a n d S A Es will be c o de d usi n g t he 
Me dical Dicti o nar y f or Re g ul at or y Acti vities 
( Me d D R A). F or eac h A E re p orte d, t he n u m ber a n d perce nt a ge of patie nts will be ta b ulate d 
base d o n s yste m or ga n class a n d preferre d t er m. Si milar ta b ulati o ns will be perf or me d b y 
severit y, relati o ns hi p t o t he st u d y pr o d uct/ pr oce d ure, acti o n ta ke n a n d o utc o me. T he n u m ber 
a n d perce nta ge of patie nts w h o e x perie nce d a n A E as d efi ne d i n t he pre- defi n e d s u bsets of 
e ve nts will als o be ta b ulate d. 
T he fre q u e nc y of A Es a n d S A Es will be esti mate d b y usi n g t he 9 5 % CI. 
A n a nal ysis of f oll o wi n g para meters will als o be p erf or me d: 
- 
Treat me nt- e mer ge nt ( S) A E ( occ urri n g or w orse ni n g aft er A L L O B ® i m pla ntati o n) 
- 
( S) A E lea di n g t o pre m at ure wit h dra wal 
1 0. 5. 7. 2  Ot her s afety v ari a bles 
F or bl o o d press ure, sta n d ar d s u m mar y statistics will be pr o vi de d at baseli ne a n d eac h f oll o w-
u p visit, i ncl u di n g me a n val ues a n d mea n c ha n ges fr o m b aseli ne. Heart rat e meas ure me nts will 
be s u m marise d f or t he m ea n val ues a n d t he mea n c ha n ges fr o m baseli ne at eac h f oll o w- u p visit 
usi n g sta n dar d s u m mar y statistics. S hift ta bles [l o w ( < 5 0 b p m), n or mal ( bet wee n 5 0 b p m a n d 
1 2 0 b p m), a n d hi g h ( > 1 2 0 b p m)] s h o wi n g eac h i n di vi d ual patie nt's baseli n e val ue a n d f oll o w-
u p vis its will be perf or me d. 
 
 
 
Sta n dar d s u m mar y statistics of la b orat or y val u es a n d s hift t a bles pres e nti n g i nci d e nce of 
la b orat or y a b n or malities 
will als o be pr o vi de d. T he fre q ue n c y of n or mal / a b n or mal 
e x a mi nati o n will be ta b ulate d f or eac h ti me p oi nt. 
Detaile d statistical met h o d ol o g y f or t h e safet y a nal ys es will be pr o vi de d i n t he S A P. 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 0 2 /1 3 6  
 
 
1 0. 5. 8  I nteri m d at a a n alysis 
1 0. 5. 8. 1  Effic acy Assess me nt 
A t M o nt h 6, t he efficac y assess me nt will be base d o n: 
- T he patie nt ha d a resc u e s ur ger y  
Or  
- T he Gl o bal Diseas e E v al uati o n sc ore ( V A S) as percei ve d b y t he patie nt has n ot i m pr o ve d 
b y at l east 2 5 % a n d t he T U S as assesse d b y C T s ca n has n ot i ncreas e d b y at least 2 p oi nts 
( vers us bas eli ne). 
F or res c ue s ur ger y, bas e d o n t he efficac y of t he treat me nt, I n vesti gat ors will ha ve t he 
o p p ort u nit y t o s witc h t o resc ue s ur ger y fr o m M o nt h 3 if t he patie nt has n ot i m pr o ve d b y at least 
1 5 % his/ her gl o bal dise ase e v al uati o n sc ore ( V A S) as percei ve d b y t he patie nt a n d his/ her 
m R U S or T U S, as a vaila ble, has n ot i m pr o ve d b y 1 p oi nt. 
T he  le vels of i m pr o ve me nts ha ve bee n calc ulate d as base d o n ot her si milar i m paire d fract ur e 
heali n g trials (e. g., P R E O B ® o n n o n- u ni o n fract ure) a n d ta ke i nt o acc o u nt sta n dar d de viati o n 
a n d patie nt varia bilit y.  
1 0. 5. 8. 2  Prese nt ati o n of t he 2-st a ge desi g n 
T he mai n o bjecti ve of t his p hase I/II- a n o n-c o m parati ve se q ue ntial desi g n is t o assess t he 
i nterest prese nte d b y t his ne w treat me nt wit h o ut perf or mi n g a c o m parati v e st u d y t hat all o ws 
i de ntif yi n g o nl y s mall differe nces of efficac y bet wee n t he ne w treat me nt a n d a c o ntr ol, w hat 
re q uires a relati vel y hi g h n u m ber of s u bjects. T h e pri nci ple of a s e q ue ntial desi g n is t o perf or m 
t he st u d y i n t w o or m or e sta ges i n or der t o mi ni mize t he n u m ber of pati e nts e x p ose d t o a n 
i neffecti ve treat me nt t o c o ncl u de i n a m ore pre mat ure wa y. 
T he  m ost a p pr o priate se q ue ntial met h o d f or t his st u d y is t he 2 –sta ge Fl e mi n g pla n. I n t his 
de si g n, t he effi cac y criteri o n is a bi nar y criteri a of “s uccess/fail ure” t y p e, wit h p 0 as t he s u peri or 
li mit of i neffecti ve ness ( ma xi m u m val ue bel o w w hic h t he ne w treat me nt is c o nsi dere d as bei n g 
i neffecti ve) a n d p 1 as t he i nferi or li mit of efficac y ( mi ni m u m val ue a b o ve w hic h t he ne w 
treat me nt is c o nsi dere d as bei n g effecti ve). T h e n ull a n d alter nati ve test h y p ot hes es are t he 
f oll o wi n g: 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 0 3 /1 3 6  
 
 
 H 0: p p 0 
 H 1: p ≥ p 1  
Usi n g α = t he t y pe I err or a n d β = t he t y pe II err or 
T he teste d h y p ot heses are as f oll o ws: 
 H 0 : a s uccess rat e  3 0 % is u ni nteresti n g ( p 0 = 0. 3 0) 
 H 1: a s uccess rat e of at least 7 0 % is e x pecte d ( p 1 = 0. 7 0) 
Usi n g  α = 0. 0 5 a n d β = 0. 2 0 
I n t he case of a t w o-sta ges Fle mi n g pla ns, t he st u d y ca n be st o p pe d f or i n effecti ve ness (if t he 
n u m ber of s uccesses is l o wer t ha n a c o m p ute d li mit) or f or effi cac y (if t he n u m ber of s uccesses 
is ≥ a c o m p ute d li mit). 
1 0. 5. 8. 3  Res ults of t he c o m p uti n g 
Acc or di n g t o t he 2 sta ges Fle mi n g met h o d, 2 0 tr eate d pa tie nts are re q uire d (t y pe I err or rate α 
of 5 % a n d a statistical p o wer of 8 0 %) . T a ki n g i nt o acc o u nt t hat p atie nts are enr oll e d b y c o h ort 
of 4 a n d c o nsi deri n g t he p ote ntial heter o ge neit y of t he p o p ulati o n, 3 2 patie nts i n t otal will be 
e nr olle d a n d tr eate d i n t h e st u d y.  
Ste p  
N b. of 
p atie nts/ ste p 
C u m ul ate d N b. 
of p atie nts  
T re at me nt i neffecti ve  
if  <  0. 3 0  
Tre at me nt effecti ve  if 
 >  0. 7 0  
1  
1 6  (assessa ble) 
- 
N u m ber of s uccesses ≤ 4  
N u m ber of s uccesses 
≥1 2  
2  
U p t o 1 6 
(assessa ble) 
3 2  
n.a.  
n.a.  
F or t he first 1 6 assessa bl e patie nts, a n i nteri m a n al ysis will be perf or me d at t he e n d of t h e 6 
m o nt hs f oll o w- u p ( Visit # 6). 
T he  st u d y will be pre mat urel y st o p p e d f or: 
- 
Safet y c o ncer ns  


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 0 4 /1 3 6  
 
 
- 
I n effecti ve ness, if l ess t ha n 4 s uccess es are o bser ve d 
- 
Efficac y, if 1 2 or m ore s uccesses are o bs er ve d 
Ot he r wise, a d diti o nal patie nts will be treate d i n or der t o reac h a t otal of 3 2 patie nts. 
1 0. 5. 9  P ost-tre at me nt d at a a n alysis 
T he fi nal C S R i ncl u di n g assess me nt of b ot h efficac y a n d safet y e n d p oi nts, will be esta blis he d 
at 6 m o nt hs. 
 
 
 
 
1 0. 6  R a n d o mis ati o n 
T here is n o ra n d o misati o n i n t he st u d y. 
1 0. 7  S a m ple size esti m ati o n  
Usi n g t he 2 sta ges Fle mi n g met h o d, a m a xi m u m of 3 2 treate d p atie nts are re q uire d. Ass u mi n g 
a rate of 1 0 % of n o n-ass essa ble patie nts, a t otal of 3 5 patie nts will ha ve t o be e nr olle d. 
1 0. 8  H a n dli n g of missi n g v al ues 
F or all effi cac y criteria,  t he i m p utati o n a p pr oac h will i nc or p orate t he patter n of missi n g val ues 
as f oll o ws: 
- 
Missi n g  data d ue t o treat me nt-relate d A E lea di n g t o st u d y wit h dra wal will be re place d b y 
t he W orst O bser vati o n C arrie d F or war d ( W O C F) met h o d fr o m s c he d ule d or u nsc he d ule d 
v isits: f or eac h p atie nt dr o p pi n g o ut d ue t o treat me nt relate d A E, his/ her w orst o bser vati o n 
will be use d t o re place his/ her missi n g val ues.  


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 0 5 /1 3 6  
 
 
- 
Missi n g data d ue t o a n y reas o n ot her t ha n treat me nt-relate d A E lea di n g t o st u d y wit h dra wal 
will be i m p ute d usi n g last o bser vati o n carrie d f or war d ( L O C F) fr o m pre vi o us visit 
(sc he d ule d or u nsc he d ule d visit).  
- 
Missi n g val ues i n- bet wee n t w o meas ure d val u es will be e xtra p olate d usi n g li near mi x e d 
m o dels . 
1 0. 9  S afet y F oll o w- u p  
F or t he first 1 6 patie nts, patie nts will be tr eate d i n t he st u d y b y s u b- gr o u p ( bl oc k) of 4. Bef ore 
starti n g t he treat me nt of a ne w bl o c k of 4 patie nts, a safet y re vie w at t he e n d of t he Visit # 3 f or 
t he first bl oc k ( 4 8 h o urs of h os pitaliz ati o n a n d first f oll o w- u p visit at 2 wee ks after i m pla ntati o n) 
a n d at t he e n d of Visit # 2 ( 4 8 h o urs h os pitalisati o n or o n-site visit) f or t he ot her bl oc ks will be 
c o n d ucte d. If fr o m t his re vie w, 3 or m ore patie nts ha ve n ot e x perie nce d S A E p ote ntiall y relate d 
t o t he I M P, i ncl u di n g s e vere A E S C, a n d res ulti n g i n d eat h, life-t hr eat e ni n g, res ulti n g i n 
persiste nt or si g nifica nt disa bilit y/i nca p acit y, re q uiri n g i nter ve nti o n t o pre ve nt per m a ne nt 
i m pair me nt or da ma ge, t he ne xt bl oc k of 4 patie nts will be all o we d f or tr eat me nt ( Visit # 2).   
T he  me m bers of t h e S M C will perf or m t his safet y m o nit ori n g a nal ysis. 
Af ter i ncl usi o n of t he first 1 6 assessa ble patie nts a n d base d o n 6- m o nt h treat me nt f oll o w- u p, a 
safet y a n d effic ac y i nteri m a nal ysis will be pla n ne d.  
1 0. 1 0  I nteri m A n al ysis 
F or t he i nteri m a nal ysis, a D S M B  will be esta blis he d b y t he S p o ns or. T he D SM B  will assess 
t he safet y d ata a n d t he efficac y e n d p oi nts w he n 6- m o nt h p ost treat me nt res ults f or t he first 1 6 
assessa ble p atie nts are a vaila ble. T he b o ar d will als o assess t he a vaila ble safet y a n d efficac y 
data of s u p ple me ntar y e nr olle d patie nts.  
T he D S M B  m a y deci de i n acc or da n ce wit h t he S p o ns or t o decreas e t he s a m ple siz e, t o m o dif y 
t he desi g n of t he st u d y, t o c o nti n ue or t o st o p t he cli nical trial.  
 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 0 6 /1 3 6  
 
 
1 1  S T U D Y M A N A G E M E N T 
1 1. 1  M o nit ori n g 
Bef ore st u d y i nitiati o n, t he C R A will visit t he I n vesti gati n g Sites t o e v al uate t he feasi bilit y of 
partici pati n g t o t he st u d y (e. g., patie nt recr uit me nt, staff a vaila bilit y, facilities, e q ui p me nt). 
D uri n g t he St u d y I nitiati o n Visit, t he C R A will i nitiate t he Pri nci pal I n v esti gat or a n d t he site 
staff i n or der t o tr ai n t he PI a n d t he site staff o n t he St u d y Pr ot oc ol a n d trial-relate d pr oce d ures, 
a n d verif y g o o d u n dersta n di n g of G C P (e. g., I n vesti gat or's res p o nsi bilities) a n d a n y ot her 
a p plica ble C o m m u nit y a n d nati o nal le gal a n d re g ulat or y re q uir e me nts, n ota bl y as re gar ds 
sta n dar ds of q ualit y a n d safet y f or t he pr oc ure me nt (i ncl u di n g patie nt selecti o n a n d i ncl usi o n), 
testi n g, distri b uti o n, a d mi nistrati o n, a n d tracea bilit y of h u ma n tiss ues a n d cells, as well as 
n otificati o n a n d re p orti n g of a n y S A E a n d/ or Seri o us A d verse Safet y/ Q ualit y E ve nts. 
Ver y s h ortl y aft er t h e first patie nt i ncl usi o n, a n o n-site m o nit ori n g visit will ta ke place i n or der 
t o verif y t h e a d here nce t o t he pr ot oc ol a n d st u d y pr oce d ures, a n d t h us a v oi di n g a n y 
misc o m plia nce i n t he f ut ure i ncl usi o ns, if a p plica ble. 
D uri n g t he c o urs e of t he st u d y, o n-site m o nit ori n g visits a n d re g ular c o ntacts wit h t he 
I n v esti gati n g Sites will be c o n d ucte d b y a m o nit or or t he S p o ns or i n or der t o pr o vi de detaile d 
i nf or mati o n a n d s u p p ort t he I n v esti gat or(s), a n d t o assess t hat t he st u d y is perf or me d i n 
c o m plia nce a n d acc or da nce t o t he St u d y Pr ot oc ol, I C H- G C P, a n d all a p plica ble C o m m u nit y 
a n d nati o nal re g ulat or y re q uire me nts. 
F or i nsta nce, t he f oll o wi n g as p ects will be cl osel y verifie d: 
 Pr oc ure me nt of si g ne d a n d date d I nf or m e d C o nse nt 
 P atie nt ri g hts, i ncl u di n g as re gar ds pr ot ecti o n of pri vac y a n d c o nfi d e ntialit y of pers o nal 
data a n d me dical rec or ds, welfare, a n d safet y 
 P atie nt recr uit me nt, eli gi bilit y, sel ecti o n, a n d i ncl usi o n 
 St u d y pr oce d ures, i n cl u di n g l a b orat or y a n d uri ne tests, trial-relate d pr oce d ures a n d 
i ma gi n g pr oce d ures  
 I M P recei pt, verificati o n, a n d fi nal deli ver y b y t h e P har macist 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 0 7 /1 3 6  
 
 
 I M P recei pt a n d v erific ati o n b y t he I n v esti gat or 
 IM P acc o u nta bilit y a n d tracea bilit y 
 S A E Seri o us A d verse Safet y/ Q ualit y E ve nts n otificati o n a n d re p orti n g 
 E me r ge nc y a n d pre g n a nc y pr oce d ures 
 Da ta ge n erati o n a n d c ollecti o n pr ocess es 
 Ac c urac y of data c ollecte d a n d rec or de d i n t he C R F 
 F acilities a n d I n v esti gati n g Site staff 
 In v esti gat or’s Trial M aster File (a n d ot her o n-site s o urce d oc u m e ntati o n) 
A n y d etecte d n o n-c o m plia nce wit h t he St u d y Pr ot oc ol, G C P, or a n y ot her a p plica ble 
C o m m u nit y a n d nati o nal le gal a n d re g ulat or y re q uire me nts will be f ull y d oc u me nte d b y t he 
m o nit or wit h t he e x pla nati o n pr o vi d e d b y t he I n vesti gat or o n a d e viati o n l o g. 
D uri n g t he m o nit ori n g visits, t he I n vesti gat or a n d cli nical st u d y staff s h o ul d be a vaila ble f or 
q uesti o ns, verific ati o n of data fr o m t h e s o urce d o c u me ntati o n, a n d p ossi ble c orrecti o ns t o t he 
C R F. 
F oll o wi n g eac h m o nit ori n g visit, t he I n v esti gat or will recei ve a f oll o w- u p letter detaili n g a n y 
acti o ns re q uire d b y eit her t he I n v esti gati n g Site staff or t he m o nit or. A n y acti o ns m ust, w here ver 
p ossi ble, be a d dress e d i m me diatel y, or b y t he ne xt sc he d ule d m o nit ori n g visit. 
T he m o nit or will c o nti n u o usl y b e reac ha ble a n d a vaila ble bet w ee n visits if t he I n v esti gat or(s), 
or ot he r st u d y staff at t he site, nee ds a d diti o nal i nf or mati o n a n d/ or a d vice. 
1 1. 2  S o urce D oc u me nts 
Eac h I n v esti gati n g Site will mai ntai n a n d arc hi ve all a p pr o priat e me dical a n d researc h rec or ds 
relate d t o t he trial, i n c o m plia nce wit h I C H E 6 G C P Secti o n 4. 9, a n d re g ulat or y a n d i nstit uti o nal 
re q uire me nts f or t he pr ot ecti o n of patie nt c o nfi de ntialit y. 
S o urce data are all i nf or mati o n, ori gi nal rec or ds of cli nical fi n di n gs, o bser vati o ns, or ot her 
d oc u me nts i n a cli nical trial necessar y f or t he rec o nstr ucti o n a n d e val uati o n of t he trial. 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 0 8 /1 3 6  
 
 
S o urce d oc u me nts ma y i ncl u de, b ut are n ot li mite d t o, a patie nt's me dical rec or ds, h os pital 
c harts if a n y, cli nic c harts if a n y, t he I n vesti gat or's p atie nt st u d y files, p h ar mac y dis pe nsi n g 
rec or ds, rec or de d data fr o m a ut o mate d i nstr u me nts, as well as t he res ults of dia g n ostic tests, 
s uc h as ra di o gra p hs, la b orat or y a n d uri n e pre g n a n c y t ests. 
T he f oll o wi n g i nf or mati o n s h o ul d be e ntere d i nt o t he patie nt's me dical r ec or d: 
 P atie nt na me, s ur na me a n d date of birt h 
 P atie nt's c o nta ct i nf or mati o n 
 Me dical c hart (e. g. h os pital s o urce d oc u m e nt trac ki n g n u m ber), if a n y 
 A state me nt t hat I C F was o btai ne d wit h t he date of I C F c ollecti o n a n d a d oc u me ntati o n 
o n t he pers o n w h o c o n d u cte d t he I nf or me d C o nse nt disc ussi o n 
 Da tes of i nitial scree ni n g a n d all patie nt visits 
 T he patie nt i de ntificati o n n u m ber  
 T he  st u d y title a n d/ or t he pr ot oc ol n u m ber a n d t he na me of t he S p o ns or 
 Me dical/s ur gical hist or y a n d p h ysi cal e xa mi nati o n  
 R es ults of bl o o d press ure, heart rate, res pir at or y rate a n d b o d y te m perat ure 
 R es ults of uri ne pre g na n c y t ests ( o nl y f or fe male wit h c hil d beari n g p ote ntial) 
 R es ults of ra di o gra p hs a n d C T Sca n 
 L a b orat or y res ults re p orts 
 All c o nc o mita nt me dicati o ns a n d c o nc urre nt pr oce d ures (list of all prescri pti o n a n d n o n-
prescri pti o n me dicati o ns bei n g ta ke n at t he ti me of e ntr y/scree ni n g of t he st u d y. At eac h 
s u bse q ue nt visit, c ha n ges t o t he list of me dicati o ns will be rec or de d.) 
 Occ urre nce a n d stat us of a n y A E a n d S A E 
 T he  date t he p atie nt e xite d t he st u d y, a n d a n ot ati o n as t o w het her t he patie nt c o m plete d 
t he st u d y or t he reas o n f or disc o nti n uati o n 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 0 9 /1 3 6  
 
 
T he q uesti o n naires are t o be c o m plete d dir ectl y b y t he p atie nt (e x ce pt f or t he Gl o bal Disease 
E val uati o n as p ercei ve d b y t he p h ysicia n). T he ori gi nal pa ges, c o nsi d ere d as s o urce data, will 
be ke pt a n d file d o n site (i n t he I n v esti gat or’s Trial Master File). 
1 1. 3  S o urce D at a V erific ati o n 
T o e ns ure t hat data i n t he C R F  are acc urate a n d c o m plete, a n d i n acc or da nce wit h patie nt s o urce 
d oc u me nts a n d ot her s o urce dat a (e. g., la b orat or y res ults f or ms), 1 0 0 % of s o urce data 
verificati o n ( S D V) will be perf or me d o n site b y t h e m o nit or s uc h as C R A o n all data a n d C R Fs 
i ncl u di n g b ut n ot li mite d t o patie nt q uesti o n naire, S A E a n d pre g na n c y-relate d d oc u me nts, 
c o nsisti n g i n a c o m paris o n of t he s o ur ce d oc u me ntati o n data wit h t he C R Fs a n d ot her rec or ds 
rele va nt t o t he st u d y. T his will re q uire direct access t o all ori gi nal rec or ds f or eac h p atie nt. 
F oll o wi n g t his S D V, a n y err ors ( discre p a ncies) greater t ha n 3 m m n otice d o n a V A S d uri n g 
i n de pe n de nt verificati o n b y/ o n be h alf of t he S p o ns or (e. g., a u dits) m ust tri g ger a p pr o priate 
c orrecti ve acti o ns t o e ns ure e x act ness of all V A S val ues i n t he st u d y. 
T he pr ocess of o btai ni n g I C a n d t he prese n ce o n file of t he si g ne d a n d date d I C F will be verifie d 
f or all patie nts scree ne d, w het her or n ot t he y were c o nsi dere d eli gi ble f or t he st u d y. 
T he  bac k-tra nscri pti o n of data fr o m t he C R F i nt o s o urce d o c u me nts is n ot all o we d, i ncl u di n g 
w he n discre p a ncies/ o missi o ns are dete cte d b y S D V. 
As s o me data will be directl y e ntere d i nt o t he C R F, t he C R F will be c o nsi dere d as s o urce 
d oc u me nt f or t hes e data. T he “ S o urce Data L ocati o n List” will be c o m plete d c o nfir mi n g t he 
l ocati o n of t he s o urce dat a. 
1 1. 4  C o m pleti o n of C ase Re p ort F o r ms, Si g ni n g, a n d Fili n g 
T he patie nts will be m o nit ore d t hr o u g h o ut t he c o urse of t he trial a n d all res ults of e val uati o ns 
will be rec or de d i n t he C R F. 
C R Fs will be c o m plete d f or eac h p atie nt scree n e d i n t he trial, i ncl u di n g scree ni n g fail ure 
patie nts. T he y will be c o m plete d as s o o n as p ossi ble after t he patie nt visit. All C R Fs will be 
c hec k e d f or c o nsiste nc y, acc urac y, a n d c o m plete ness, a n d will be date d a n d si g ne d o n a n 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 1 0 /1 3 6  
 
 
o n g oi n g basis b y t he I n v esti gat or. T his will be d o n e as s o o n as p ossi ble after eac h p atie nt st u d y 
visit. 
I n a d diti o n, a p ers o nal l o g, d etaili n g eac h site staff me m ber w or ki n g o n t h e trial, will be k e pt 
u p t o date i n t he I n v esti gat or File. T his l o g will rec or d e x a m ples of eac h i n di vi d ual's 
ha n d writi n g, si g nat ure/i nitials a n d j o b title as well as t he tas ks t he I n v esti gat or has del e gate d t o 
his staff ( wit h date of dele gati o n). T he I n vesti gat or m ust si g n t his l o g t o i n dicate his/ her 
a ut h orisati o n. 
T he I n v esti gat or will b e res p o nsi ble f or t he p u nct ualit y, c o m plete ness, c o nsiste nc y a n d 
acc urac y of C R Fs. C R Fs a n d relate d s o urce d ata will be ma de a vaila ble b y t he I n vesti gat or f or 
data verifi cati o n at eac h s c he d ule d m o nit ori n g visit. 
C o m plete d C R F a n d S A E/ Pre g n a nc y-relate d d o c u me nts will be c ollecte d b y t he m o nit or f or 
a nal ysis a n d fili n g. A c o p y of all t hese d o c u me nts will be st ore d i n t he I n vesti gat or's arc hi v es 
after c o m pleti o n or dis c o nti n uati o n of t he trial f or a d urati o n of 3 0 years acc or di n g t o S p o ns or’s 
S O P a n d E ur o pea n Directi ve. 
1 1. 5  D at a M a n a ge me nt 
T he st u d y D ata Ma na ge me nt Pla n ( D M P) will descri be met h o ds use d t o c ollect, c hec k, a n d 
pr ocess cli nic al data, as well as t he pr oce d ure t o f oll o w f or dat a base l oc k. T he D M P will be 
de vel o pe d b y t he C R O a n d/ or t he S p o ns or a n d a p pr o ve d b y t he S p o ns or. It will als o list t he 
r oles a n d res p o nsi bilities of t he pers o n nel ( wit h t he c orres p o n di n g f u ncti o ns) i n v ol ve d i n data 
ma na ge me nt pr o cess. 
T he data base l oc k will be p ossi ble after a p pr o val b y at least 2 a ut h orise d re prese ntati ves of t he 
S p o ns or (i ncl u di n g at least t he Direct or of Cli nical De vel o p me nt). 
1 1. 6  A u d its a n d I ns pecti o ns 
A ut h orise d re pres e ntati ves of t he S p o ns or, C R O, C R A, C As, a n d/ or E Cs ma y visit t he site at 
a n y ti me d uri n g or after t he st u d y t o p erf or m a u dits a n d/ or i ns pecti o ns, i ncl u di n g S D V. T h e 
p ur p ose of s uc h a u dit or i ns pecti o n is t o s yste mati call y a n d i n de pe n de ntl y e x a mi ne all st u d y-
relate d pr oce d ures a n d d oc u me nts a n d t o d eter mi ne w het her t hese data a n d pr oce d ures were 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 1 1 /1 3 6  
 
 
c o n d ucte d, c ollect e d, rec or de d, a nal yse d, a n d re p orte d acc uratel y a n d i n acc or da n ce wit h t he 
a p pr o ve d St u d y Pr ot oc ol, G C P, a n d all a p plica bl e C o m m u nit y a n d nati o nal le gal a n d re g ulat or y 
re q uire me nts (s ee refere n ce d oc u me nts i n Secti o n 1 2. 1). 
T he I n vesti gat or m ust i m me diatel y i nf or m t he C R A a n d/ or t he C R O  a n d/ or t he S p o ns or if 
c o ntacte d b y a C A a n d/ or E C a b o ut a n i ns pecti o n at his or her site. 
T he prese nce of t he C R A o n t he site is ma n dat or y i n case of visit/a u dit (at least f or t h e S D V 
a u dit a n d D e briefi n g wit h t he I n v esti gat or) b y a n y a ut h orise d re prese ntati ve of t h e S p o ns or. 
Ne vert hel ess, w he n j ustifie d, t he C R A ma y be re prese nte d b y a n ot her re prese ntati ve i n v ol ve d 
i n t he st u d y. 
D uri n g t h ese a u dits a n d i ns pecti o ns, pr otecti o n of t he patie nt ri g hts a n d pri vac y, a n d 
c o nfi de ntialit y of t he p atie nt pers o n nel data a n d m e dical rec or ds, will be strictl y res p ecte d, a n d 
patie nts will be i nf or me d t hat a ut h orise d re pres e ntati ves fr o m t he S p o ns or, C As a n d/ or E Cs 
ma y wis h t o i ns pect t heir me dical rec or ds. 
A n y res ults a n d i nf or m ati o n arisi n g fr o m t h e i ns pecti o ns b y t he C As a n d/ or E Cs will be 
i m me diatel y c o m m u nicat e d b y t h e I n vesti gat or t o t he C R O a n d/ or S p o ns or. 
T he  I n vesti gat or s h o ul d ta ke all t he c orrecti ve acti o ns f or a n y iss ue or pr o ble m i de ntifie d a n d 
raise d d uri n g a u dit / i ns pecti o ns. 
1 1. 7  Ac cess t o S o urce D at a 
A ut h orise d re pres e ntati ves of t he C R A, C R O, C As a n d/ or E Cs will be all o we d t o ha ve f ull a n d 
direct access t o t h e vari o us rec or ds rel ati n g t o t he trial t o verif y a d here nce t o t he St u d y Pr ot oc ol, 
G C P, a n d a n y a p plica ble C o m m u nit y a n d n ati o nal le gislati o n a n d re g ulat or y re q uire me nts, a n d 
t he c o m plete ness, c o nsist e nc y, a n d acc urac y of t he data bei n g re p orte d. 
1 1. 8  T r ai ni n g of St aff 
T he I n vesti gat or will mai ntai n rec or ds of all i n di vi d uals i n v ol ve d i n t he st u d y c o n d uct ( me di cal, 
n ursi n g, a n d ot her staff). T he I n vesti gat or will e ns ure t hat a p pr o priate i nf or mati o n rele va nt t o 
t he st u d y is gi ve n t o t he st u d y staff, a n d t hat a n y n e w i nf or m ati o n of rel e va nce t o t he 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 1 2 /1 3 6  
 
 
perf or ma n ce of t he st u d y will be pr o vi de d t o t h e staff i n v ol ve d. T h e I n v esti gat or m ust i nf or m 
t he m o nit or, i n a ti mel y ma n ner, of a n y c ha n ge i n t he st u d y site staff. 
1 1. 9  C h a n ges t o t he Pr ot oc ol 
T he I n vesti gat or ca n n ot i m ple me nt a n y d e viati o n fr o m or c ha n ges t o t he St u d y Pr ot oc ol wit h o ut 
pri or 
a p pr o val 
b y t h e 
S p o ns or 
a n d 
pri or 
s u b missi o n, re vie w 
a n d 
d oc u me nte d 
a p pr o val/fa v o ura ble o pi ni o n fr o m t he C As a n d E Cs (e x ce pt w he n necessar y t o eli mi nate 
i m me diate hazar ds t o st u d y patie nts, or w he n c ha n ges i n v ol ve o nl y l o gistical or a d mi nistrati ve 
as pects of t he st u d y, e. g. c ha n ges i n m o nit ors or p h o ne n u m bers). A n y d e vi ati o n fr o m t he St u d y 
Pr ot oc ol will be i de ntifie d, re vie we d, a n d re p ort e d b y t h e C R A wit h a n e x pla nati o n pr o vi de d 
b y t he I n vesti gat or, w he n a p plica ble. 
If it is necessar y f or t h e St u d y Pr ot oc ol t o be a m e n de d, t he a me n d me nt or a ne w versi o n of t h e 
St u d y Pr ot o c ol will be s u b mitte d t o a n d a p pr o ve d b y t he C As a n d E Cs bef ore i m ple me ntati o n. 
If a pr ot oc ol a me n d me nt re q uires a c h a n ge t o a partic ular site's I C F, t he C R A, C R O, S p o ns or, 
a n d site's C A will be n otifie d. A p pr o val of t he re vise d I C F b y t he C R A, C R O, S p o ns or, a n d 
c o ncer ne d C As a n d E Cs, if a p plica bl e, is re q uire d bef ore t h e re vise d f or m is use d. 
T he C R A or C R O ( u n der t he s u per visi o n of t he S p o ns or) will distri b ute a me n d me nts a n d n e w 
versi o ns of t he St u d y Pr ot oc ol t o eac h I n vesti gat or f or re vi e w a n d a p pr o val, a n d t o t he site staff. 
T he distri b uti o n of t hese d oc u me nts t o t he C As a n d E Cs will be ha n dle d acc or di n g t o l ocal 
practice. 
A me n d me nts t o t he trial are re gar de d as “s u bst a ntial” if t he y are li kel y t o ha ve a si g nifica nt 
i m pact o n: 
 T he  safet y, p h ysic al healt h, a n d me ntal i nte grit y of t he s u bjects; 
 T he scie ntific val u e of t h e trial; 
 T he  c o n d uct or m a na ge m e nt of t he trial; 
 T he q ualit y a n d/ or safet y of a n y I M P use d i n t he trial. 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 1 3 /1 3 6  
 
 
If a n y ne w e ve nt o cc urs or a n y i nf or mati o n bec o mes a vaila ble re gar di n g eit her c o n d u ct of t h e 
trial or de vel o p me nt of t he I M P, w hic h ma y i m pact safet y of t he patie nt p o p ulati o n or 
e val uati o n of t he ris k- be nefit rati o f or t he cli nical trial, t he S p o ns or will i m me diatel y i nf or m 
t he I n v esti gat ors, a n d a p pr o priate safet y meas ures will be ta ke n t o pr otect s u bjects a gai nst a n y 
i m me diate hazar d. T h e St u d y Safet y Officer ( u n der t he s u p er visi o n of t h e S p o ns or) will als o 
i m me diatel y i nf or m C As a n d E Cs of t hese e v e nts a n d/ or data, a n d t h e meas ures ta ke n. 
Detaile d des cri pti o n of t he n otificati o n, re p orti n g, i n vesti gati o n, a n d i m plicati o ns of safet y 
e ve nts f or t he c o n d u ct of t he cli nical trial, i ncl u di n g s us pe nsi o n of t he trial, safet y-relate d 
a me n d me nts t o t he St u d y Pr ot oc ol, c h a n ge or u p d ate of t h e S u bject I nf or m ati o n S heet a n d I C F, 
a n d/ or I n vesti gat or’s Br oc h ure, is pr o vi de d i n Secti o ns 7 & 8. 
 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 1 4 /1 3 6  
 
 
1 2  A D MI NI S T R A TI V E, L E G A L, A N D E T HI C A L A S P E C T S  
1 2. 1  E t hic al Pri nci ples a n d C o n d uct of t he Tri al 
T he trial will be c o n d uct e d i n acc or da nce wit h all a p plica ble C o m m u nit y a n d nati o nal l a ws, 
re g ulati o ns, g ui d a nce, g ui deli nes, a n d pri nci ples re gar di n g: 
 P r otecti o n of t he ri g hts, safet y, pri vac y, a n d welfare of h u ma n s u bjects 
 Et hi cal pri nci ples f or me dical rese arc h i n v ol vi n g h u ma n s u bjects 
 G o o d Cli nical Practice as re gar ds c o n d uct of cli nical trials a n d i n vesti gati o n al me dici nal 
pr o d ucts f or h u ma n us e 
 C li nical safet y d ata m a na ge me nt, n otificati o n, a n d re p orti n g wit hi n t h e c o nte xt of 
cli nical trials 
 A d va nce d T h er a p y Me di ci nal Pr o d ucts 
 R e q uire me nts a n d sta n d ar ds of q ualit y a n d safet y f or d o nati o n, pr oc ure me nt, testi n g, 
pr ocessi n g, preser vati o n, st ora ge, tr acea bilit y, a n d distri b uti o n of h u ma n tiss ues a n d 
cells 
 G o o d 
Ma n ufact uri n g 
Practice a n d 
q u alit y re q uire me nts f or 
ma n ufact ur e 
of 
i n vesti gati o nal me dici nal pr o d ucts f or h u ma n us e 
 S ta n dar d O perati n g Pr oce d ures ( S O Ps) of t he rele va nt i nstit uti o ns 
T his i ncl u des n ota bl y t he f oll o wi n gs r efere nce d oc u me nts: 
 W orl d Me dical Ass oci ati o n Decl arati o n of Helsi n ki o n Et hical Pri nci ples f or Me dical 
Researc h i n v ol vi n g H u m a n S u bjects ( wit h a me n d me nts) 
 C harter of F u n da me nt al Ri g hts of t he E ur o pea n U ni o n ( 2 0 1 0/ C 2 3/ 0 2) 
 Dire cti ve 9 5/ 4 6/ E C of t he E ur o pea n Parlia me nt a n d of t he C o u ncil of 2 4 Oct o ber 1 9 9 5 
o n t he pr otecti o n of i n di vi d uals wit h re gar d t o t h e pr ocessi n g of pers o nal data a n d o n 
t he free m o ve me nt of s uc h data 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 1 5 /1 3 6  
 
 
 Sta n dar ds f or Pri vac y of I n di vi d uall y I d e ntifia ble Healt h I nf or mati o n - 4 5 C F R Parts 
1 6 0 a n d 1 6 4 ( A pril 0 3, 2 0 0 3, Pri vac y R ule, U nite d States De part me nt of Healt h a n d 
H u ma n Ser vices) 
 Healt h I ns ura n ce P orta bilit y a n d Acc o u nt a bilit y Act of 1 9 9 6, P u blic La w 1 0 4- 9 1 
( A u g ust, 2 1, 1 9 9 6, 1 0 4t h C o n gress, U nite d States of A merica) 
 IC H T o pic E 6 ( R 1) - G ui deli ne f or G o o d Cli nical Practice - (J ul y 1 9 9 6, E ur o pea n 
Me dici nes A ge n c y, C P M P/I C H/ 1 3 5/ 9 5) 
 IC H T o pic E 8 - Ge n eral C o nsi derati o ns f or Cli nical Trials - ( Marc h 1 9 9 8, E ur o pea n 
Me dici nes A ge n c y, C P M P/I C H/ 2 9 1/ 9 5) 
 IC H T o pi c E 9 –  N ote f or g ui d a nce o n statistical pri nci ples f or cli nical trials ( Marc h 
1 9 9 2, E ur o pea n M e dici ne A ge nc y, C P M P/I C H/ 3 6 3/ 9 6) 
 Dire cti ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d of t he C o u ncil of 4 A pril 2 0 0 1 
o n t he a p pr o xi mati o n of t he la ws, re g ulati o ns a n d a d mi nistrati ve pr o visi o ns of t he 
Me m ber States relati n g t o t he i m ple me ntati o n of g o o d cli nical practice i n t he c o n d uct 
of cli nical trials o n me dici nal pr o d ucts f or h u ma n use 
 C o m missi o n Directi ve 2 0 0 5/ 2 8/ E C of 8 A pril 2 0 0 5 la yi n g d o w n pri nci ples a n d detaile d 
g ui deli nes f or g o o d cli nical practice as re gar ds i n vesti gati o nal me dici nal pr o d ucts f or 
h u ma n use, as well as t h e re q uire me nts f or a ut h orisati o n of t he ma n ufact uri n g or 
i m p ortati o n of s uc h pr o d ucts 
 Detaile d G ui deli nes o n G o o d Cli nical Practice s pecific t o A d va nce d T hera p y Me dici n al 
Pr o d ucts - E ur o pea n C o m missi o n ( 0 3 Dece m ber 2 0 0 9, E N T R/ F/ 2/ S F/ d n D) 
 G ui de li ne o n 
H u ma n Cell- Base d 
Me dici n al Pr o d ucts ( 2 1 
Ma y 2 0 0 8, E ur o pea n 
Me dici nes 
A ge n c y, 
C o m mittee 
f or 
Me dici nal 
Pr o d uct 
f or 
H u ma n 
Use, 
E M E A/ C H M P/ 4 1 0 8 6 9/ 2 0 0 6) 
 Reflecti o n Pa per o n Ste m Cell- Base d Me dici nal Pr o d ucts ( 1 4 J a n uar y 2 0 1 1, E ur o pea n 
Me dici nes A ge n c y, C o m mittee f or A d va n ce d T hera pies, E M A/ C A T/ 5 7 1 1 3 4/ 2 0 0 9) 
 I C H T o pi c E 2 A - Cli nical Safet y Data M a na ge me nt : Defi niti o ns a n d Sta n dar ds f or 
E x pe dite d Re p orti n g - (J u ne 1 9 9 5, E ur o pea n Me dici nes A ge nc y, C P M P/I C H/ 3 7 7/ 9 5) 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 1 6 /1 3 6  
 
 
 Detaile d G ui da nce o n t he C ollecti o n, Verificati o n a n d Prese ntati o n of A d verse Reacti o n 
Re p orts arisi n g fr o m Cli nical Trials o n Me dici nal Pr o d ucts f or H u ma n Use - E ur o pea n 
C o m missi o n ( A pril 2 0 0 6, E N T R/ C T 3) 
 Detaile d G ui d a nce o n t he E ur o pea n dat a base of S us pecte d U ne x pecte d Seri o us A d verse 
Reacti o ns ( E u dra vi gila n ce, Cli nical Trial M o d ule) - E ur o pea n C o m missi o n ( A pril 2 0 0 4, 
E N T R/ C T 4) 
 G ui de li ne o n Safet y a n d Efficac y F oll o w- u p Ris k Ma na ge me nt of A d va n ce d T hera p y 
Me dici nal Pr o d ucts ( 2 0 N o ve m ber, 2 0 0 8, E ur o pea n Me dici nes A ge n c y, C o m mittee f or 
Me dical Pr o d ucts f or H u ma n Use – C H M P, E M E A/ 1 4 9 9 9 5/ 2 0 0 8) 
 Dr aft G ui deli ne o n t he Ris k- Bas e d A p pr oac h acc or di n g t o A n ne x I, Part I V of Directi ve 
2 0 0 1/ 8 3/ E C A p plie d t o A d va nce d T hera p y 
Me dici nal Pr o d ucts ( 1 9 J a n uar y 2 0 1 2, 
E ur o pea n Me dici nes A ge nc y, C o m mittee f or Me dici nal Pr o d ucts f or H u ma n Use – 
C H M P, E M A/ C A T/ C P W P/ 6 8 6 6 3 7/ 2 0 1 1) 
 Dire cti ve 2 0 0 4/ 2 3/ E C of t he E ur o pea n Parlia m e nt a n d of t he C o u ncil of 3 1 Marc h 2 0 0 4 
o n setti n g t he sta n dar ds of q ualit y a n d safet y f or t he d o nati o n, pr oc ure me nt, testi n g, 
pr ocessi n g, preser vati o n, st ora ge a n d distri b uti o n of h u ma n tiss ues a n d cells 
 C o m missi o n 
Directi ve 2 0 0 6/ 1 7/ E C of 8 Fe br uar y 2 0 0 6 i m ple me nti n g 
Directi ve 
2 0 0 4/ 2 3/ E C of t he E ur o p ea n Parlia me nt a n d of t he C o u ncil as re gar ds certai n tec h nical 
re q uire me nts f or t he d o n ati o n, pr oc ure m e nt a n d testi n g of h u ma n tiss ues a n d cells 
 C o m missi o n 
Directi ve 2 0 1 2/ 3 9/ E U of 2 6 
N o ve m ber 2 0 1 2 a me n di n g 
Directi v e 
2 0 0 6/ 1 7/ E C of t he E ur o p ea n Parlia me nt a n d of t he C o u ncil as re gar ds certai n tec h nical 
re q uire me nts f or t he testi n g of h u m a n tiss ues a n d cells 
 Dire cti ve 2 0 0 6/ 8 6/ E C of 2 4 Oct o ber 2 0 0 6 i m ple me nti n g Directi ve 2 0 0 4/ 2 3/ E C of t he 
E ur o pea n Parlia me nt a n d of t he 
C o u ncil as re gar ds tracea bilit y re q uire me nts, 
n otificati o n of seri o us a d verse reacti o ns a n d e v e nts a n d certai n tec h nical re q uire me nts 
f or t he c o di n g, pr ocessi n g, pres er vati o n, st ora ge a n d distri b uti o n of h u ma n tiss ues a n d 
cells 
 C o m missi o n Directi ve 2 0 0 9/ 1 2 0/ E C of 1 4 Se pte m ber 2 0 0 9 a me n di n g Directi ve 
2 0 0 1/ 8 3/ E C of t he E ur o pea n Parlia m e nt a n d of t he C o u ncil o n t he C o m m u nit y c o d e 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 1 7 /1 3 6  
 
 
relati n g t o me dici nal pr o d ucts f or h u ma n use as re gar ds a d v a nce d t hera p y m e dici nal 
pr o d ucts 
 R e g ulati o n ( E C) 1 3 9 4/ 2 0 0 7 of t he E ur o pea n Parlia me nt a n d of t he C o u ncil of 1 3 
N o ve m ber 2 0 0 7 o n a d va nce d t hera p y 
me dici nal pr o d ucts a n d a me n di n g Directi ve 
2 0 0 1/ 8 3/ E C a n d Re g ulati o n ( E C) 7 2 6/ 2 0 0 4 
 C o m missi o n Directi ve 2 0 0 3/ 9 4/ E C of 8 Oct o ber 2 0 0 3 la yi n g d o w n t he pri nci ples a n d 
g ui deli nes of g o o d ma n ufact uri n g practice i n res p ect of me dici nal pr o d ucts f or h u ma n 
use a n d i n vesti gati o nal me dici nal pr o d ucts f or h u ma n use 
 E ur o pea n U ni o n G ui deli nes t o G o o d Ma n ufact uri n g Practice - Me dici nal Pr o d ucts f or 
H u ma n a n d Vet eri nar y Use - I n v esti gati o nal M e dici nal Pr o d ucts ( R ules G o ver ni n g 
Pr o d ucts i n t he E ur o pea n U ni o n, E u drale x V ol u me 4, A n ne x e 1 3, 0 3 Fe br uar y 2 0 1 0, 
E N T R/ F/ 2/ A M/a n D ( 2 0 1 0) 3 3 7 4) 
 G ui deli ne o n t he 
Re q uire me nts t o t he 
C h e mical a n d P har mace utical 
Q ualit y 
D oc u me ntati o n c o ncer ni n g I n vesti gati o nal 
Me di ci nal Pr o d ucts i n Cli nical Trials - 
C o m mittee f or 
Me dici n al Pr o d ucts f or H u ma n Use ( C H M P) E ur o pea n 
Me dici nes 
A ge nc y ( 3 1 M arc h 2 0 0 6, C H M P/ Q W P/ 1 8 5 4 0 1/ 2 0 0 4) 
 G ui da nce o n I n vesti gati o nal 
Me dici nal Pr o d ucts (I M Ps) a n d ‘ n o n i n vesti gati o nal 
me dici nal pr o d ucts’ ( NI M Ps) - E ur o pea n C o m missi o n ( 1 8 
Marc h 2 0 1 1, E u drale x 
V ol u me  
1 0  
-  
Cli nical  
Trials,  
N otice  
t o  
A p plica nts, 
S A N C O/ C/ 8/ S F/c g/a. 5. 0 0 1( 2 0 1 1) 3 3 2 8 5 5) 
 P oi nts t o C o nsi der o n t he Ma n ufact ure a n d Q ualit y C o ntr ol of H u ma n S o matic Cell 
T hera p y Me dici nal Pr o d ucts ( 3 1 Ma y 2 0 0 1, E ur o pea n Me dici nes A ge nc y, C o m mittee 
f or Pr o prietar y M e dici nal Pr o d ucts - C P M P) 
 A n d a n y ot her a p plica ble a n d rele va nt nati o nal la ws a n d re g ulati o ns 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 1 8 /1 3 6  
 
 
1 2. 2  He alt h A ut h orities a n d I n de pe n de nt Et hics C o m mittees/I nstit uti o n al Re vie w B o ar d 
Bef ore t he b e gi n ni n g of t he trial: 
 T he Cli nical Tri al A p plic ati o n ( C T A) will be s u b mitte d t o a n d a p pr o ve d/a ut h orize d b y 
t he C As 
 T he  rele va nt E Cs will a p pr o ve a n d/ or pr o vi de fa v o ura ble o pi ni o n o n t he cli nical trial, 
base d o n a c o m pre he nsi ve file, i ncl u di n g (as re q uire d) t he St u d y Pr ot oc ol ( wit h 
a me n d me nts), writte n S u bject I nf or mati o n S heet a n d I nf or m e d C o nse nt F or m, ot her 
writte n i nf or mati o n t o be pr o vi de d t o s u bjects (s uc h as t h e Patie nt St u d y C ar d), s u bject 
recr uit me nt 
pr oce d ures, I n vesti gat or's 
Br oc h ure, a vaila ble safet y i nf or mati o n, 
i nf or mati o n a b o ut p a y m e nts a n d c o m pe nsati o n a vaila ble t o s u bjects, t he I n vesti gat ors 
c urre nt c urric ul u m vitae a n d/ or ot her d oc u me ntati o n e vi de nci n g q ualificati o ns, a list of 
i n v ol ve d E Cs a n d atte n d ees, a n d a n y ot her d oc u me nts t hat t he E Cs ma y nee d t o f ulfil 
its res p o nsi bilities, t he s uita bilit y of t he I n v esti gat or(s), faciliti es, a n d t he met h o ds a n d 
material t o be use d i n o btai ni n g a n d d oc u me nti n g i nf or me d c o nse nt of t he trial s u bjects.  
 T he  a b o ve- me nti o ne d d o c u me nts ma y als o nee d t o be s u bse q ue ntl y re vise d d uri n g t he 
c o urse of t he tri al, f or i nsta nce w he ne ver i m p orta nt ne w i nf or mati o n t hat ma y be 
rele va nt t o t he patie nts' safet y a n d/ or re-e val uati o n of t he ris k/ be nefit rati o bec o mes 
a vaila ble. I n t his case, a n y c h a n ge, u p date, a n d/ or a me n d me nts t o t hese d oc u me nts will 
al wa ys be first s u b mitte d t o a n d a p pr o ve d b y t he C As a n d E Cs pri or t o a n y s u b missi o n 
t o t he patie nts (a n d all c o ncer ne d I n vesti gat ors a n d I n v esti gati n g Sites). 
 
T he S p o ns or has pre pare d a te m plate of t he I C F, w hic h e m b o dies t he I C H G C P re q uire d 
ele me nts a n d i ncl u des a n y l o cal re g ul ati o ns t o be discl ose d f or t he c o ns e nt t o be le gall y 
effecti ve.  
T he fi nal v ersi o n of t he St u d y Pr ot oc ol, t he S u bject I nf or mati o n S heet a n d I C F, will be 
s u b mitte d t o a n d a p pr o ve d a n d/ or pr o vi de d a fa v o ura ble o pi ni o n i n writi n g b y t h e rele va nt C As 
a n d E Cs bef ore t he be gi n ni n g of t he trial. T hese d oc u me nts (a n d t he I n v esti gat or Br oc h ure) 
ma y als o nee d t o be s u bse q ue ntl y re vise d d uri n g t he c o urse of t he trial, w he ne ver i m p orta nt 
ne w i nf or mati o n t hat ma y b e rele v a nt t o t he patie nts' safet y a n d/ or re-e val uati o n of t he 
ris k/ be nefit rati o b ec o mes a vaila ble. I n t his cas e, a n y c ha n ge, u p dat e, a n d/ or a me n d me nts t o 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 1 9 /1 3 6  
 
 
t hese d oc u me nts will al wa ys be first s u b mitte d t o a n d a p pr o ve d b y t he C As a n d E Cs pri or t o 
a n y s u b missi o n t o t he patie nts (a n d all c o ncer ne d I n vesti gat ors a n d I n vesti gati n g Sites).  
T he I n v esti gat or a n d I n v esti gati n g Site will n ot i nitiate n or a p pl y a n y st u d y pr oce d ure or deli ver 
I M P u ntil a p pr o vals ha ve bee n o btai ne d fr o m t he C As a n d E Cs. C o pies of a n y c orres p o n d e nce 
bet wee n t he I n vesti gat or a n d t he C As a n d/ or E Cs will be gi ve n t o t he C R O or t he S p o ns or. 
T he I n v esti gat or will i m me diatel y n otif y t he St u d y Safet y Officer a n d/ or t h e S p o ns or a b o ut t h e 
occ urre nce of a n y S A E a n d ot her rele va nt Seri o us A d verse Safet y/ Q u alit y E ve nts, i n or der t o 
all o w pr o per n otificati o n a n d re p orti n g of t h es e e ve nts t o t he C As, E Cs, a n d t he ot her 
I n v esti gat ors i n v ol ve d i n t he trial. Detaile d descri pti o n of Safet y Dat a N otificati o n, Re p orti n g, 
a n d Ma na ge m e nt pr oce d ures is pr o vi de d i n Secti o n 7 ). 
T he  S p o ns or ( wit h or wit h o ut t he s u p p ort fr o m t h e C R O) is res p o nsi ble f or s u b mitti n g t o t he 
C As a n d E Cs a n y a m e n d me nt t o t he St u d y Pr ot oc ol, a n d a n y c ha n ges t o t he S u bject I nf or mati o n 
S heet a n d I nf or me d 
C o nse nt a n d/ or I n v esti gat or’s 
Br oc h ure, f or a p pr o val pri or t o 
i m ple me ntati o n. 
T he I n vesti gat or will pre pare a n d s u b mit ( wit h or wit h o ut t he s u p p ort fr o m t he C R O) a n n ual 
re p orts t o t he C A S a n d E Cs, a n d acc or di n g t o l ocal re g ulati o ns a n d g ui deli nes. T he I n v esti gat or 
( wit h s u p p ort fr o m t he St u d y Safet y Officer) m ust als o pr o vi de t he C As a n d E Cs wit h a n y 
re p orts of S A Es fr o m t he st u d y site, as dictate d b y t he C As a n d E Cs re q uire me nts. 
T he  C As a n d E Cs will b e n otifie d b y t h e S p o ns or a b o ut t he e n d of t he trial wit hi n 9 0 da ys. If 
t he trial is ter mi nat e d earlier, t he C As will be n otifie d wit hi n 1 5 da ys. A re p ort s u m marisi n g 
t he st u d y res ults will be se nt t o t he C As wit hi n o ne year after t he e n d of t he trial. 
1 2. 3  S u bject D at a Pr otecti o n a n d C o nfi de nti alit y 
T he c o nfi de ntialit y of dat a a n d rec or ds t hat c o ul d i de ntif y patie nts will be pr otecte d i n or der t o 
res pect pri vac y a n d c o nfi de ntialit y r ules, i n acc or da nce wit h all a p plica bl e C o m m u nit y a n d 
nati o nal le gislati o n a n d re g ul at or y re q uire me nts (see t he refere n ce d o c u me nts i n Secti o n 1 2. 1). 
A re p ort of t he res ults of t he st u d y m a y b e p u blis he d or se nt t o t he a p pr o priate C As i n a n y 
c o u ntr y i n w hic h t h e st u d y dr u g ma y ulti matel y be mar kete d, b ut t he patie nt's n a me will n ot be 
discl ose d i n t hese d oc u me nts. T he patie nt's na m e ma y be discl ose d t o t h e C R A  or t he C As, 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 2 0 /1 3 6  
 
 
d uri n g i ns pe cti o ns of trial rec or ds a n d data. A p pr o priate preca uti o ns will al wa ys be ta ke n t o 
mai ntai n c o nfi de ntialit y of me dical r ec or ds a n d p ers o nal i nf or mati o n. 
B y t he wa y of t he I C F, writte n a ut h orisati o n will be o btai ne d fr o m eac h p atie nt pri or t o e ntr y 
i nt o t he st u d y, i n acc or da nce wit h a p plica bl e C o m m u nit y a n d nati o nal le gislati o n a n d re g ulat or y 
re q uire me nts (s ee t he refere nce d oc u m e nts i n Secti o n 1 2. 1). T he patie nts will be i nf or me d t hat 
t he res ults will be ke pt a n d a nal ys e d i n a c o m p uter b ut t hat n ot hi n g a part fr o m w hat has bee n 
rec or de d i n t he C R F will be re gistere d. T h e y will als o be i nf or me d t hat t heir data will o nl y be 
a vaila ble t o t he a b o v e- m e nti o ne d e ntities. 
T he writte n I C F will e x plai n t hat st u d y d ata will b e st ore d i n a c o m p uter d ata b ase, mai ntai ni n g 
c o nfi de ntialit y i n acc or da nce wit h all a p plica ble C o m m u nit y a n d nati o n al le gislati o n a n d 
re g ulat or y re q uire me nts. T he patie nt‘s na mes will n ot be rec or de d i n t his data base. T he writte n 
I C F will als o e x plai n t hat, f or data verificati o n p ur p oses, a ut h orise d re prese ntati ves of t h e 
S p o ns or (i ncl u di n g C R A, C R O), C As, a n d/ or E Cs ma y re q uir e direct access t o parts of t h e 
h os pital or practice rec or ds rele va nt t o t he st u d y, i ncl u di n g patie nts' me dical hist or y. 
F i nall y, i n or der t o e ns ure pr o per i d e ntificati o n of t he patie nt, t o get h er wit h t he re q uir e me nts as 
re gar ds pr otecti o n of pri v ac y a n d c o nfi de ntialit y of pers o nal data a n d m e dical rec or ds, a u ni q ue 
i de ntificati o n c o de ( Patie nt I de ntificati o n N u m ber) will be all ocat e d d uri n g scree ni n g of t he 
patie nt. T he li n k bet wee n t he i de ntit y of t he patie nt a n d t he i de ntificati o n c o de will be pr otecte d 
a n d ke pt strictl y c o nfi d e ntial. T his i nf or mati o n will be k n o w n a n d rec or de d o nly  b y t he 
I n v esti gat or a n d will be k e pt a n d rec or de d i n restri cte d access files: t he I n vesti gat or’s Site File 
at t he I n vesti gati n g Site.  
1 2. 4  I ns ur a nce 
T he S p o ns or ’s lia bilities i n c o n necti o n wit h t he st u d y will be c o vere d b y a n i ns ura nce p olic y, 
i ncl u di n g a n y e v e nt, da m a ge, i nj ur y, or deat h of t h e patie nt, o cc urri n g d uri n g t h e c o urse of t he 
st u d y a n d bei n g or n ot, directl y or i n directl y, li n ke d t o t he st u d y, a n d i n acc or da n ce wit h a n y 
a p plica ble C o m m u nit y a n d nati o nal le gislati o n a n d re g ulat or y re q uire me nts. 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 2 1 /1 3 6  
 
 
T he S p o ns or i ns ura nce will als o c o ver all i n di vi d uals partici pati n g t o a n d/ or i nter ve ni n g i n t he 
st u d y, i n de pe n d e ntl y fr o m t he nat ure of t he e xisti n g li n k bet wee n t he S p o ns or, partici pa nt, a n d 
patie nt. 
1 2. 5  F i n a nci al as pects 
Fi na ncial d etails re gar di n g perf or ma n ce of t he st u d y will be s pecifie d i n a n I n vesti gat or’s 
A gree me nt si g n e d b y t h e S p o ns or a n d t he I n vesti gat or (a n d relate d parties if nee d e d) b ef ore 
start of t he st u d y. 
T he I n vesti gat or at eac h site m ust c o m pl y wit h all t he ter ms, c o n diti o ns, a n d o bli gati o ns of t he 
I n v esti gat or’s A gree me nt. 
1 2. 6  Ar c hi vi n g at t he E n d of t he St u d y 
After t he cl ose- o ut visit at eac h site, a c o p y of t h e f oll o wi n g d oc u me ntati o n ( n o n-e x ha usti ve 
list) will be st ore d i n t he I n vesti gat or's arc hi ves f or a peri o d of ti me of 3 0 years acc or di n g t o 
E ur o pea n dir ecti ves, n ati o nal la ws a n d S p o ns or’s S O P.  Arc hi vi n g res p o nsi bilities ca n n ot be 
tra nsferre d t o t he S p o ns or. 
 In v esti gat or's Trial Mast er Site File wit h t he fi n al Pr ot oc ol a n d c urre nt I n v esti gat or 
Br oc h ure 
 C o p y of c o m plet e d C R Fs, S A E, a n d Pre g na nc y F or ms 
 S i g ne d I C Fs 
 P atie nt scree ni n g/i ncl usi o n l o g a n d Patie nt/ S u bject I d e ntificati o n C o de List 
 S o urce d oc u me ntati o n 
 All re q uire d re g ulat or y d oc u me nts re q uire d b y I C H- G C P, a n d a n y ot her a p plica ble 
C o m m u nit y a n d/ or n ati o nal la ws a n d re g ulati o ns 
All st u d y-relat e d d oc u me ntati o n m ust be st ore d i n a sec ure ma n ner a n d m ust re mai n a vaila ble 
u p o n re q uest fr o m t he S p o ns or or a n y C As a n d/ or E Cs. 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 2 2 /1 3 6  
 
 
Bef ore or at t he e n d of t h e arc hi vi n g peri o d, t he S p o ns or ca n re q uest a n e xte nsi o n of t he st ora ge 
of all materi als, or part of t he m, f or a f urt her p eri o d. A n a p pr o priate a gree me nt will be dra w n 
u p acc or di n gl y. If a n e xte nsi o n of t he st ora ge is n ot re q uir e d, it is t he res p o nsi bilit y of t he 
I n v esti gat or t o d eci de t o destr o y or kee p t hes e st u d y-relate d materi als after t his arc hi vi n g 
peri o d. 
It is t he res p o nsi bilit y of t he S p o ns or t o i nf or m t he sit es w he n arc hi vi n g is n o l o n ger nee d e d. 
 
 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 2 3 /1 3 6  
 
 
1 3  R E P O R TI N G A N D P U B LI C A TI O N S P O LI C Y 
1 3. 1  Cli n ic al St u d y Re p ort 
W he n all c o m plete d C R Fs a n d all Data Clarificati o n F or ms ( D C Fs) will ha ve bee n c ollect e d, 
a n d w he n all c ollecte d data will ha ve bee n a nal yse d, a draft of t h e Cli nical St u d y Re p ort ( C S R) 
will be pr o d uce d a n d se nt t o t he Pri nci pal I n vesti gat ors ( desi g n ate d pri or t o writi n g), f or re vie w 
a n d c o m me nts.  
T he C S R will i ncl u de t he "I n di vi d ual Patie nt Dat a Listi n g" ( 1 6. 4 of C S R acc or di n g t o t he I C H). 
T he res ults will be ta b ul ate d, e val u ate d, a n d iss u e d as a c o m plete fi nal Cli nical St u d y Re p ort 
acc or di n g t o t he I C H- E 3 “ N ote f or g ui da nce o n str uct ure a n d c o nte nt of cli nical st u d y re p orts ” . 
T his re p ort will be writte n i n E n glis h. 
T he S p o ns or will se n d a s u m mar y of t his Cli nical St u d y Re p ort t o b ot h t he C As a n d E Cs wit hi n 
o ne year after t he e n d of t he trial.  
1 3. 2  P u blic ati o ns a n d P osters 
A n y a n d all S p o ns or C o nfi de ntial I nf or mati o n, i ncl u di n g b ut n ot li mite d t o scie ntific, tec h nical, 
cli nical, me dical a n d/ or re g ulat or y i nf or mati o n, d oc u me nts, data a n d dat a bases, b asic a n d/ or 
cli nical researc h res ults, pr o d uct i nf or mati o n a n d met h o ds, materials, pate nts a n d pate nt 
a p plicati o ns, k n o wle d ge, k n o w- h o w, i deas, c o nce pts, desi g n, al g orit h ms, tra de secrets, researc h 
a n d de v el o p me nt acti vities, pr ojects, a n d pla ns, strate gic orie ntati o ns, str u ct ure, or ga nizati o n 
a n d c olla b orati o ns, c o ntr acts a n d a gree me nts, b usi ness, fi na ncial a n d/ or m ar keti n g pla ns a n d 
i nf or mati o n, w het her i n oral, writte n (i n cl u di n g b ut n ot li mite d t o writte n d oc u me nts, 
me m ora n d u m, 
mi n utes, c orres p o n de nce, re p orts), gra p hic (i ncl u di n g b ut n ot li mite d t o 
dra wi n gs, fi g ures, sc he m a or ot her material) or c o m p uter-rea da ble f or m, will re mai n t he s ole 
pr o pert y of t he S p o ns or. 
A n y a n d all St u d y data, data bases, res ults, materials, a nal ysis, i nf or mati o n, d oc u me nts, a n d 
re p orts (i ncl u di n g b ut n ot li mite d t o C R Fs) ge nerate d, create d, writte n, a n d/ or ot her wise 
c ollecte d or o btai n e d d uri n g ( or i n c o n n ecti o n wit h) t he St u d y u n d er t he St u d y Pr ot o c ol (e x ce pt 
f or St u d y patie nt’s me di cal rec or ds), w het her i n oral, writte n (i n cl u di n g b ut n ot li mite d t o 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 2 4 /1 3 6  
 
 
d oc u me nts, me m ora n d u m, mi n utes, re p orts, c orres p o n de n ce), gra p hic (i ncl u di n g b ut n ot 
li mite d t o dra wi n gs, fi g ures, sc he m a or ot her material) or c o m p uter-rea d a ble f or m, will b ec o me 
t he pr o pert y of t he S p o ns or. 
T he I n vesti gat or, w h o will ha ve i nf or mati o n or data of a n y ki n d pertai ni n g t o t he St u d y, 
i ncl u di n g b ut n ot li mite d t o St u d y res ults fr o m i n di vi d ual St u d y sites, as well as a n y S p o ns or 
C o nfi de ntial I nf or mati o n f or t he p ur p ose of t he St u d y, w het her i n a n y a n d all i nta n gi ble a n d/ or 
ta n gi ble e x pressi o ns, i n a n y me dia, i n stri ct c o nfi d e nce, s h all n ot directl y or i n directl y p u blis h, 
c o m m u nicate, disse mi nate, dis pla y, deli ver, distri b ute, re pr o d uce, discl os e, or ot her wise ma ke 
a vaila ble s uc h i nf or mati o n a n d/ or data t o a n y t hir d part y pri or writte n a p pr o val fr o m t he 
S p o ns or. 
P u blicati o n, c o m m u nicati o n (i ncl u di n g b ut n ot li mite d t o a bstracts a n d p osters), discl os ur e, 
releas e, or disse mi nati o n of a n y i nf or mati o n or data of a n y ki n d pertai ni n g t o t h e st u d y, 
i ncl u di n g st u d y res ults fr o m i n di vi d ual st u d y sites, is h o we ver p ossi ble i n m ut ual a gree me nt 
bet wee n t he I n vesti gat or a n d t he S p o ns or, pr o vi de d t hat:  
 A n y pr o p ose d c o m m u nicati o n (i ncl u di n g, b ut n ot li mite d t o a bstracts a n d p osters) or 
p u blicati o n will be s u b mitte d t o t he S p o ns or pri or t o a n y s u b missi o n; a n d 
 A n y pr o p os e d c o m m u nic ati o n or p u blicati o n will reflect t he c olla b orati o n a n d res pecti ve 
r oles of t he I n v esti gat ors, I n v esti gati n g Sites, a n d S p o ns or’s pers o n nel; a n d 
 T he  S p o ns or s hall be gi ve n t hirt y ( 3 0) da ys t o re vie w c o m m u nicati o ns (a bstracts a n d 
p osters), a n d si xt y ( 6 0) d a ys t o r e vie w p u blicati o ns; a n d 
 I n t he e ve nt t hat t he S p o ns or d oes n ot o bject t o t he pr o p ose d c o m m u nicati o n or 
p u blicati o n wit hi n t hirt y ( 3 0) da ys or si xt y ( 6 0) da ys of its recei pt res pecti vel y, as t he case 
ma y b e, it will be dee me d t o ha ve bee n a p pr o ve d; a n d 
 In t he e v e nt t hat t he S p o ns or  o bjects t o t he pr o p ose d c o m m u nicati o n or p u blicati o n f or 
reas o ns relati n g t o t he p ate nta bilit y of a n i n ve nti o n or t he pr otecti o n of a n y ot her f or ms 
of i ntellect ual pr o pert y ri g hts t hat w o ul d be discl ose d b y s uc h pr o p ose d c o m m u nicati o n 
or p u blicati o n, t he n s u b missi o n of t he c o m m u nicati o n or p u blicati o n will be dela ye d f or 
a ma xi m u m of si x ( 6) m o nt hs t o e na ble t he S p o ns or t o pr otect its ri g hts; a n d 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 2 5 /1 3 6  
 
 
 I n t he e ve nt t hat B o ne T hera pe utics reas o n a bl y o bjects t o t he pr o p ose d c o m m u nicati o n 
or p u blicati o n as c o nflicti n g wit h or c o m pr o misi n g t he S p o ns or’s i ntellect ual pr o pert y 
ri g hts or i nterests, t he pr o p ose d c o m m u nicati o n or p u blicati o n s hall be m o difie d i n or der 
t o f ull y a d dress t he S p o ns or’s c o ncer ns a n d re q uests of m o dificati o ns (i ncl u di n g, b ut n ot 
limite d t o deleti o n of a n y S p o ns or C o nfi de ntial I nf or mati o n fr o m t he pr o p os e d 
c o m m u nicati o n or p u blicati o n), a n d s uc h m o difi e d c o m m u nicati o n or p u blicati o n ma y 
n ot be s u b mitte d, p u blis he d, discl ose d, or disse mi nate d u ntil t he S p o ns or has c o nfir me d 
its a gree me nt i n writi n g; a n d 
 A n y o bjecti o n/re q ueste d m o dificati o n ma de b y t he S p o ns or c o ncer ni n g a pr o p ose d 
c o m m u nicati o n or p u blicati o n s hall be i m ple me nte d. 
 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 2 6 /1 3 6  
 
 
1 4  R E F E R E N C E S 
- Al - A ql Z. S, Ala gl A. S, Gra ves D. T, Gerste nfel d L. C, Ei n h or n T. A. M olec ul ar Mec h a nis ms 
C o ntr olli n g B o ne F or m ati o n d uri n g Fract ure Heali n g a n d Distracti o n Oste o ge nesis. J 
D E N T R E S Fe br uar y 2 0 0 8; 8 7: 1 0 7- 1 1 8. 
- Alt V, Me yer C, Litzl ba uer H D, Sc h n ettler R. Treat me nt of a d o u ble n o n u ni o n of t he fe m ur 
b y r h B M P- 2. J Ort h o p Tra u ma. 2 0 0 7; 2 1( 1 0): 7 3 4- 7 3 7. 
- A merica n C olle ge of R he u mat ol o g y ( A C R), c o m mittee t o ree val uate i m pr o ve me nt criteria, 
2 0 0 7. A pr o p ose d Re visi o n t o t he A C R 2 0: T he h y bri d M eas ure of A meri ca n C olle ge of 
R he u mat ol o g y Res p o nse. 2 0 0 7; 5 7( 2): 1 9 3- 2 0 2 
- A x elra d T. W, Ei n h or n T. A. Use of Cli nical Ass ess me nt T o ols i n t he E v al uati o n of Fract ure 
Heali n g. I nj ur y. I nt. J. Care I nj ure d 2 0 1 1; 4 2: 3 0 1- 3 0 5. 
- Baja d a S , Mars hall MJ , Wri g ht K T , Ric har ds o n J B , J o h ns o n W E. Decreas e d oste o ge nesis, 
i ncreas e d cell se nesce n ce a n d ele vate d Dic k k o pf- 1 secreti o n i n h u ma n fract ure n o n- u ni o n 
str o mal cells. B o ne.  2 0 0 9; 4 5( 4): 7 2 6- 3 5 
- B ha n dari M, G u yatt G, S wi o nt k o ws ki M. F., T or netta P, S pra g ue S, Sc he mitsc h E. H, A 
lack of c o nse ns us i n t he assess me nt of fract ur e heali n g a m o n g ort h o pae dic s ur ge o ns, 
J o ur nal of ort h o pae dic Tra u ma, 2 0 0 2; 1 6 ( 8): 5 6 2- 5 6 6 
- B ha n dari M, F o n g K, S pra g ue S, Willia ms D, Pe tris or B, Varia bilit y i n t he defi niti o n a n d 
percei v e d ca uses of dela ye d u ni o n a n d n o n u ni o ns, T he J o ur nal of B o ne a n d J oi nt S ur ger y, 
2 0 1 2, 9 4:e 1 0 9( 1- 6) 
- B hattac h ar y ya T, B o uc h ar d K, P ha d k e A, Mei gs J. B, Kassarjia n A, Sala mi p o ur H. T he 
Acc urac y of C o m p ute d T o m o gra p h y f or t h e Dia g n osis of Ti bial N o n u ni o n. J B o ne J oi nt 
S ur g A m.  2 0 0 6; 8 8( 4): 6 9 2- 6 9 7  
- Bis h o p J A, Pala nca A A, Belli n o 
MJ, L o we n ber g D W. Assess me nt of c o m pr o mise d 
fract ur e heali n g. J A m Aca d Ort h o p S ur g 2 0 1 2; 2 0: 2 7 3- 2 8 2 
- Brei vi k H, B orc h gre vi n k P C, Alle n S M, R ossela n d L, Brei vi k Hals E K, K varstei n G, 
St u b ha u g A. Assess m e nt of pai n. Br. J. A naest h. 2 0 0 8; 1 0 1: 1 7- 2 4. 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 2 7 /1 3 6  
 
 
- Br ya nt D , Fer na n des N . 
Meas uri n g patie nt o utc o mes: a pri mer. I nj ur y. 2 0 1 1 
Mar; 
4 2( 3): 2 3 2- 5.  
- B usse J, B ha n d ari M, K ul kar ni A, T u n ks E. T h e effect of l o w-i nte nsit y p ulse d ultras o u n d 
t hera p y o n ti me t o fract ur e heali n g: a meta-a nal ysis. C M AJ, 2 0 0 2; 1 6 6( 4): 4 3 7- 4 1 
- Cal ori G M, Al bisetti 
W., A g us A, L ori S, Ta glia b ue L. Ris ks fact ors c o ntri b uti n g t o 
fract ur e n o n- u ni o ns. I nj ur y I nt. J. Care I nj ure d. 2 0 0 7; 3 8 5: S 1 1- 1 8. 
- C orrales L A, M ors he d S, B ha n d ari M, Micla u T. Varia bilit y i n t h e assess me nt of fract ur e-
heali n g i n ort h o p ae dic tra u ma st u dies. J. B o ne J oi nt S ur g. A m. 2 0 0 8; 9 0: 1 8 6 2- 1 8 6 8. 
- C o urt- Br o w n C a n d Mc Q uee n M.  C o m part me nt s y n dr o me dela ys ti bial u ni o n. Acta 
Ort h o p Sca n d. 1 9 8 7; 5 8: 2 4 9- 5 2. 
- Cr o wle y DJ, Ka na karis N K, Gia n n o u dis P V. Fe m oral dia p h yseal ase ptic n o n- u ni o ns: Is 
t here a n i de al met h o d of treat me nt? I nt. J. Care I nj ure d 2 0 0 7; 3 8: S 5 5- 6 3. 
- Ei n h or n T A. E n ha nse me nt of fract ure heali n g. J B o ne J oi nt S ur g A m. 1 9 9 5; 7 7( 6): 9 4 0- 5 6 
- Ellis H. T he s p ee d of h eali n g after fract ure of t he ti bial s haft. J B o ne J oi nt S ur g; 1 9 5 8; 4 0-
B: 4 2- 6 
- Fels o n D T , Z ha n g Y , H a n na n M T , Nai mar k A , Weiss ma n B , Alia ba di P , Le v y D . Ris k 
fact ors f or i n ci de nt ra di o gra p hic k nee oste o art hritis i n t he el d erl y: t he Fra mi n g ha m St u d y. 
Art hritis R he u m.  1 9 9 7; 4 0( 4): 7 2 8- 3 3. 
- Frie dla e n der G E , Perr y C R , C ole J D , C o o k S D , Cier n y G , M usc hler G F , Z yc h G A , 
Cal h o u n J H , La F ort e AJ , Yi n S . Oste o ge nic pr otei n- 1 ( B o n e M or p h o ge n etic Pr otei n- 7) i n 
t he treat me nt of ti bial n o n u ni o ns: A pr os pecti ve, ra n d o mize d cli nical trial c o m pari n g 
R H O P- 1 wit h fres h b o ne. J. B o ne J oi nt S ur g. A m. 2 0 0 1; 8 3 A( 1, Pt 2): S 1 5 1- 1 5 8. 
- Gast o n M S a n d Si m ps o n A H. I n hi biti o n of fract ure heali n g. J B o ne J oi nt S ur g Br, 2 0 0 7; 
8 9( 1 2): 1 5 5 3- 6 0. 
- Ge or ge A , P o pe J E . T he mi ni mall y i m p orta nt differe n ce ( MI D) f or patie nt-re p ort e d 
o utc o mes i ncl u di n g p ai n, fati g u e, slee p a n d t he healt h assess me nt q uesti o n naire disa bilit y 
i n de x ( H A Q- DI) i n pri mar y Sj ö gre n's s y n dr o me. Cli n E x p R he u mat ol.  2 0 1 1; 2 9( 2): 2 4 8-
5 3.  


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 2 8 /1 3 6  
 
 
- Gia n n o u dis, P V, Mac D o nal d, D A, Matt he ws SJ, S mit h, R M, F url o n g, AJ, a n d De B oer, P. 
N o n u ni o n of t he fe m or al dia p h ysis: T he i nfl ue n ce of rea mi n g a n d n o n-ster oi dal a nti-
i nfla mat or y dr u gs. J B o ne J oi nt S ur g. 2 0 0 0; 8 2- B: 6 5 5- 8. 
- Ha k DJ, Fitz patric k D, Bis h o p J A, Mars h J L, Til p S, Sc h nettler R, Si m ps o n H, Alt V. 
Dela ye d u ni o n a n d n o n u ni o ns: E pi de mi ol o g y, cli nical iss ues, a n d fi na n cial as pects. I nj ur y 
2 0 1 4; 4 5 S: S 3- S 7  
- Ha uze ur J P, Orl off S, Ta ver ne -Ver ba nc k J, Pasteels J L. Dia g n osis of ase pti c oste o necr osis 
of t he fe m or al hea d b y perc uta n e o us  tra nstr oc h a nteria n nee dl e bi o ps y. Cli n R he u mat ol. 
1 9 8 6; 5: 3 4 6 -3 5 8.  
- Ha ys R D, M orales L S. T he R A N D- 3 6 meas ure of healt h-rel ate d q ualit y of life. A n n Me d 
2 0 0 1; 3 3( 5): 3 5 0- 7 
- Hec k ma n J, Saras o h n- K a h n J. T he ec o n o mics of tr eati n g fract ure ti bia, t he c ost of dela ye d 
u ni o n. B ulleti n H os pital f or J oi nt diseases, 1 9 9 7; 5 6( 1) 
- J o nes C B , Ma y o K A . N o n u ni o n treat me nt: iliac crest b o n e graft tec h ni q ues. J Ort h o p 
Tra u ma.  2 0 0 5 N o v- Dec; 1 9( 1 0 S u p pl): S 1 1- 3. 
- Ka na karis N, Pali o beis C H, Ma ni da kis N, Gia n n o u dis P. Bi ol o gical e n ha nce me nt of ti bial 
dia p h yseal as e ptic n o n- u ni o ns: t he efficac y of a ut ol o g o us b o ne grafti n g, B M Ps a n d 
rea mi n g b y- pr o d ucts. I nj ur y 2 0 0 7; 3 8 S: S 6 5- S 7 5. 
- Kell y A M. D oes t h e Cli nical Si g nifi ca nt Differe nce i n Vis ual A nal o g Scale Pai n Sc ores 
Var y wit h Ge n d er, A ge, or Ca use of Pai n? Aca de mic E mer ge n c y Me di ci ne. N o ve m ber 
1 9 9 8, v ol u me 5, n u m ber 1 1 
- Kell y A M. T h e mi ni m u m cli nicall y si g nifica nt differe n ce i n vis ual a nal o g ue scale p ai n 
sc ore d oes n ot differ wit h se verit y of pai n. E mer g. Me d. J. 2 0 0 1; 1 8: 2 0 5- 2 0 7. 
- Ke n dall H, S pe nce J, M ur p h y M. F, Re vie w of Pai n- Meas ure me nt T o ols. A n n E mer g Me d 
A pril 1 9 9 6; 2 7: 4 2 7- 4 3 2. 
- K n o x H. T, Cli nical vers us Statistical Si g nifica nce i n t he Assess me nt of Pai n Relief. A n n 
E mer g Me d A pril 1 9 9 6; 2 7: 4 3 9- 4 4 1. 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 2 9 /1 3 6  
 
 
- K o nta kis G M et al. I ntr a me d ullar y naili n g f or n o n- u ni o n of t he h u meral dia p h ysis: A 
re vie w. I nt. J. Care I nj ur e d 2 0 0 6; 3 7: 9 5 3- 9 6 0. 
- K o oistra B W, Dij k ma n B G, B usse J W, S pra g ue S, Sc h mitsc h E H, B ha n dri M. ra di o gra p hic 
u ni o n scale i n ti bial fract ures: relia bilit y a n d vali dit y. J. Ort h o p. Tra u ma. 2 0 1 0; 2 4: S 8 1-
S 8 6  
- K w o k T , P o pe J E . 
Mi ni mall y i m p orta nt differe nce f or patie nt-re p orte d o utc o mes i n 
ps oriatic art hritis: Healt h Assess me nt Q uesti o n naire a n d p ai n, fati g u e, a n d gl o bal vis ual 
a nal o g scales. J R he u mat ol. 2 0 1 0  Ma y; 3 7( 5): 1 0 2 4- 8.  
- Ma ki n o T, Ha k DJ, Hazel w o o d SJ, C urtiss S, Re d di A H. Pre ve nti o n of atr o p hic n o n u ni o n 
de vel o p me nt b y rec o m bi na nt h u ma n b o n e m or p h o ge n etic pr ot ei n- 7. J Ort h o p Res. 2 0 0 5; 
2 3( 3): 6 3 2- 6 3 8. 
- Mc Q uee n 
M M, C hristie J, C o urt- Br o w n C M. Ac ute c o m part me nt s y n dr o me i n ti bial 
dia p h yseal fract ur es. J B o ne J oi nt S ur g Br 1 9 9 6; 7 8 ( 1): 9 5- 8. 
- Me gas P. Classificati o n of n o n- u ni o n. I nj ur y, I nt J Care I nj ur e d. 2 0 0 5; 3 6 S: S 3 0- S 3 7. 
- M ora R., 
Pale y D., N o n u ni o n  of t he L o n g B o nes: Dia g n osis a n d treat me nt wit h 
c o m pressi o n -distracti o n t ec h ni q ue. Marc h 8, S pri n ger e diti o n( 1), Mar 8, 2 0 0 6 . 
- M ors he d S, C orrales L, Ge na nt, Micla u T. O ut c o me Assess me nt i n Cli nical Trials of 
Fract ure- Heali n g. J B o ne J oi nt S ur g A m. 2 0 0 8; 9 0( S u p pl 1): 6 2- 7. 
- M üller M E, Nazari a n S, K oc h P, Sc hatz ker J. T he c o m pre he nsi ve classi ﬁcati o n of fract ures 
of l o n g b o n es. Berli n: S pri n ger- V erla g, 1 9 9 0. 
- Nic oll E. A. Fract ur es of t he ti bial s haft: a s ur ve y of 7 0 5 cas es. J B o ne J oi nt S ur g. 1 9 6 4; 
4 6- B: 3 7 3- 8 7 
- N oci ni P F , Be d o g ni A , V alsecc hi S , Tre visi ol L , Ferrari F , Fi or A , Saia G . Of t he iliac crest 
f oll o wi n g a nteri or a n d p osteri or b o ne graft har vesti n g: Re vie w of t he literat ure a n d case 
prese ntati o n. Mi ner va St o mat ol. 2 0 0 3; 5 2 ( 1 0). 
- Oa kle y MJ , S mit h W R , M or ga n SJ , Zira n N M , Zira n B H . Re p etiti ve p osteri or iliac crest 
a ut o graft h ar vest res ulti n g i n a n u nsta ble pel vic fract ure a n d i nf ecte d n o n- u ni o n: Case 
re p ort a n d re vie w of t he literat ure. Patie nt Safet y i n S ur ger y 2 0 0 7; 1: 6. 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 3 0 /1 3 6  
 
 
- Osi graft ®  Pr o d uct I nf or mati o n a n d Scie ntific Disc ussi o n, E P A R p u blis he d o n E M A 
we bsite, 0 2/ 0 4/ 2 0 0 8 Osi graft- H- C- 2 9 3- II- 3 8 
- Pies ke O , Witt ma n n A , Zas pel J , L öffl er T , R u be n ba uer B , Tre ntzsc h H , P iltz S. B o ne graft 
vers us de mi neralise d b o ne matri x i n i nter nal fi x ati o n of u n u nite d l o n g b o nes. J o ur nal of 
Tra u ma Ma n a ge me nt & O utc o mes 2 0 0 9; 3: 1 1. 
- P o pe J E , K ha n na D , N orrie D , O ui met J M. T he mi ni mall y  i m p ort a nt differe nce  f or t he 
healt h  assess me nt  q uesti o n naire  i n r he u mat oi d art hritis cli nical practice is s maller t ha n i n 
ra n d o mize d c o ntr olle d trials. J R he u mat ol. 2 0 0 9 Fe b; 3 6( 2): 2 5 4- 9. 
- Pr oietti L , Mala p o nte G , Li bra M , Na v ola nic P M , Be velac q u a Y , Tra vali S , Mazzari n o 
M C . A nal ysis of he patitis C vir us i nfecti o n a m o n g healt h-care w or k ers: a n o bser vati o nal 
st u d y. Mi ner v a Gastr o e nter ol Diet ol.  2 0 0 5 Se p; 5 1( 3): 2 5 5- 9. 
- R o n ga M, Bal d o F, Za p pala G, C her u bi n o P. Rec o m bi na nt h u ma n b o ne m or p h o ge neti c 
pr otei n- 7 f or treat me nt of l o n g b o ne n o n- u ni o n : A n o bser vati o nal, retr os pecti ve, n o n-
ra n d o mize d st u d y of 1 0 5 patie nts. I nj ur y 2 0 0 6; 3 7 S: S 5 1- S 5 6. 
- Sa msa G, E del ma n D, R ot h ma n M L, Willia ms G R, Li ps c o m b J, Matc har D. Deter mi ni n g 
cli nicall y i m p orta nt differe nces i n healt h stat us meas ures: a ge n eral a p pr oac h wit h 
ill ustrati o n t o t he Healt h Utilities I n de x Mar k II. P har mac o ec o n o mics, 1 9 9 9; 1 5: 1 4 1- 5 5. 
- Sc he pers T , Kie b o o m B C , Besse ms G H , V o gels L M , v a n Lies h o ut E M , Pat ka P . S u btalar 
vers us tri ple art hr o d esis after i ntra -artic ular cal ca neal fract ures. Strate gi es Tra u ma Li m b 
Rec o nstr.  2 0 1 0 A u g; 5( 2): 9 7- 1 0 3.  
- Sc h mitz M A, Fi n ne ga n M, Nataraja n R, C ha m pi ne J. Effect of s m o ki n g o n ti bial s haft 
fract ur e heali n g. Cli n Ort h o p Relat Res 1 9 9 9; 3 6 5: 1 8 4- 2 0 0. 
- Se n M K, Micla u T. A ut ol o g o us iliac crest b o ne graft: S h o ul d it still be t he g ol d sta n dar d 
f or treati n g n o n u ni o ns. I nj ur y 2 0 0 7; 3 8 S 1: S 7 5- S 8 0. 
- S hearer D, M ors he d S. C o m m o n ge n eric meas ures of healt h rel ate d q ualit y of life i n i nj ur e d 
patie nts. I nj ur y, I nt. J. Care I nj ure d 4 2. 2 0 1 1: 2 4 1 – 2 4 7 
- Sc h oe nfel d D. Statistical c o nsi derati o ns f or pil ot st u dies. I nt J Ra diati o n O nc ol Bi ol 
P h ysics 1 9 8 0; 6: 3 7 1- 3 7 4. 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 3 1 /1 3 6  
 
 
- S o ucac os P N, D ailia na Z, Beris A E, J o h ns o n E O. Vasc ul arise d b o n e grafts f or t he 
ma na ge me nt of n o n- u ni o n. I nt. J. Care I nj ur e d 2 0 0 6; 3 7 S: S 4 1- S 5 0. 
- T u v o G., 
M ora R., G alli G. B. Treat me nt of N o ni nfecte d N o n u ni o ns : N or m otr o p hic 
N o n u ni o ns. I n N o n u ni o n of t he L o n g B o n es, R. M ora, S pri n ger, 2 0 0 6 
- Va n na b o uat h o n g C, S pra g ue S, B ha n d ari M. G ui deli nes f or fract ure heali n g ass ess me nts 
i n cli nical trials. Part I: Defi niti o ns a n d e n d p oi nt c o m mittees I nj ur y, I nt. J. Care I nj ure d. 
2 0 1 1; 4 2: 3 1 4 – 3 1 6. 
- We ber B G, Cec h O. Pse u d oart hr osis: Pat h ol o g y, Bi o mec ha ni cs, T hera p y, Res ults. Ber ne, 
S witz erla n d: Ha ns H u ber Me dical P u blis her; 1 9 7 6. 
- W hela n d B, B ha n dri M, Mc Kee M D, G u yatt G H, Kre der HJ, Ste p he n D, Sc h mitsc h E H. 
I nter o bser ver a n d i ntra o bser ver variati o n i n t he assess me nt of t he heali n g of ti bial fract ures 
after i ntra m e d ullar y fi x ati o n. J. B o ne J oi nt S ur g. 2 0 0 2; 8 4 B: 1 5 -1 8  
- W hela n D B, B ha n d ari M, Ste p he n D, Kre d er HJ, Mc Kee M D, Z der o R. de vel o p me nt of 
ra di o gra p hic u ni o n sc ore f or ti bial fract ures f or t he assess me nt of ti bial fract ur e heali n g 
after i ntra me d ullar y fi x ati o n. J. of Tra u ma, I nj ur y, I nfecti o n & Critical Care. 2 0 1 0; 6 8 ( 3): 
6 2 9- 6 3 2 
- Wiss  D A, Stets o n W B. Ti bial N o n u ni o n: Treat me nt Alter nati ves. J A m Aca d Ort h o p S ur g 
1 9 9 6; 4 ( 5): 2 4 9- 2 5 7. 
- Zi m mer ma n n G., M üller A, We ntze nse n A. T he val ue of la b orat or y a n d i ma gi n g st u dies 
i n t he e val uati o n of l o n g- b o ne n o n- u ni o ns. I nj ur y, 2 0 0 7; 3 8 S, 3 3- 3 7 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 3 2 /1 3 6  
 
 
1 5  A N N E X E S  
 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 3 3 /1 3 6  
 
 
1 5. 2  A N N E X 
1: 
VI S U A L 
A N A L O G U E 
S C A L E 
O F 
G L O B A L 
DI S E A S E 
E V A L U A TI O N 
 
I n t he p atie nt’s a n d I n v esti gat or’s q uesti o n nair es, t he Vis ual A nal o g ue Scale f or Gl o bal Disease 
E val uati o n is prese nte d as f oll o ws: 
 
“ C o nsi deri n g ( o ver t he last wee k *) all t he wa y y o ur disease (i.e., dela ye d- u ni o n fract ure) affects 
y o u, pleas e i n dicate b y a n X o n t his h oriz o ntal li ne h o w well y o u are d oi n g wit h t he w orst 
p ossi ble ge n eral he alt h ( 1 0 0) a n d best p ossi ble ge neral healt h ( 0).”  
 
 
                           0                                                                                         1 0 0 
 
* O r as perceive d by t he I nvesti g at or d uri n g t he visit 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 3 4 /1 3 6  
 
 
1 5. 3  A N N E X 2: VI S U A L A N A L O G U E S C A L E O F P AI N 
In t he p atie nt’s q uesti o n n aires, t he Vis ual A n al o g u e Scale f or pai n is prese nte d as f oll o ws: 
“ T he h oriz o ntal li ne bel o w re prese nts e x tre me pai n ( 1 0 0) a n d n o p ai n ( 0). Please i n dicate o n 
t his h oriz o ntal li ne t he p ositi o n reflecti n g t h e best y o ur a ns wer t o t he bel o w q uesti o n b y a X”  
 
1 5. 3. 1  P ai n at rest 
O n a vera ge, h o w w o ul d y o u q ualif y y o ur pai n at rest o ver t he last wee k? 
 
                          0                                                                                           1 0 0 
 
1 5. 3. 2  P ai n d uri n g activities 
O n a vera ge, h o w w o ul d y o u q ualif y y o ur pai n d uri n g dail y life acti vities o ver t he last wee k? 
 
                          0                                                                                           1 0 0 
 
1 5. 3. 3  P ai n at p al p ati o n ( perf or me d by t he I nvesti g at or or t he n urse) 
H o w w o ul d y o u q u alif y t he pai n at pal pati o n? 
 
                          0                                                                                          1 0 0 


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 3 5 /1 3 6  
 
 
1 5. 4  A N N E X 3: W EI G H T B E A RI N G S C O R E  
F or a dela ye d- u ni o n fract ure of a l o wer e xtre mit y, t he patie nt will be re q ueste d t o sta n d or wal k. 
F or a dela ye d- u ni o n fract ure of a n u p per e xtre mit y, t he patie nt will b e re q u este d, w hile 
sta n di n g, t o p us h wit h t he i nj ure d ar m o n a ta ble. 
T he test will b e d o ne “as t olerate d ” b y t h e patie nt w h o will c o m plet e t he q uesti o n naire b el o w 
acc or di n g t o t he fract ure site. 
Fract ure site:  
Sc ore  L o w er E xtre mit y L o n g B o nes 
 
U p per E xtre mit y L o n g b o nes 
 
0 
 
N o wei g ht o n i nj ure d le g is all o we d. W hile 
t he patie nt sta n ds or wal ks, he/s he m ust 
h ol d le g off t he fl o or.  
N o wei g ht o n i nj ure d ar m is all o we d. W hile 
t he patie nt sta n ds, he/s he m ust h ol d i nj ure d 
ar m off t he ta ble.  
1 
 
W he n t he patie nt sta n ds or wal ks, he/s he 
ma y o nl y t o uc h t he fl o or f or bala nce. N o 
b o d y wei g ht ca n be place d o n t he le g.  
W he n t he patie nt sta n ds, he/s he ma y o nl y 
t o uc h t he ta ble. N o b o d y wei ght ca n be place d 
o n t he ar m.  
2 
 
T he patie nt ma y place s o me of his/ her 
b o d y wei g ht o n t he i nj ure d le g w he n 
he/s he sta n ds or wal ks.  
T he patie nt ma y place s o me of his/ her b o d y  
wei g ht o n t he i nj ure d ar m w he n he/s he sta n ds 
a n d lea ns o n t he ta ble.  
3 
 
F ull wei g ht beari n g.  
F ull wei g ht beari n g.  


C O N FI D E N TI A L 
 
A L L O B -D U 1  - Cli nic al St u d y Pr ot oc ol  
A L L O B -D U 1 _ C S P  
V 0 5  
A ut h or: G H E  
Fe br uar y 0 2, 2 0 1 7  
P g. 1 3 6 /1 3 6  
 
 
1 5. 5  A N N E X 4: R A DI O L O GI C A L E V A L U A TI O N: M O DI FI E D R U S  / T U S 
T he  ra di ol o gical e v al uati o n will be d o ne usi n g c o n ve nti o nal X-ra y (i ncl. a nter o- p osteri or, 
later o-lateral) a n d C T Sca n. 
T he  sc ores us e d i n t he i ma gi n g i nter pretati o n are:  
- Sc ore 0 = Call us is A bse nt a n d Fract ure li ne is A bse nt; Fract ure is rece nt ( < 6 wee ks)  
- Sc ore 1 = Call us is A bse nt a n d Fract ure li ne is Visi ble 
- Sc ore 2 = Call us is Prese nt a n d Fract ure li ne is Visi ble 
- Sc ore 3 = Call us is Prese nt a n d Fract ure li ne is I n visi ble 
- Sc ore 4 = Call us is A bse nt a n d Fract ure li ne is A bse nt; Fract ure is n ot rece nt ( > 6 wee ks) 
T he mi ni m u m m R U S/ T U S sc ore is 2 ( prese n ce of a fract ure li ne at l east o n 2 vie ws), 
ma xi m u m is 1 6 ( b o ne is t otall y re p aire d). 
m R U S / T U S S C O R E:  I n di vi d ual c ortical s c ore ( Lateral, 
Me di al, A nteri or a n d P osteri or 
C orte x) 
M o difie d R U S / T U S 
Lateral C orte x  
 0  
 1  
 2  
 3  
 4  
Me dial C orte x  
 0  
 1  
 2  
 3  
 4  
A nteri or C orte x  
 0  
 1  
 2  
 3  
 4  
P osteri or C orte x  
 0  
 1  
 2  
 3  
 4  
 
 T he t otal m R U S/ T U S sc ore ( 2 –  1 6) is t he a d diti o n of t he i n di vi d ual sc ores ( Lateral, Me dial, 
A nteri or a n d P osteri or C orte x)