A Multi-Center, Randomized, Pivotal Study Evaluating AMPLEX Compared To Autogenous Bone Graft in Subjects Indicated for Arthrodesis Surgery Involving the Hindfoot or Ankle
Phase: NA
Conditions: Arthrodesis Surgery Involving the Hindfoot or Ankle
Sponsor: Ferring Pharmaceuticals

Protocol (consolidated protocol incorporating amendment 2) 
Title of trial: 
A multi-center, randomized, pivotal study evaluating AMPLEX compared to 
autogenous bone graft in subjects indicated for arthrodesis surgery involving 
the hindfoot or ankle 
NCT number: 
NCT03028415 
Sponsor trial code: 
000226 
Date: 
14 March 2018 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page l of '9 l 
CLINICAL TRIAL PROTOCOL 
A Multi-Center, Randomized, Pivotal Study Evaluating AMPLEX® Compared To 
Autogenous Bone Graft in Subjects Indicated for Arthrodesis Surgery Involving the Hindfoot 
or Ankle 
Trial Code: 000226 
Consolidated Protocol Incorporating Amendment 2.0 
IDE Number: 
Investigational Device: 
Indication: 
Phase: 
Name and Address of Sponsor: 
GCP Statement: 
G150153 
AMPLEX® (B2A ® Enhanced Ceramic Granules) 
AMPLEX is indicated for use as an alternative to 
autograft in hindfoot and ankle fusion procedures that 
require supplemental graft material, including tibiotalar, 
talocalcaneal, talonavicular and calcaneocuboid fusions 
Pivotal IDE 
Perring International Pharmascience Center U.S., Inc. 
(FJPCUS) 
100 Interpace Parkway 
Parsippany, NJ 07054 
1-973-796-1600
This trial will be performed in compliance with GCP. 
The information in this document is confidential and is proprietary to Ferring Pharmaceuticals A/S or another company 
within the Ferring Group. It is understood that information in this document shall not be disclosed to any third party, in 
any form, without prior written consent of an authorized officer of Perring Pharmaceuticals A/S or another company 
within the Ferring Group. 
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 2 of '91 
SYNOPSIS 
TITLE OF TRIAL 
A Multi-Center, Randomized, Pivotal Study Evaluating AMPLEX Compared To Autogenous 
Bone Graft in Subjects Indicated for Arthrodesis Surgery Involving the Hindfoot or Ankle 
SIGNATORY INVESTIGATOR(S) 
TRIAL SITE(S) 
Up to a total of 50 centers; 35-40 US centers and 10-15 Canadian centers 
PLANNED TRIAL PERIOD 
Study Start-up: 6 months 
Subject Enrollment: 18 months 
Treatment and Follow-up: 18 months 
Study Closeout: 4 months 
OBJECTIVE 
CLINICAL PHASE 
Pivotal 
To demonstrate that AMPLEX is non-inferior to autogenous bone graft (ABG) for bone fusion in 
a population indicated for single, double, or triple hindfoot arthrodesis or ankle arthrodesis 
surgery with supplemental graft material. 
ENDPOINTS 
Primary Efficacy Endpoint 
•
Proportion of subjects who meet all the following criteria for the Subject Performance
Composite (SPC) Endpoint at 52 weeks:
o
Improvement in pain on weight-bearing at fusion site ( 20 mm reduction from
baseline on I 00 mm VAS)
o
Absence of significant graft harvest site pain ( < 20 mm on 100 mm VAS)
o
Improvement in Foot and Ankle Ability Measure Activities of Daily Living
subscale (FAAM-ADL) k 8 points improvement from baseline)
o
Absence of device related or procedure related SAEs (up to Week 52)
o
Absence of secondary surgical or nonsurgical interventions intended to promote
fusion (up to Week 52)
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Key Secondary Endpoint 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 3 of '9 l 
•
Proportion of subjects who meet the following criteria for Computerized Tomography
(CT) radiographic fusion success at 52 weeks:
o
Radiographic evidence of fusion by CT scan ( 50% bone bridging across the
joint space for the full complement of joints in the absence of secondary surgical
or nonsurgical interventions intended to promote fusion)
Seconda,y Endpoints 
•
Proportion of subjects achieving CT radiographic fusion success at 12 and 24 weeks (in
the absence of secondary surgical or nonsurgical interventions intended to promote
fusion)
•
Change from baseline in pain on weight-bearing at fusion site at 12, 24, and 52 weeks k
20 mm reduction from baseline on I 00 mm VAS)
•
ABG harvest site pain at 2, 6, 12, 24, and 52 weeks(< 20 mm on 100 mm VAS)
•
Change from baseline in FAAM-ADL at 12, 24, and 52 weeks
•
SPC at 12 and 24 weeks
•
Change from baseline in Short Form-12 (SF-12) at 24 and 52 weeks
Safety Endpoints 
•
Frequency, severity and seriousness of Adverse Events (AEs)
•
Device or Procedure Related SAEs
•
Secondary surgical intervention including revision, removal, reoperation or supplemental
fixation
•
Subsidence, device migration, nonunion, osteolysis and/or heterotopic ossification in the
area surrounding the implant site by radiographic assessment
•
Presence of anti-B2A antibodies (Ab) in serum
Pharmacokinetic Assessment 
•
Plasma B2A levels at Days I, 2, 4, 7, and 15
•
AUC, AUCt, % AUC extrap, Cmax, Tmax, tYi, lamda z, CL/F, Vz/F for B2A
METHODOLOGY 
The study will be conducted at up to a total of 50 centers; 35-40 US centers and 10-15 Canadian 
centers, following approval by appropriate oversight and regulatory agencies [Institutional 
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 4 of '91 
Review Board (IRB) and Food and Drug Administration, USA (FDA) or the local Research 
Ethics Board (REB) and Health Canada, respectively]. Following appropriate informed consent 
procedures, subjects will undergo screening evaluations to determine eligibility before 
randomization. 
Prior to surgery, each subject will have baseline information collected which will include medical 
history, injury/disease etiology, diagnosis, clinical laboratory assessments (including serum for 
anti-B2A antibody analysis), pain and disability assessments, in addition to radiographic 
1magmg. 
At the screening/pre-operative visit anterior/posterior (A/P), lateral and oblique X-rays will be 
collected. Historical X-rays, taken up to 24 weeks prior to the planned date of surgery, will also 
be accepted provided they are inclusive of A/P, lateral and oblique views and are available in a 
readily copied format [e.g., electronic images on Compact Disc (CD)]. These pre-operative X­
rays will be the baseline for subsequent safety evaluation. 
As part of eligibility determination, the Investigator will review any relevant diagnostic imaging 
results and comorbidities to ensure that subjects meet the appropriate eligibility criteria and that 
ankle or hindfoot arthrodesis surgery with supplemental graft material is indicated. Eligible 
subjects will be randomized as close to the procedure as possible, preferably on the day of the 
surgery. 
Approximately 480 subjects will be randomized to one of two treatment groups in a 2: 1 ratio 
(320 AMPLEX: 160 ABG). 
Surgeries will be performed by board-certified/board eligible orthopedic surgeons. Perioperative 
prophylactic antibiotics will be administered before surgical incision in accordance with 
investigational site guidelines. Standard anesthesia procedures will be used. Standard surgical 
technique will be employed to gain access to each fusion site and to ensure rigid fixation of the 
fusion site. The joint will be exposed and prepared as per standard practice (please refer to the 
Surgical Manual for more details). The graft material should be placed in the joint space to 
minimize the chance of extrusion while maximizing bone-on-bone contact. Once the graft is 
placed, internal fixation screws will be placed across the joint. At least one ( 1) and up to three 
(3) screws can be used per joint. Supplemental pins and staples may be used, as well as
supplemental screws and plates external to the fusion site(s). The surgical site will be closed in
layers using standard surgical technique. Surgical exposure and technique will be documented
on the case report form (CRF).
Subjects will be followed for 78 weeks. Post discharge clinical visits will include visits at 2, 6, 
12, 24, 52, and 78 weeks. Adverse event data will be collected throughout the study. The 
primary endpoint will be assessed at 52 weeks. 
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 5 of '9 l 
A Pharmacokinetic (PK) assessment will be conducted to assess the amount of B2A in blood 
(plasma) after surgery, on Days 1, 2, 4, 7, and 15, and will include a baseline, pre-procedure 
evaluation. The PK assessment will include a sub-set of up to approximately 30 AMPLEX 
subjects, allowing pharmacokinetic evaluation in at least 20 AMPLEX subjects. Both genders 
will be represented. Blood samples will be collected and processed to plasma for laboratory 
evaluation (plasma B2A concentration). Data will be descriptive in nature and report, to the 
extent possible, the following for plasma: AUC, AUCt, % AUC extrap, Cmax, Tmax, tYi, lamda 
z, CVF, Vz/F. 
NUMBER OF SUBJECTS 
Approximately 480 subjects will be randomized in a 2: 1 ratio (Treatment: Control) with 
approximately 320 to receive AMPLEX and 160 to receive ABG. 
CRITERIA FOR INCLUSION/ EXCLUSION 
Inclusion Criteria 
Subjects enrolled in the study must meet the following incllllsion criteria: 
1. Signed written informed consent
2. Male or female at least 18 years of age but less than age 75
3. Indicated for ankle or hind foot arthrodesis and require one of the following arthrodesis
procedures:
o
Tibiotalar (ankle)
o
Talocalcaneal (subtalar)
o
Talonavicular
o
Calcaneocuboid
o
Double hindfoot (e.g., talonavicular and talocalcaneal joints)
o
Triple hindfoot (subtalar, talonavicular and calcaneocuboid joints)
4. Presents with pain on weight-bearing of at least 40 mm on a 100 mm VAS
at the area indicated for arthrodesis
5. Presents whh at least one comorbid risk factor (based on Baumhauer et al 2013) that
warrant the use of supplemental autogenous bone or allograft
o
Radiographic evidence of bone defect, deficit, subsidence or subchondral cyst
o
More than one joint to be fused
o
Involvement of other adjacent or nonadjacent joints
o
Large surface area
o
Intra-articular or extra-articular deformity
o
Post-traumatic arthritis
o
Diagnosis of osteoporosis
6. The Investigator determines if the joint space(s) can be adequately filled with graft
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 6 of '91 
material (AMPLEX or ABG) according to the following parameters: 
o
Single hindfoot joint fusion: up to 5 cm3
o
Double or triple hindfoot fusion: each individual joint up to 5 cm3, but overall,
not more than 10 cm3 for the full complement of joints
o
Ankle fusion: up to IO cm3
7. Each fused! joint can be rigidly stabilized with at least 1 and no more than 3 screws across
the fusion plane. (Supplemental pins and staples may be used, as well as supplemental
screws and! plates external to the fusion site(s).)
8.
Willing and able to comply with all study requirements including all postoperative
clinical and radiographic evaluations
9. For women of childbearing potential (not post-menopausal for 12 months or surgically
sterile), a urine pregnancy test with a negative result must be obtained at screening and on
the day of surgery, prior to procedure. These trial participants must commit to adequate
birth control (e.g., oral contraceptive, two methods of barrier birth control, or abstinence)
through the 78 week follow-up
Exdusion Criteria 
Participants who have or meet any of the following exclusion criteria will not be eligible for the 
Study: 
1. Bone deficit requiring a structural graft
2. Charcot foot disease
3. Radiographic evidence of open physes
4. Prior arthroplasty, arthrodesis, major surgical repair or reconstruction of the index ankle
or hindfootjoint(s)
5. Requires osteotomy or fusion of any midfoot joints
6. BMI greater than 45 kg/m2
7. Documented medical history of, or radiographic evidence of, a bone disease ( e.g.
avascular necrosis) or other condition (e.g., osteolysis) that would preclude the subject
from receiving screw fixation in the opinion of the surgeon
8. Requires intramedullary nail fixation or an external fixator
9. Comorbidity that would limit the ability to administer any functional measurements such
asFAAM-ADL
10. Has at the time of surgery, a systemic infection or local infection at the site of surgery
11. Medical condition, serious intercurrent illness, or extenuating circumstance that, in the
opinion of the Investigator, would preclude participation in the study or potentially
decrease survival or interfere with ambulation or rehabilitation (e.g., history of transient
ischemic attack, strnke or liver disease)
12. HgbAlc level greater than or equal to 8%
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 7 of '91 
13. Known hypersensitivity to any of the components of the product [e.g. B2A peptide,
Hydroxyapatite (HA): beta-tricalcium phosphate (­TCP), ceramic granule]
14. Currently receiving treatment with a drug known to interfere with bone metabolism [e.g.,
systemic corticosteroid therapy ( topical corticosteroid therapy is permissible),
methotrexate]
15. Has previously received treatment with a drug known to interfere with bone metabolism
[e.g., systemic corticosteroid therapy (topical corticosteroid therapy is permissible),
methotrexate] and in the opinion of the investigator could continue to negatively interfere
with bone metabolism or bone healing
16. History of any severe allergy or anaphylaxis, or a history of hypersensitivity to protein
pharmaceuticals [ e.g., monoclonal antibodies or gamma globulins, recombinant Bone
Morphogenetic Proteins (BMPs)]
17. Medical condition requiring radiation, chemotherapy or irnrnunosuppression
18. Have a prior or active history of malignancy ( except for basal cell carcinoma of the skin)
19. Has a history of autoimmune disease known to effect bone metabolism. Examples include
spondyloarthropathies ( e.g., ankylosing spondylitis, Crohn's disease, and ulcerative
colitis), Juvenile Arthritis, Grave's disease and Hashimoto's thyroiditis; Rheumatoid
Arthritis is allowed.
20. Have pathological or genetic liver disease or who have clinically significant, elevated
baseline liver function enzymes
21. Has obvious and/or docU1mented alcohol or illicit drug addictions
22. Is a prisoner in a correctional institution/facility
23. Actively involved in litigation or workman's compensation
24. Has participated in clinical studies evaluating investigational devices, pharmaceuticals or
biologics within 6 months of randomization
25. Requires chronic therapeutic use ofNSAID during the first 6 post-operative weeks
(except aspirin up to 325 mg bid for cardiovascular protection and/or DVT prophylaxis)
26. Has previously been treated with, or exposed to, therapeutic levels of synthetic or
recombinant BMPs
27. Requires chronic subcutaneous or intravenous heparin therapies
INVESTIGATIONAL DEVICE 
AMPLEX, the investigational device, is a synthetic bone graft substitute comprised of two parts; 
1) a synthetic bone void filler (BVF) that functions as an osteoconductive scaffold and 2) a
syntlhetic peptide (B2A) that augments osteodifferentiation.
AMPLEX is suppEied in kit form (AMPLEX kit) and the components must be combined and 
utilized in accordance with the Instructions for Use (IFU). 
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 8 of '9 l 
AMPLEX, B2A Enhanced Ceramic Granules (AMPLEX), is the Investigational Device supplied 
in kit form and must be used as a system. When fully prepared according to the IFU, AMPLEX 
consists of osteoconductive granules (BVF) with bound synthetic B2A peptide. 
The AMPLEX kit contains two sterile, non-pyrogenic components that must be used as a system: 
•
Part I: Bone void filler (BVF); I to 2 millimeter (mm) diameter granules, 5 cm3/vial,
two (2) vials per kit
•
Part 2: Lyophilized B2A Peptide Powder, 2.8 mg/vial
Part 1: BVF consists of two (2) vials of 5 cc, sterile, ceramic granules. The granules are 
composed of 20% HA and 80% P-TCP. 
Part 2: Lyophilized B2A Peptide Powder, is formulated as a sterile product containing 2.8 mg 
B2A with mannitol and glycine as excipients, and is lyophilized in borosilicate glass vials. Each 
vial contains a white to off-white caked powder composed of highly purified B2A (acetate salt), 
mannitol (USP), and glycine (USP) under an atmosphere of nitrogen (nitrogen headspace gas). 
The vials are closed with a Daikyo VIO RB2-TR FluroTec® coated stopper and with an 
aluminum-based, flip-top closure. 
For preparation of implant-ready AMPLEX by following the instmctions in IFU, the lyophilized 
drug product (DP) is reconstituted in sterile water for injection (WFI). In-use stability of the 
reconstituted drug product has been demonstrated by measuring purity of the solution following 
reconstitution over a six (6) hour period. After reconstitution, a defined volume of B2A solution 
is wiithdrawn, added to the granules (BVF) and mixed according to the IFU. Implant-ready 
AMPLEX, with 0.225mg B2A/cm3 granules should be used within four (4) hours of preparation. 
The control materiial, ABG, is harvested at the discretion of the surgeon from a location other 
than the graft site, for example, the calcaneus, proximal tibia, distal tibia or iliac crest and 
administered by surgical implant. 
The aggregate volume of graft material (AMPLEX or ABG) utilized in index joints will be at the 
discretion of the surgeon, provided the joint space(s) can be adequately filled with graft material 
according to the following parameters: 
•
Single hindfoot joint fusion: up to 5 cm3
•
Double or triple hindfoot fusion: each individual joint up to 5 cm3, but overall, not
more than 10 cm3 for the full complement of joints
•
Ankle fusion: up to 10 cm3
ABG will be obtained from a location other than the graft site, for example, the calcaneus, 
proximal tibia, distal tibia, or iliac crest using standard surgiical procedure. The selection of the 
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 9 of '91 
ABG harvest site will be at the discretion of the surgeon and based on medical judgment. The 
harvested bone will be cleaned of soft tissue and morselized. The volume of ABG harvested for 
treatment will be measured using a syringe. 
DURATION OF TREATMENT 
Treatment and Follow-up: 78 weeks (primary endpoint at 52 weeks) 
SCHEDULE OF ASSESSMENTS 
Screening 
Treatment 
Follow-up 
Visit numbet· 
Vl 
V2 
VJ 
V4 
VS 
V6 
V7 
vs 
Procedure 
Weeks 
-l2 
--
2 
6 
12 
24 
52 
78 
Days 
Days -84 to 
Day 1 
Day lS 
Day43 
Day85 
Day 169 
Day 365 
Day 547 
-1
(+/- 3) 
(+/-14) 
(+/- 14) 
(+/- 30) 
(+/- 30) 
(+/- 30) 
Informed consent 
X 
Medical History/ comorbiditics 
X 
X 
Supplemental graft requirement 
X 
confinnation 
El igibiliry criteria verification 
X 
X 
Physical assessment of 
X 
X 
X 
X 
X 
X 
X 
X 
foot/hindfoot, vital signs 
Pregnancy test [I] (if applicable) 
X 
X 
Standard Urinalysis (2] 
X 
Clin. labs: chemistry and 
X 
X 
X 
X 
hematology (3) 
Immunological Testing for HBV, 
X 
HCVand HIV 
Semm for B2A Ab testing (4) 
X 
X 
X 
Identification of target arthrodesis 
X 
X 
site 
Subject randomization [5) 
X 
Anhrodesis procedure 
X 
Specific intraoperative data 
X 
collection [6] 
Graft material volumes 
X 
A/P, lateral and oblique X-rays of 
Xt 
X[7) 
X 
X 
X 
X 
X 
hi11dfoot/ankle 
Foot and ank.le CT scan 
X 
X 
X 
FAAM-ADL 
X 
X 
X 
X 
Weight bearing pain at fusion site 
X 
X 
X 
X 
VAS 
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Gran Harvest site pain VAS 
SF-12 
Adverse event evaluation (8] 
Concomitant Medications 
Trial Code: 000226 
X 
X 
X 
X 
X 
X 
X 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 10 of 91 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
t At the screening/pre-operative visit, A/P, oblique and lateral X-rays will be collecte·d (historical X-rays taken up to 24 weeks prior to 
the planned date of surgery will also be accepted). 
[I] Pregnancy test may be performed within 24 hours of the procedure.
(2] If positive for blood, leukocytes, or nitrite, microscopic unrinalysis will be perfom1ed. 
[3] HbA I c is to be perfonned at screening for all subjects. 
(4] B2A Antibody testing may continue past the 12 week follow-up visit if there is a positive test at 12 weeks.
[5] The subject will be randomized as close to the time of surgery as possible, with the recommendation that the randomization be
performed on the day of the surgical procedure.
[6] See Section 6.1.4 referencing the Surgical Manual.
[7] Perform immediately following surgery or within I week following the procedure.
[8] Collected from time of infonned consent. Post-treatment outcomes that are evaluate.ct as efficacy endpoints, such as pain on weight-
bemmg, harvest site pa in, etc. will not be reported as AEs
SCHEDULE OF ASSESSMENTS FOR PK SAMPLING 
Screening T1·eatmeot 
Follow-up 
Visit number 
Vl 
V2 
V3* 
V4 
vs 
V6 
V7 
vs 
Procedure 
Weeks 
-12 
-
2 
6 
12 
24 
52 
78 
Days 
Days -84 
Day 1 
Day2 Day4 Day 7 Day 15 
Day43 
Day85 
Day 169 
Day 365 
Day 547 
to -1 
(+/- 14) (+/- 14) 
(+/- 30) 
(+/- 30) 
(+/- 30) 
PK assessment [ 11 
X 
X 
X 
X 
X 
[l) A sub-set ofup to 20 evaluable AMPLEX subjects will have a PK assessment. An additional sample of blood will be collected at 
pre-procedure and after surgery on Days I, 2, 4, 7 and 15. 
* Visit 3 will also consist of Days 2, 4 and 7, for which there will be an option for blood to be collected at home by a mobile 
laborato1·y uuit. 
STATISTICAL METHODS 
Sample Size: 
Assuming true success rates of tbe primary endpoint to be 60% for ABG and 62% for AMPLEX 
groups, respectively, 396 subjects are needed to maintain 85% power to demonstrate non­
inferiority of AMPLEX to ABG with a non-inferiority margin of -12% (AMPLEX minus ABG) 
at a type I error rate of I-sided 5% in a 2:1 randomization (264 for AMPLEX and 132 for ABG). 
To account for approximately 15% lost to follow-up, a total of 480 subjects (320 for AMPLEX 
and 160 for ABG) will be randomized. 
Analysis Set: 
Modlified Intent-to-Treat (mITT) analysis set: The mITT analysis set will include all randomized 
subjects who have an attempted fusion of the index joint(s). 
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page l l of 91 
Per-protocol (PP) analysis set: The PP analysis set will consist of all randomized subjects that: 
[1] complete the fusion procedure and receive either AMPLEX or ABG as assigned, [2] meet
critical study eligibility criteria, and [3] have no significant protocol deviations.
Efficacy Analysis: 
The primary efficacy analysis will be based on the mITT population. A sensitivity analysis will 
be conducted for the PP population. In the analysis on the mITT population, subjects who do not 
receive the assigned treatment will be analyzed as randomized. 
The primary efficacy endpoint will be the proportion of subjects who meet all of the following 
criteria for the SPC at 52 weeks: 
•
Improvement in pain on weight-bearing at fusion site k 20 mm reduction from
baseline on 100 mm VAS)
•
Absence of significant graft harvest site pain ( < 20 mm on 100 mm VAS)
•
Improvement in Foot and Ankle Ability Measure Activities of Daily Living subscale
(FAAM-ADL) (È8 points improvement from baseline)
•
Absence of device related or procedure related SAEs (up to W,eek 52)
•
Absence of secondary surgical or nonsurgical interventions intended to promote
fusion (up to Week 52)
The key secondary efficacy endpoint will be the proportion of subjects who meet the following 
criteria for the CT radiographic fusion success at 52 weeks: 
•
Radiographic evidence of fusion by CT scan (É 50% bone bridging across the joint
space for the full complement of joints in the absence of secondary surgical or
nonsurgical interventions intended to promote fusion)
The primary and key secondary efficacy endpoints will be analyzed by a fixed-sequence 
procedure according to the following order to maintain the overall Type 1 error rate to a one­
sided 5% for non-inferiority and a one-sided 2.5% for superiority testings. 
1. Non-inferiority of AMPLEX to ABG in the primary efficacy endpoint
2. Non-inferiority of AMPLEX to ABG in the key secondary efficacy endpoint
3.
Superiority of AMPLEX to ABG in the key secondary efficacy endpoint
4.
Superiority of AMPLEX to ABG in the primary efficacy endpoint
Testing procedure will begin with the non-inferiority in the primary efficacy endpoint, and each 
test will be conducted without adjustment of multiplicity as long as all preceding tests are 
significant. The non;inferiority will be claimed if the lower bound of the 2;sided 90% confidence 
interval (CI) for the difference in the proportions (AMPLEX minus ABG) is greater than -12.0%. 
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 12 of 91 
The superiority will be claimed if the lower bound of the 2-sided 95% CI is greater than zero. 
The CI will be constructed with the normal approximation to the binomial. 
For the primary and key secondary analyses, the last observation carried forward (LOCF) 
approach will be U!sed for subjects with missing SPC endpoint at 52 weeks. 
Safety Analysis: 
All safety endpoints will be descriptively summarized. 
Pharmacokinetic Assessment: 
Pharmcokinetic (PK) data will be descriptively tabulated and summarized for plasma AUC, 
AU Ct,% AUC extrap, Cmax, Tmax, tYi, lamda z, CL/F, Vz/F. 
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 13 of 91 
TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................................. 13 
LIST OF TABLES ........................................................................................................................................ 17 
LIST OF FIGURES ...................................................................................................................................... 17 
LIST OF ABBREVIATIONS & DEFINITION OF TERMS ................................................................... 18 
1 
INTRODUCTION ............................................................................................................................. 21 
I . I 
Background ............................................................................................................................. 21 
l.2 
Scientific Justification for Conducting the Trial.. ................................................................... 22 
1.3 
Benefit/ Risk Aspects ............................................................................................................. 23 
1.4 
Clinical Benefit ....................................................................................................................... 23 
1.5 
Analysis of Increased Risks to Treatment Subjects ................................................................ 24 
2 
TRIAL OBJECTIVES AND ENDPOINTS ..................................................................................... 27 
2.1 
Primary Objective ................................................................................................................... 27 
2.2 
Endpoints ................................................................................................................................ 27 
2.2.1 
Primary Efficacy Endpoint. ........................................................................................ 27 
2.2.2 
Secondary Endpoints ................................................................................................. 27 
2.2.3 
Safety Endpoints ........................................................................................................ 28 
2.2.4 
Pharmocokinetic Endpoints ....................................................................................... 28 
3 
INVESTIGATIONAL PLAN ........................................................................................................... 29 
3.1 
Overall Trial Design ................................................................................................................ 29 
3.1. l 
Trial Design Diagram ................................................................................................. 29 
3.1.2 
Trial Scheduk ............................................................................................................ 29 
3.2 
Planned Number of Trial Sites and Subjects ........................................................................... 30 
3.3 
Study Oversight. ...................................................................................................................... 30 
3.3.1 
Clinical Events Committee ........................................................................................ 30 
3.3.2 
Data Monitoring Committee ...................................................................................... 30 
3.3.3 
Imaging Core Laboratory ........................................................................................... 31 
3 .4 
Discussion of Overall Trial Design and Choice of Control Groups ....................................... 31 
3.4.1 
Trial Design ............................................................................................................... 31 
3.4.2 
Selection of Endpoints ............................................................................................... 32 
3.4.3 
Blinding ...................................................................................................................... 33 
3.4.4 
Trial Population ......................................................................................................... 33 
3.4.5 
Withdrawal Criteria ................................................................................................... 33 
4 
SELECTION OF TRIAL POPULATION ...................................................................................... 34 
4.1 
Trial Population ....................................................................................................................... 34 
4.1.1 
Inclusion Criteria ....................................................................................................... 34 
4.1.2 
Exclusion Criteria ...................................................................................................... 35 
4.2 
Method of Assigning Subjects to Treatment Groups .............................................................. 36 
4.2.1 
Recruitment. ............................................................................................................... 36 
4.2.2 
Randomization ........................................................................................................... 37 
5 
TREATMENTS ................................................................................................................................. 38 
5.1 
Treatments Administered ........................................................................................................ 38 
5.1.1 
Investigational Device ................................................................................................ 38 
5.1.2 
Non-Investigational Material ..................................................................................... 39 
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 14 of 91 
5.1.3 
Investigational Device and Non-lnvestigational Material ......................................... 39 
5.2 
Characteristics and Source of Supply ..................................................................................... 39 
5.2. l 
Investigational Device Manufacturing ....................................................................... 40 
5.3 
Packaging and Labeltiing ......................................................................................................... 40 
5.3.1 
Investigational Device Packaging .............................................................................. 40 
5.3.2 
Non-Investigational Material (ABG) ......................................................................... 41 
5.4 
Conditions for Storage and Use .............................................................................................. 41 
5.4.1 
Investigational Device Storage .................................................................................. 41 
5.5 
Treatment Compliance ............................................................................................................ 41 
5.5.1 
Dispensing and Accountability .................................................................................. 41 
5.6 
Return and Destruction of Medicinal Products and Auxiliary Supplies ................................. 42 
6 
TRIAL PROCEDURES .................................................................................................................... 43 
6.1.1 
Subject Recruitment ................................................................................................... 43 
6.1.2 
Screening/Pre-Operative Visit ................................................................................... 43 
6.1.3 
Day of Surgery ........................................................................................................... 44 
6.1.4 
Surgical procedure ..................................................................................................... 45 
6.1.5 
Post-Operative Care ................................................................................................... 46 
6.1.6 
Follow-up Viisit at 2 Weeks ....................................................................................... 47 
6.1.7 
Follow-up Visit at 6 Weeks ....................................................................................... 47 
6. l.8 
Follow-up Viisit at 12 Weeks ..................................................................................... 48 
6.1.9 
Follow-up Viisit at 24 Weeks ..................................................................................... 48 
6.1.10 Follow-up Viisit at 52 Weeks ..................................................................................... 48 
6. l .11 Follow-up Viisit at 78 Weeks ..................................................................................... 49 
6.2 
Trial Flow Chart. ..................................................................................................................... 50 
7 
TRIAL ASSESSMENTS ................................................................................................................... 51 
7 .1 
Schedule of Assessments ........................................................................................................ 51 
7.2 
Assessments Related to Endpoints .......................................................................................... 52 
7 .2.1 
Radiographic Assessments ......................................................................................... 52 
7.2.2 
Subject self-assessments ............................................................................................ 53 
7.3 
Other Assessments .................................................................................................................. 54 
7 .3 .1 
Concomitant Medications .......................................................................................... 54 
7.3.2 
Vital Signs .................................................................................................................. 54 
7.3.3 
Clinical Laboratory Testing ....................................................................................... 54 
7.3.4 
Antibody Monitoring ................................................................................................. 55 
7.4 
Human PK Assessment ........................................................................................................... 55 
8 
ADVERSE EVENTS ......................................................................................................................... 56 
8.1 
Definitions ............................................................................................................................... 56 
8.2 
Collection and Recording of Adverse Events ......................................................................... 57 
8.2.1 
Collection of Adverse Events .................................................................................... 57 
8.2.2 
Recording of Adverse Events .................................................................................... 57 
8.2.3 
Assessment of Adverse Events .................................................................................. 58 
8.3 
Pregnancy ................................................................................................................................ 59 
8.4 
Collection, Recording and Reporting of Serious Adverse Events .......................................... 60 
8.5 
Follow-up of Adverse Events and Serious Adverse Events .................................................... 61 
8.5.1 
Follow-up of Adverse Events with Onset during the Trial ........................................ 61 
8.5.2 
Collection of Serious Adverse Events with Onset after Last Trial Visit ................... 61 
Fening Phannaceuticals 
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B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 15 of 91 
9 
STATISTICAL METHODS ............................................................................................................. 62 
9.1 
Determination of Sample Size ................................................................................................ 62 
9.2 
Subject Disposition ................................................................................................................. 62 
9.3 
Protocol Deviations ................................................................................................................. 62 
9.4 
Analysis Sets ........................................................................................................................... 63 
9 .4 .1 
Modified Intention-to-Treat (mlTT) Analysis Dataset .. ............................................ 63 
9.4.2 
Per Protocol (PP) Dataset.. ......................................................................................... 63 
9.4.3 
Safety Dataset ............................................................................................................ 63 
9.5 
Trial Population ....................................................................................................................... 63 
9.5.1 
Demographics and other Baseline Characteristics ..................................................... 63 
9.5.2 
Medical History, Concomitant Medication and Other Safety Evaluations ................ 63 
9.6 
Endpoint Assessments ............................................................................................................. 63 
9.6.1 
General Considerations .............................................................................................. 63 
9.6.2 
Primary Endpoint ....................................................................................................... 64 
9.6.3 
Key Secondary Endpoint ........................................................................................... 65 
9.6.4 
Secondary Endpoint(s) ............................................................................................... 65 
9.7 
Safety ...................................................................................................................................... 66 
9.7.1 
General Considerations .............................................................................................. 66 
9.7.2 
Adverse Events .......................................................................................................... 66 
9.7.3 
Other Safety Variables ............................................................................................... 67 
9.8 
Pharmacokinetic Assessment .................................................................................................. 67 
9 .9 
Handling of Missing Data ....................................................................................................... 67 
9 .10 
Pooling of Site Data ................................................................................................................ 68 
10 
DATA HANDLING ........................................................................................................................... 69 
10.1 
Source Data and Source Documents ....................................................................................... 69 
10.2 
eCRF ....................................................................................................................................... 69 
10.3 
Investigator Records ............................................................................................................... 70 
10.4 
Investigator Reports ................................................................................................................ 70 
I 0.5 
Data Management ................................................................................................................... 71 
10.6 
Provision of Additional Information ....................................................................................... 71 
11 
MONITORJNG PROCEDURES ..................................................................................................... 72 
11.1 
Periodic Monitoring ................................................................................................................ 72 
11.2 
Audit and Inspection ............................................................................................................... 72 
11.3 
Confidentiality of Subject Data ............................................................................................... 72 
12 
CHANGES IN THE CONDUCT OF THE TRIAL ........................................................................ 73 
12.l
Protocol Amendments ............................................................................................................. 73 
12.2
Deviations from the Protocol .................................................................................................. 73 
12.3
Premature Trial Termination ................................................................................................... 73 
13 
REPORTING AND PUBLICATION .............................................................................................. 74 
13.1 
Clinical Trial Report ............................................................................................................... 74 
13.2 
Confidentiality and Ownership of Trial Data .......................................................................... 74 
13.3 
Publications and Public Disclosure ......................................................................................... 74 
13.3.1 Publication Policy ...................................................................................................... 74 
13.3.2 Public Disclosure Policy ............................................................................................ 75 
14 
ETHICAL AND REGULATORY ASPECTS ................................................................................. 76 
14.1 
Institutional Review Board (IRB) or Research Ethics Board (REB) ...................................... 76 
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B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 16 of 91 
14.2 
Regulatory Authority .............................................................................................................. 76 
14.3 
End-of-Trial and End-of-Trial Notification ............................................................................ 76 
14.4 
Ethical Conduct of the Trial... ................................................................................................. 76 
14.5 
Subject Information and Consent ............................................................................................ 77 
14.5.1 Subject Unable to Read or Write ............................................................................... 77 
14.5.2 Emergency Consent ................................................................................................... 78 
14.5.3 New Information ........................................................................................................ 78 
14.6 
Subject Information Card ........................................................................................................ 78 
14.7 
Compliance Reference Documents ......................................................................................... 79 
15 
LIABILITIES AND INSUAANCE .................................................................................................. 80 
15.1 
ICH-GCP Responsibilities ...................................................................................................... 80 
15.2 
Liabilities and Insurance ......................................................................................................... 80 
16 
ARCIDVING ...................................................................................................................................... 81 
16. I
Investigator File ...................................................................................................................... 81 
16.2
Trial Master File ...................................................................................................................... 81 
17 
REFERENCES ................................................................................................................................... 82 
18 
APPENDICES .................................................................................................................................... 85 
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 17 of 91 
LIST OF TABLES 
Table 1 
Table 2 
Table 3 
Table 4 
Table 5 
Risks: Description & Mitigation ..................................................................................... 24 
Post-operative Rehabilitation Guidance ......................................................................... .47 
Schedule of Assessments ................................................................................................ 51 
Schedule of Assessments for PK Sampling .................................................................... 52 
AE Severity Grading Scale ............................................................................................. 58 
LIST OF FIGURES 
Figure 1 
Figure 2 
Trial Design Diagram ...................................................................................................... 29 
Trial Flow Chart .............................................................................................................. 50 
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 18 of 91 
LIST OF ABBREVIATIONS & DEFINITION OF TERMS 
List of Abbreviations 
Ab 
ABG 
AE 
A/P 
ALT 
APT 
ASA 
AST 
ATC 
AUC 
BID 
BMI 
BMP 
BMP-2 
BMPR 
pTCP 
BVF 
cc 
CEC 
CD 
CI 
cm 
CRA 
CRF 
CRO 
cs 
CT 
eCRF 
DMC 
DP 
DVT 
Antibody 
Autogenous Bone Graft 
Adverse Event 
Anterior/Posterior 
Alanine Transaminase 
Alkaline Phosphatase 
Acetylsalicylic Aciid 
Aspartate Aminotransferase 
Anatomical Therapeutic Chemical 
Area Under the Cuirve 
Twice daily 
Body Mass Index 
Bone Morphogenetic Proteins 
Bone Morphogenetic Protein 2 
Bone Morphogenetic Protein Receptors 
Beta-Tri-Calcium-Phosphate 
Bone Void Filler 
Cubic Centimeter 
Clinical Events Committee 
Compact Disc 
Confidence Interval 
Centimeter 
Clinical Research Associate 
Case Report Form 
Contract Research Organization 
Clinically Significant 
Computerized Tomography 
Electronic Case Report Form 
Data Monitoring Committee 
Drug Product 
Deep Vein Thrombosis 
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 19 of 91 
F AAM-ADL 
Foot and Ankle Ability Measure - Activities of Daily Living 
FDA 
Food and Drug Administration, USA 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transferase 
GMP 
Good Manufacturing Practice 
HA 
Hydroxyapatite 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
ICH 
International Conference on Hannonization 
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IFU 
Instructions For Use 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ISO 
International Standard Organization 
kg 
Kilogram 
LOCF 
Last Observation Carried Forward 
MCJD 
Minimal Clinically Important Difference 
MDC 
Minimal Detectable Change 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mITT 
Modified Intention-to-Treat 
mL 
Milliliter 
mm 
Millimeter 
NCS 
Not Clinically Significant 
NIH 
U.S. National Institutes of Health 
NLM 
National Library of Medicine 
NSAID 
Non-Steroidal Anti.-inflammatory Drug 
PK 
Pharmacokinetic 
PP 
Per-Protocol 
PT 
Preferred Term 
REB 
Research Ethics Board 
REP 
Radiographic Evaluation Protocol 
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 20 of 91 
RHPDGF 
Recombinant Human Platelet-Derived Growth Factor 
RHPDGF-BB 
Recombinant Human Platelet-Derived Growth Factor-BB 
SAE 
SAP 
SF-12 
soc 
SPC 
SRM 
TEAE 
UADE 
WFI 
WHO-Drug 
VAS 
Serious Adverse Event 
Statistical Analysis Plan 
Short Fonn-12 
Systems Organ Class 
Subject Performance Composite 
Site Reference Manual 
Treatment Emergent Adverse Event 
Unanticipated Adverse Device Effect 
Water for Injection 
World Health Organization Drug Dictionary 
Visual Analog Scale 
Pharmacokinetic Terms and Definitions 
AUC 
AUCt
% AUCextrap 
Cmax 
CL 
F 
NCA 
tmax 
Area under the concentration-time curve from dosing to infinity 
Area under the concentration-time curve from dosing up to time t, where t 
is the last time point at which the concentration is above the lower limit of 
quantification 
Percentage of AUC that is due to extrapolation from the last measurable 
concentration 
Maximum concentration observed 
Clearance 
Bioavailability 
First-order rate constant associated with the terminal (log-linear) portion 
of the concentration-time curve 
Non-compartmental analysis 
Terminal elimination half-life 
Time of maximum observed concentration (Cmax) 
Distribution volume 
Ferring Phannaceuticals 
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B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
1 
INTRODUCTION 
1.1 
Background 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 21 of 91 
The foot and ankle articular complex must work in concert to enable normal ambulation and 
movement. In some individuals, either from traumatic injury or due to the degenerative effects of 
arthritis, motion at one or more of these joints becomes markedly painful, resulting in impaired 
function and quality of life. 1 When non-operative measures are no longer effective, arthrodesis is an
accepted operative treatment option for patients with severe pain or disability caused by arthritis or 
deformity of the ankle or hindfoot. 
Approximately 110,000 foot and ankle arthrodesis were performed in tbe United States in 2009 and 
this number is increasing annually because of both an aging population and the continued 
prevalence of contributory comorbidities. 2 Arthrodesis is designed to relieve pain and restore 
function associated with the numerous maladies that cause joint destruction, including trauma, 
diabetes, inflammatory arthridities, seronegative arthropathy, instability, malalignment, and 
congenital.3"8 Although arthrodesis has long been the mainstay of surgical treatment for foot and 
ankle arthritis, nonunion of the intended fusion construct remains one of the most common 
complications resulting in morbidity and disabi lity.9•11 In fact, there are a number of factors 
associated with a higher risk for a nonunion result, including: age::: 60 years, obesity, diabetes 
mellitus and tobacco product use, etc., which often requires the use of bone grafting to improve 
fusion rates and, ultimately long-term clinical outcomes. 12 
The biological process involved in bone regeneration requires (i) osteogenic potential that is 
capable of directly providing cells to the newly forming bone, (ii) osteoinductive factors that are 
able to cause the osteoblastic differentiation of osteogeprogenitor stem cells and (iii) 
osteoconductive scaffold that facilitate the neovascularization and supports the ingrowth of bone. 
Successful fusion surgery must engage the bone regeneration process to produce new bone to 
bridge the area previously occupied by the joint space and articular cartilage. To enable this 
process, orthopedic surgeons often will harvest bone, known as autologous bone graft (ABG), from 
elsewhere in the body to fill the joint. 
ABG provides an effective osteoconductive scaffold for new bone formation and contains 
appropriate growth factors and cells to potentiate new bone formation (osteoinductive). The 
availability of locally-harvested bone in ankle or foot arthrodesis can be limited, therefore, a second 
harvest site is often required from either the iliac crest, proximal or distal tibia to facilitate the 
acquisition of enough bone to support the graft substitute application. Harvesting ABG, however, 
is associated with both short- and long-term morbidity. Complications of autograft harvest include 
blood loss, postoperative pain, fracture, infection, other non-infectious wound complications, 
heterotopic bone formation, hernia, and nerve injury.13"16 Baumhauer and colleagues recently
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 22 of 91 
reported the results of a prospective randomized study of patients undergoing ankle and hindfoot 
fusion procedures U1sing ABG harvested from one of four sites (iliac crest, proximal tibia, distal 
tibia, and calcaneus). Clinically significant pain at the bone graft harvest site was reported by 35% 
of patients 3 weeks postoperatively and 18% had persistent pain up to 1 year. 17 A review of the 
literature suggests that the overall complication rate from tibial graft sites, although it has become a 
favored source for autograft material for foot and ankle surgery, is 5.5%.18 These complications 
range in severity from hematoma/seroma and paresthesia to infection, fracture and invasion of the 
joint space. 
Though advances have been made in improving the safety and efficacy of foot and ankle 
arthrodesis procedures by utilizing better fixation devices, more recent emphasis has been placed on 
the biological aspects of bone healing and the development of alternatives that eliminate the need to 
harvest bone graft to augment fusion.19 AMPLEX is in development as an alternative to ABG in 
hindfoot and ankle fusion procedures that require supplemental graft material, including tibiotalar, 
talocalcaneal, talonavicular and calcaneocuboid fusions. This investigational bone graft substitute 
is comprised of two parts: 1) bone void filler (BVF) granules made from hydroxyapatite (HA) and 
beta tricalcium-phosphate (PTCP) that functions as an osteoconductive scaffold and 2) the synthetic 
peptide B2A that augments local osteodifferentiation. Clinical studies on AMPLEX demonstrated 
benefit as a bone SU1bstitute without the need for a second procedure and the resulting morbidity 
associated with that second procedure. In a pilot randomized study of 24 subjects comparing 
AMPLEX to ABG, bone fusion was similar in both groups, and the AMPLEX group demonstrated 
improvements in bone density, healing and patient functional capacity.20 No device-related 
complications were reported. 
1.2 
Scientific Justification for Conducting the Trial 
AMPLEX is an investigational medical device supplied in kit form (AMPLEX kit) and must be 
used as a system. When fully prepared, AMPLEX consists of osteoconductive ceramic granules 
(BVF) mixed with synthetic B2A peptide. The principal mode of action of the device is based on 
the osteoconductive granules that act as a scaffold for cellular ingrowth; B2A augments that action. 
The sterile ceramic granules, supplied by a third party vendor, are currently cleared for use as a 
BVF for bony voids or gaps of the skeletal system (e.g., extremities, spine and pelvis) that are not 
intrinsic to the stability of the bony structure. These defects may be surgically- or traumatically­
created osseous defects to the bone (K063527, MBCP+).21 
The primary mode of action of AMPLEX is achieved by the osteoconductive ceramic granules. 22-26 
The granules provide a biocompa.tible scaffold that enables the migration, proliferation and 
differentiation of host pre-osteobfast cells, the basis of bone repair. B2A, a synthetic peptide, 
complements the action of the granules by facilitating osteodifferentiation through its actions on 
bone morphogenetic protein receptors (BMPRs), augmenting the cell response to local bone 
morphogenetic proteins (BMPs).27·32 
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 23 of 91 
The growth and differentiation of pre-osteoblasts on the ceramic granules is assisted and 
complemented by B2A in a cooperative process with the native osteoinductive proteins generated 
as a part of normal bone healing. B2A therefore acts primarily as a selective positive receptor 
modulator, increasing the sensitivity of cells to natural (endogenous), physiologically-active levels 
of BMP-2, and thereby augmenting osteodifferentiation. The augmentation of osteodifferentiation 
can only occur, however, when B2A and BMP-2 are each above their respective biological 
threshold levels. This only occurs at the implant site where the B2A-coated granules are located 
and where BMP-2 is up-regulated as a part of the normal bone healing process. Over time, the 
scaffold is naturally resorbed by the body, leaving only the newly formed bone in its place. 
The control material used in this study, ABG, is harvested from a location other than the graft site, 
for example, the calcaneus, proximal tibia, distal tibia or iliac crest, and administered by standard 
surgical procedure. The selection of the ABG harvest site is at the discretion of the surgeon and 
based on medical judgment. The harvested bone is cleaned of soft tissue and morselized in 
standard fashion. 
1.3 
Benefit / Risk Aspects 
Arthrodesis remains the most common surgical procedure for patients with debilitating ankle and 
hindfoot arthritis. Average nonunion rates remain high (10-15%) but can be substantially higher in 
patients with co-morbid factors such as diabetes and other metabolic diseases, obesity, smoking, 
ageª 65 and osteoporosis.33 The data with both ABG and bone graft replacement products, 
particularly in light of their nearly ubiquitous use in this setting and the apparent equivalence of 
their fusion rates, suggest that a major differentiator is the lack of pain, dysfunction and morbidity 
related to graft donor sites when bone graft replacement products are utilized. 
The inclusion of patient reported outcomes, functional evaluations and quality of life assessments is 
therefore important in evaluating the differences between these approaches. The current clinical 
trial was designed with this in mind, incorporating both radiologic assessment of fusion rate and 
validated scales to assess pain and functional outcome_34-4o 
1.4 
Clinical Benefit 
The proposed clinical study is designed to demonstrate that AMPLEX is non-inferior to ABG for 
bone fusion in a population indicated for single, double, or triple hindfoot arthrodesis or ankle 
arthrodesis surgery with supplemental graft material. The potential benefit to AMPLEX subjects is 
successful fusion of the ankle or hindfoot via an operation that is smaller in magnitude and devoid 
of the risks and additional pain associated with the harvesting of autogenous bone graft. Subjects 
who receive AMPLEX may experience the following potential benefits: 
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 24 of 91 
1.
Similar rate of fusion compared to autograft without the additional risks of the
autograft procedure (i.e., harvest site pain, longer anesthetic and longer procedure,
harvest site infection, harvest site fracture, or other complications)
2. Higher rate of fusion compared to autograft without the additional risks of the
autograft procedure
3. Similar or higher rate of fusion at earlier time points than auto graft without the
additional risks of the autograft procedure
4.
Similar or larger extent of fusion as measured by trabecular bridging of bone across
the fusion site.
1.5 
Analysis of Increased Risks to Treatment Subjects 
Pre-dinical testing and pilot studies conducted outside the United States indicate that AMPLEX 
should be safe and effective. However, until this is proven in a prospective, randomized clinical 
trial ll!tilizing a concurrent control group comprised of subjects undergoing ankle or hindfoot 
fusions, subjects receiving AMPLEX may experience increased risk of: 
1. Allergic reaction (local or systemic response)
2. Ectopic bone growth (bone forming outside of normal bone growth areas)
3. Abnormal cell growth (growth of tissue or cells beyond the norm)
4. Negative effects on pregnancy or fetus
5. Immune response (bodily response against foreign material)
6.
Significant increase in liver enzyme measures
Table 1. Below describes these increased risks to treatment subjects and their mitigation. 
Additional descriptions of procedure and study related risks are provided in Appendix I, 
Anticipated Adverse Events. 
Table 1 
Risks: Description & Mitigation 
Risks 
Description/Mitigation 
Biocompatibility testing has been performed on the AMPLEX 
material demonstrating a minimal reactivity. 
Allergic reaction (local 
Monitoring of study conduct and safety data will be 
or systemic response) 
conducted on an ongomg basis by Sponsor and Data 
Monitoring Committee, governed by a Charter. If these 
groups identify any new or unforeseen risks they will notify 
the Sponsor and render an opm10n on potential study 
modiifications/stopping. 
Ectopic bone growth 
Osteoconductive materials, including allograft bone, have a 
(bone forming outside 
risk of ectopic bone growth. The preclinical battery of in-
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
of normal bone growth 
areas) 
Abnormal cell growth 
(growth of tissue or 
cells beyond the norm) 
Negative effects on 
pregnancy or fetus 
Immune response 
(bodily response 
against foreign 
material) 
Fening Phannaceuticals 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 25 of 91 
vitro and in-vivo animal testing performed on AMPLEX has 
not identified any instances of exuberant bone growth. It has 
also not been seen in any of the feasibility clinical cases. 
Monitoring of study conduct and safety data will be 
conducted on an ongoing basis by Sponsor and Data Safety 
Monitoring Committee, governed by a Charter. Evidence of 
this would be detectable on the CT scans used to evaluate 
efficacy. If these groups identify any new or unforeseen risks 
they will notify the Sponsor and render an opinion on 
potential study modifications/stopping. 
An extensive prechnical battery of in vitro and in vivo animal 
testing of AMPLEX and PREFIX did not identify an impact 
on tumor cell growth, tumor promotion, or metastatic 
behavior, thus minimizing the potential for such an event to 
occur with the treatment device. The study enrollment criteria 
include an exclusion for subjects with a prior history of active 
malignancy with the exclusion of basal cell carcinoma of the 
skin. 
Monitoring of study conduct and safety data will be 
conducted on an ongomg basis by Sponsor and Data 
Monitoring Committee, governed by a Charter. If these 
groups identify any new or unforeseen risks they will notify 
the Sponsor and render an opinion on potential study 
modifications/stopping. 
The preclinical testing has projected that the B2A component 
of AMPLEX is completely eliminated within six weeks of 
implantation and during that time that circulating B2A levels 
are quite low. Therefore, the risk of an effect on a fetus is 
unlikely. 
However, to avoid this potential risk, female subjects are 
excluded from the trial if they are pregnant or lactating, or 
intend to become pregnant during the course of this study. 
Monitoring of study conduct and safety data will be conducted 
on an ongoing basis by Sponsor and Data Monitoring 
Committee, governed by a Charter. If these groups identify any 
new or unforeseen risks they will notify the Sponsor and render 
an opinion on potential study modifications/stopping. 
Pre-clinical and clinical immunogenicity testing during 
PREFIX and AMPLEX development have not demonstrated 
any immune reactions nor development of significant anti-B2A 
antibody formation. 
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B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Elevated liver 
enzymes ( from the 
B2A peptide) 
Ferring Phannaceuticals 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 26 of 91 
Although remote, based on the established data, this risk is 
mitigated through single exposure to AMPLEX and the 
protocol specified assessment of antibody response. 
Despite this being a remote risk, monitoring of study conduct 
and safety data will be conducted on an ongoing basis by 
Sponsor and Data Monitoring Committee, governed by a 
Charter. If these groups identify any new or unforeseen risks 
they will notify the Sponsor and render an opinion on potential 
study modifications/stopping 
Transient excursions in lab values, specifically liver function 
enzymes, have been noted in the pilot clinical studies 
conducted in both the treatment and control groups. After 
extensive consultation with various experts, it was determined 
that these elevations are largely related to surgery itself, 
concomitant medications and pre-existing conditions. 
Despite this being a remote risk, monitoring of study conduct 
and safety data will be conducted on an ongoing basis by 
Sponsor and Data Monitoring Committee (DMC), governed by 
a Charter. If these groups identify any new or unforeseen risks 
they will notify the Sponsor and render an opinion on potential 
study modifications/stopping. 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
2 
TRIAL OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objective 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page27of 91 
The primary objective of this pivotal study is to demonstrate that AMPLEX is non-inferior to ABG 
for bone fusion in a population indicated for single, double, or triple hindfoot arthrodesis or ankle 
arthrodesis surgery with supplemental graft material. 
2.2 
Endpoints 
2.2.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of subjects who meet all the following criteria for 
the Subject Performance Compos.ite (SPC) End!point at 52 weeks: 
•
Improvement in pain on weight-bearing at fusion site (2: 20 mm reduction from baseline on
100 mm VAS)
•
Absence of significant graft harvest site pain ( < 20 mm on 100 mm VAS)
•
Improvement in Foot and Ankle Ability Measure Activities of Daily Living subscale
(FAAM-ADL) (2: 8 points improvement from baseline)
•
Absence of device related or procedure related SAEs (up to Week 52)
•
Absence of secondary surgical or nonsurgical interventions intended to promote fusion (up
to Week 52)
2.2.2 
Secondary Endpoints 
The key secondary endpoint is the proportion of subjects achieving CT radiographic fusion success 
at 52 weeks: 
•
Radiographic evidence of fusion by CT scan (2: 50% bone bridging across the joint space for
the full complement of joints in the absence of secondary surgical or nonsurgical
interventions intended to promote fusion)
The other secondary endpoints are as follows: 
•
Proportion of subjects achieving CT radiographic fusiion success at 12 and 24 weeks (in the
absence of secondary surgical or nonsurgical interventions intended to promote fusion)
•
Change from baseline in pain on weight-bearing at fusion site at 12, 24, and 52 weeks (2: 20
mm reduction from baseline on I 00 mm VAS)
•
ABG harvest site pain at 2, 6, 12, 24, and 52 weeks(< 20 mm on 100 mm VAS)
•
Change from baseline in FAAM-ADL at 12, 24 and 52 weeks
•
SPC at 12 and 24 weeks
•
Change from baseline in Short Form-12 (SF-12) at 24 and 52 weeks
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
2.2.3 
Safety Endpoints 
The safety endpoints are as follows: 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 28 of 91 
•
Frequency, severity and seriousness of Adverse Events (AEs)
•
Device or Procedure Related SAEs
•
Secondary surgical intervention including revision, removal, reoperation or supplemental
fixation
•
Subsidence, device migration, nonunion, osteolysis and/or heterotopic ossification in the
area surrounding the implant site by radiographic assessment
•
Presence of anti-B2A antibodies (Ab) in serum
2.2.4 
Pharmocokinetic Endpoints 
•
Plasma B2A levels at Days 1, 2, 4, 7, and 15
•
Plasma AUC, AUCt, Cmax, Tmax, tY:z, CL/F, Vz/F for B2A
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 29 of 91 
3 
INVESTIGA TIONAL PLAN 
3.1 
Overall Trial Design 
3.1.1 
Trial Design Diagram 
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Figure 1 
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3.1.2 
Trial Schedule 
Investigational Device Exemption (IDE) Approval: 20 November 2015 
Study Start-up: 6 months 
Fening Phannaceuticals 
CONFIDENTIAL 
S11Mly \'1,11 B 
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I 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 30 of 91 
Subject Enrollment: 18 months 
Treatment and Follow-up: 18 months 
Study Closeout: 4 months 
Total Duration: 46 months 
3.2 
Planned Number of Trial Sites and Subjects 
The study will be conducted at up to a total of 50 centers; 35-40 US centers and 10-15 Canadian 
centers, following approval by appropriate oversight committees and regulatory agencies 
[Institutional Review Board (IRB) and Food and Drug Administration, USA (FDA) or the local 
Research Ethics Board (REB) and Health Canada, respectively] with informed consent obtained 
from all subjects. 
Approximately 480 subjects will ibe randomized in a 2: 1 ratio (Treatment: Control) with 
approximately 320 to receive AMPLEX and 160 to receive ABG. 
3.3 
Study Oversight 
3.3.1 
Clinical Events Committee 
An independent group of physicians that are not involved in the clinical investigations will act as 
the Clinical Events Committee (CEC). The CEC will be responsible for the review and 
adjudication of Investigator-reported events and events identified in the monitoring process. Any 
potential device, ancillary device or procedural related AEs, all events associated with secondary 
surgical intervention, and any other AEs specified in the CBC Charter will be adjudicated. 
Subsequent to Investigator determination of severity and relatedness of the event, the CEC shall 
classify each of these adverse events based on severity and association to the device and/ or 
procedure. During the review of the events, the CEC will be blinded to the clinical site and 
treatment. The CEC Charter will be developed upon identification of committee members and shall 
include consistent definitions for each type of event and shall outline the review process. 
3.3.2 
Data Monitoring Committee 
An independent panel of medical and biostatistics experts will serve in the capacity of Data 
Monitoring Committee (DMC). The DMC will periodically review clinical study data to ensure 
patient safety, trial integrity, and scientific rigor. DMC members will have relevant orthopedic 
experience and medical knowledge of the product under investigation. The DMC will develop and 
ratify a Charter that provides guidelines for oversight of trial safety. The Charter will define the 
scope and DMC's responsibilities, quorum, operating guidelines, sample template for required data 
analyses, pre-defined stopping rules, communication pathway to the study Sponsor, and frequency 
of meetings. 
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
3.3.3 
Imaging Core Laboratory 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 31 of 91 
An independent imaging core laboratory will be utilized for assessment of radiographic images at 
each follow-up visit in which a radiographic image is obtained. A comprehensive description of the 
imaging methodology will be detailed in an imaging core lab Radiographic Evaluation Protocol 
(REP) provided in the Site Reference Manual (SRM). All radiographic imaging shall be performed 
in accordance with this protocol. 
Prior to development of the REP, the imaging core laboratory conducted a Radiographic Image 
Review and Validation Assessment to determine the impact of any potential confounding factor 
(i.e., metallic screws in the graft site, radio-opacity of the graft material) on the ability of readability 
of the images and utilized the information to develop the REP. 
The assessment of fusion status and device condition shall be performed by an independent imaging 
core lab in compliance with their REP provided in the SRM. Results of these assessments will not 
be adjudicated by the CEC, 
3.4 
Discussion of Overall Trial Design and Choice of Control Groups 
3.4.1 
Trial Design 
This is a prospective, multi-center clinical trial in subjects (2:18 and <75 years of age) undergoing 
tibiotalar (ankle) arthrodesis or single, double, or triple hindfoot (talocalcaneal-, calcaneocuboid- or 
talonavicular-joint) arthrodesis with supplemental graft material and internal fixation with up to 3 
screws per joint. 
Subjects will be followed for 78 weeks. Post-discharge clinical visits will include visits at 2, 6, 12, 
24, 52 and 78 weeks. Adverse event data will be collected throughout the study. The primary 
endpoint will be assessed at 52 weeks. 
The objective of the trial is to demonstrate that AMPLEX is non-inferior to ABG for bone fusion in 
a population indicated for ankle arthrodesis or single, double, or triple hindfoot arthrodesis surgery 
with supplemental graft material. The study will be declared successful if non-inferiority of 
AMPLEX compared to ABG in the primary efficacy endpoint is demonstrated in the mITT analysis 
population within a non-inferiority margin of -12.0% at a type I error rate of I-sided 5%. 
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
3.4.2 
Selection of Endpoints 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 32 of 91 
The primary endpoint of this trial is the success in the SPC, which consists of improvement in pain 
on weight bearing at fusion site, absence of significant graft harvest site pain, functional 
improvement, absence of device related SAEs or procedure related SAEs and absence of secondary 
surgical or non-surgical interventions intended to promote fusion. This endpoint is considered to 
provide relevant assessment to determine the benefit/risk profile of the investigational device 
(AMPLEX) compared to the control material (ABG) used in arthrodesis surgery involving hindfoot 
or ankle. 
Functional improvement will be measured by tine FAAM-ADL. It is a reliable and valid self­
assessment instrument that was specifically developed to measure physical function for subjects 
with foot and ankle disorders (Martin, Irrgang, Burdett, Conti, & van Swearingen, 2005). The 
validity evidence for test content, internal structure, score stability, and responsiveness was 
demonstrated in 243 subjects including 51 (21 % ) subjects who underwent foot and ankle related 
surgery (Martin, Irrgang, Burdett, Conti, & van Swearingen, 2005). The reliability and 
responsiveness were further demonstrated in 311 subjects who underwent elective surgery for a 
foot or ankle related disorder (Hung, Baumhauer, Brodsky, & al., 2014). The minimal detectable 
change (MDC) and minimal clinically important difference (MCID) were identified as 5. 7 and 8 
points (Martin, Irrgang, Burdett, Conti, & van Swearingen, 2005). 
Both harvest site pain and pain on weight bearing at fusion site will be measured by the 100 mm 
VAS. The 100mm VAS is a reliable self-assessment instrument commonly used in the assessment 
of pain. The VAS has been widely used in the clinical arena and research setting (Hawker, Mian, 
Kendzerska, & French, 2011) and is frequently employed in patients with musculoskeletal disorders 
(Tubach, et al., 2012). Minimal clinically important improvement in pain has been reported for 
knee and hip osteoarthritis at 19.9 mm and 15.3 mm respectively (Tubach, et al., 2005, p. 31). 
Additionally, improvement in baseline weight-bearing pain of >20 mm has been used as a 
component of a subject performance composite endpoint in other studies of ankle and hindfoot 
fusion. (FDA Orthopaedic and Rehabilitation Devices Division, 2011 [May]) (Daniels, et al., 2015, 
pp. 743-746) (Baurnhauer J. et al, 2014, p. 107). 
CT imaging is logistically feasible, is a meaningful endpoint and has been used in past FDA 
studies. It reflects the proposed benefit of the therapies, the underlying clinical condition and has 
precedence for use. Its use is also independent of the assigned randomization and would therefore 
represent an objective measure of efficacy. Consistent interpretation in these complex anatomies is 
important in obtaining unbiased assessments, supporting the use of an independent imaging core lab 
with expertise in this area for image interpretation. The blinding of radiographic reviewers from 
clinical information further adds to the validity of the assessments. Although there may be 
radiographic differences observed in the treatments, the blinding of the reviewers in this trial is 
consistent with the current draft guidance on imaging in clinical trials.44 
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
3.4.3 
Blinding 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 33 of 91 
The Investigator cannot be blinded to the device because of system-specific requirements for use. 
The independent radiologist(s) at the imaging core laboratory will remain formally blinded to the 
treatment assignment. In addition, PK assessment will not be performed in a blinded manner. 
Blinding of the subjects is not possible due to the need for a surgical incision at a secondary site in 
the control group. Since subjects may not be blinded due to the presence of a second surgical site 
for the ABG Control treatment, subjects will be blinded until after the procedure to mitigate the 
impact of unblinded randomization and potential subsequent withdrawal of consent prior to 
treatment. In this process and following appropriate informed consent procedures, subjects will 
undergo screening evaluations to determine eligibility before randomization. Eligible subjects will 
then be randomized! as close to the procedure as possible. 
3.4.4 
Trial Population 
Subjects will be 2'.:18 and< 75 years of age and candidates for tibiotalar (ankle) arthrodesis or 
single, double, or triple hindfoot (talocalcaneal-, calcaneocuboid- or talonavicular-joint) arthrodesis 
with supplemental graft material. Subjects shall be screened prior to randomization to ensure they 
meet inclusion/exclusion criteria. The screening will include a review of all imaging and critical 
comorbid risk factors for nonunion by the Investigator. 
A Pharmacokinetic (PK) assessment will be conducted in a sub-set of subjects to assess the amount 
ofB2A in blood (plasma) after surgery, on Days 1, 2, 4, 7, and 15, and will include a baseline, pre­
procedure evaluation. The sub-set of subjects will include up to approximately 30 AMPLEX 
subjects, allowing pharmacokinetic evaluation in at least 20 AMPLEX subjects. Both genders will 
be represented. Blood samples will be collected and processed to plasma for laboratory evaluation 
(plasma B2A concentration). 
3.4.5 
Withdrawal Criteria 
A study subject will be discontinued from participation in the study if: 
•
The Investigator feels that the subject can no longer fully comply with the requirements of
the study or if any of the study procedures would not be in the best interest of the subject.
•
The subject is lost to follow up. A subject will be considered "lost to follow-up" and
terminated from the study when all of the following criteria have been met:
o
Failure to complete the remainder of the scheduled study visits without due cause;
and
o
Documentation of three unsuccessful attempts to contact the subject via telephone
and by certified mail.
•
The subject wishes to withdraw their consent for participation in the study.
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
4 
SELECTION OF TRIAL POPULATION 
4.1 
Trial Population 
4.1.1 
Inclusion Criteria 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 34 of 91 
Subjects enrolled in the study must meet the following inclusion criteria: 
1.
Signed written informed consent
2. Male or female at least 18 years of age but less than age 75
3.
Indicated for ankle or hind foot arthrodesis and require one of the following arthrodesis
procedures:
o
Tibiotalar (ankle)
o
Talocalcaneal (subtalar)
o
Talonavicular
o
Calcaneocuboid
o
Double hindfoot ( e.g., talonavicular and talocalcaneal joints)
o
Triple hindfoot (subtalar, talonavicular and calcaneocuboid joints)
4. Presents with pain on weight-bearing of at least 40 mm on a 100 mm VAS
at the area indicated for arthrodesis
5. Presents with at least one comorbid risk factor (based on Baurnhauer et al 2013) that
warrant the use of supplemental autogenous bone or allograft
o
Radiographic evidence of bone defect, deficit, subsidence or subchondral cyst
o
More than one joint to be fused
o
Involvement of other adjacent or nonadjacent joints
o
Large surface area
o
Intra-articular or extra-articular deformity
o
Post-traumatic arthritis
o
Diagnosis of osteoporosis
6. The Investigator determines the joint space(s) can be adequately filled with graft material
(AMPLEX or ABG) according to the following parameters:
o
Single hindfoot joint fusion: up to 5 cm3 
o
Double or triple hindfoot fusion: each individual joint up to 5 cm3, but overall, not
more than 10 cm3 for the full complement of joints
o
Ankle fusion: up to IO cm3
7.
Each fused joint can be rigidly stabilized with at least I and no more than 3 screws across
the fusion pfane. (Supplemental pins and staples may be used, as well as supplemental
screws and plates external to the fusion site(s).)
8.
Willing and able to comply with all study requirements including all postoperative clinical
and radiographic evaluations
9.
For women of childbearing potential (not post-menopausal for 12 months or surgically
sterile), a urine pregnancy test with a negative result must be obtained at screening and
within 24 hours prior to procedure. These trial participants must commit to adequate birth
control (e.g., oral contraceptive, two methods of barrier birth control, or abstinence) through
the 78 week follow-up
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
4.1.2 
Exclusion Criteria 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page35of 91 
Participants who have or meet any of the following exclusion criteria will not be eligible for the 
Study: 
1. Bone deficit requiring a structural graft
2. Charcot foot disease
3.
Radiographic evidence of open physes
4. Prior arthroplasty, arthrodesis, major surgical repair or reconstruction of the index ankle or
hindfoot joint(s)
5. Requires osteotomy or fusion of any midfoot joints
6. BMI greater than 45 kg/m2
7. Documented medical history of, or radiographic evidence of, a bone disease (e.g. avascular
necrosis) or other condition (e.g., osteolysis) that would preclude the subject from receiving
screw fixation in the opinion of the surgeon
8. Requires intramedullary nail fixation or an external fixator
9. Comorbidity that would limit the ability to administer any functional measurements such as
the FAAM-ADL
10. Has at the time of surgery, a systemic infection or local infection at the site of surgery
11. Medical condition, serious intercurrent illness, or extenuating circumstance that, in the
opinion of the Investigator, would preclude participation in the study or potentially decrease
survival or interfere with ambulation or rehabilitation ( e.g., history of transient ischemic
attack, stroke or liver disease)
12. HgbAlc level greater than or equal to 8%
13. Known hypersensitivity to any of the components of the product [e.g. B2A peptide,
Hydroxyapatite (HA): beta-tricalcium phosphate WTCP), ceramic granule]
14. Currently receiving treatment with a drug known to interfere with bone metabolism [e.g.,
systemic corticosteroid therapy (topical corticosteroid therapy is permissible), methotrexate]
15. Has previously received treatment with a drug known to interfere with bone metabolism
[e.g., systemic corticosteroid therapy (topical corticosteroid therapy is permissible),
methotrexate] and in the opinion of the -investigator could continue to negatively interfere
with bone metabolism or bone healing
16. History of any severe allergy or anaphyfaxis, or a history of hypersensitivity to protein
pharmaceuticals [ e.g., monoclonal antibodies or gamma globulins, recombinant Bone
Morphogenetic Proteins (BMPs)]
17. Medical condition requiring radiation, chemotherapy or irnrnunosuppression
18. Have a prior or active history of malignancy ( except for basal cell carcinoma of the skin)
19. Has a history of autoimmune disease known to affect bone metabolism. Examples include
spondyloarthropathies (e.g., ankylosing spondylitis, Crohn's disease, and ulcerative colitis),
Juvenile Arthritis, Grave's disease and Hashimoto's thyroiditis; Rheumatoid Arthritis is
alowed.
20. Have pathological or genetic liver disease or who have clinically significant, elevated
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
baseline liver function enzymes 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 36 of 91 
21. Has obvious and/or documented alcohol or illicit drug addictions
22. Is a prisoner in a correctional institution/facility
23. Actively involved in litigation or workman's compensation
24. Has participated in clinical studies evaluating investigational devices, pharmaceuticals or
biologics within 6 months of randomization
25. Requires chronic therapeutic use ofNSAID during the first 6 post-operative weeks (except
aspirin up to 325 mg bid for cardiovascular protection and/or DVT prophylaxis)
26. Has previously been treated with, or exposed to, therapeutic levels of synthetic or
recombinant BMPs
27. Requires chronic subcutaneous or intravenous heparin therapies
4.2 
Method of Assigning Subjects to Treatment Groups 
4.2.1 
Recruitment 
Each Investigator will recruit subjects who are undergoing surgical treatment for hindfoot or ankle 
arthritis equitably in an effort to ensure to the best extent possible that the subject pool is 
representative in gender, race, ethnicity, and age of the population affected by the condition being 
studied. The Investigator or his/her designee such as the study coordinator will notify Ferring or 
their designee of each potential subject. The coordinator win assign each consented subject a 
subject identification number in consecutive, ascending, and chronological order. This number will 
serve as a subject's identifier on all study-related documentation. 
All subjects screened for the trial will be recorded on a screening log, including subject age, sex, 
race and ethnicity. The reason of non-eligibility for all subjects who are deemed ineligible by the 
Investigator should also be recorded on the study screening log. The screening log serves as a 
method for Ferring or their authorized designee to ensure that there is no selection bias in the trial. 
Screening logs will be periodically examined to evaluate reasons for non-enrollment of women or 
other key demographic groups. 
Once it is determined that the subject is eligible for the study, the site will inform the Perring 
representative or designee of the surgery date. The subject will be randomized according to the 
randomization schedule for each site as close to the time of surgery as possible, with the 
recommendation that the randomization be performed on the day of the surgical procedure. The 
subject randomization number will then be recorded on the relevant CRF. The randomization 
number will be assigned prior to surgery in a sequential, chronological order. Randomization 
numbers will not be reassigned. 
Evaluations performed at each study visit are summarized in Section 6: Trial Procedures. If a 
subject misses a visit, all reasonable efforts should be made to reschedule tlhe missed visit within 
the allocated visit window. If the visit cannot be rescheduled within the allocated visit window, the 
site should schedule a visit with the subject as soon as possible. 
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
4.2.2 
Randomization 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 37 of 91 
Once written informed consent is obtained and eligibility is confirmed the subject can be 
randomized. Randomization must occur prior to surgery, with a recommendation to take place on 
the day of surgery or as close to the procedure as possible. Subjects will not be made aware of their 
randomization result prior to surgery. 
Subjects will be randomly assigned on a two to one (2: 1) basis to either the treatment group 
(AMPLEX) or the control group (ABG). Randomization will be stratified by clinical center, 
surgical site (hindfoot vs. ankle), and nonunion risk factors (none vs. any of: obesity, diabetes, 
previous hind foot/ankle surgery, or smoking history). Permuted block randomization wi II be 
performed within strata. To minimize the opportunity for the sequence to be predicted, the block 
size will be variable. The randomization schedules for all strata will be generated in advance by an 
independent statistician who is not going to be involved in the study conduct using a computerized 
random number generator. Investigational sites will not have access to the randomization 
schedules. 
Administration of randomization assignments will be accomplished using an electronic system. 
The study coordinator or a designee will obtain the randomization assignment per the provided 
randomization instructions. A copy of the randomization assignment will be maintained in the 
subject's file. 
If, between the time of randomization and the beginning of surgery, the subject becomes ineligible 
or withdraws, the reason for failure to treat will be recorded in the subject's study records. 
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
5 
TREATMENTS 
Trial Code: 000226 
5.1 
Treatments Administered 
5.1.1 
Investigational Device 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page38of 91 
AMPLEX, the investigational device, is a synthetic bone graft substitute comprised of two parts; I) 
a synthetic bone void filler (BVF) that functions as an osteoconductive scaffold and 2) a synthetic 
peptide (B2A) that augments osteodifferentiation. 
The principal mode of action of the device is based on the osteoconductive granules that act as a 
scaffold for cellular ingrowth; B2A augments that action. The sterile ceramic granules, supplied by 
a third party vendor, are currently cleared for use as a BVF for bony voids or gaps of the skeletal 
system ( e.g., extremities, spine and pelvis) that are not intrinsic to the stability of the bony 
structure. These defects may be surgically- or traumatically-created osseous defects to the bone 
(K063527, MBCP+).21
AMPLEX is supplied in kit form (AMPLEX kit) and the components must be combined and 
utilized in accordance with the Instructions for Use (IFU). 
AMPLEX, B2A Enhanced Ceramic Granules (AMPLEX), is the Investigational Device supplied in 
kit form and must be used as a system. When fully prepared according to the IFU, AMPLEX 
consists of osteoconductive granules (BVF) with bound synthetic B2A peptide. 
The AMPLEX kit contains two sterile, non-pyrogenic components that must be used as a system: 
•
Part I: Bone void filler (BVF); 1 to 2 millimeter (mm) diameter granules, 5 cm3/vial, two
(2) vials per kit
•
Part 2: Lyophilized B2A Peptide Powder, 2.8 mg/vial
Part I: BVF consists of two (2) vials of 5 cc, sterile, ceramic granules. The granules are composed 
of 20% HA and 80% P-TCP. 
Part 2: Lyophilized B2A Peptide Powder, is formulated as a sterile product containing 2.8 mg B2A 
with mannitol and glycine as exciipients, and is lyophilized in borosilicate glass vial. Each vial 
contains a white to off-white caked powder composed of highly purified B2A (acetate salt), 
mannitol (USP), and glycine (USP) under an atmosphere of nitrogen (nitrogen headspace gas). The 
vials are closed with a Daikyo VlO RB2-TR FluroTec® coated stopper and with an aluminum­
based, flip-top closure. Each vial contains sufficient B2A to prepare both vials of Part 1 ceramic 
granules. 
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 39 of 91 
For preparation of implant-ready AMPLEX by following the instructions in IFU, the lyophilized 
drug product (DP) is reconstituted in sterile water for injection (WFI). In-use stability of the 
reconstituted drug product has been demonstrated by measuring purity of the solution following 
reconstitution over a six (6) hour period. After reconstitution, a defined volume of B2A solution is 
withdrawn, added to the granules (BVF) and mixed according to the IFU. Implant-ready 
AMPLEX, with 0.225mg B2A/cm3 granules should be used within four (4) hours of preparation. 
5.1.2 
Non-Investigational Material 
The control material, Autogenous Bone Graft (ABG), is harvested from a location other than the 
graft site, for example, the calcaneus, proximal tibia, distal tibia or iliac crest and administered by 
surgical implant. 
5.1.3 
Investigational Device and Non-Investigational Material 
The aggregate volume of the investigational device (AMPLEX) or control material (ABG) utilized 
in index joints will be at the discretion of the surgeon, provided the joint space(s) can be adequately 
filled with graft material according to the following parameters: 
•
Single hindfoot joint fusion: up to 5 cm3
•
Double or triple hindfoot fusion: each individual joint up to 5 cm3, but overall, not more
than IO cm3 for the full complement of joints
•
Ankle fusion: up to 10 cm3
ABG will be obtained from a location other than the graft site, for example, the calcaneus, proximal 
tibia, distal tibia, or iliac crest using standard surgical procedure. The selection of the ABG harvest 
site will be at the discretion of the surgeon and based on medical judgment. The harvested bone 
will be cleaned of soft tissue and morselized. The volume of ABG harvested for treatment will be 
measured using a syringe and the amount implanted, including the treated joint( s) recorded. 
5.2 
Characteristics and Source of Supply 
All devices are provided by Perring Pharmaceuticals and will be handled according to the principles 
of Good Manufacturing Practice (GMP). 
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
5.2.1 
Investigational Device Manufacturing 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 40 of 91 
Perring Pharmaceuticals Inc. is the specification developer and legal manufacturer of AMPLEX. 
The components of AMPLEX are manufactured using contract manufacturers. The BVF is 
manufactured by Biomatlante (Nantes, France) (FDA registration #3002673655). It is noted that 
separately, the BVF component has been cleared by the FDA via 51 Ok as K063527 (referred to 
with the trade name MBCP+). Tlhe manufacturer ofB2A Drug Substance will be Bachem Inc. 
(Torrance, CA). Bachem Inc. is a GMP-compliant, FDA-registered and California-licensed facility 
that specializes in tine synthesis of peptide drug substances. The manufacturer of B2A Drug 
Product to be utilized in pivotal clinical trials will be AAI Pharma, Charleston, SC. AAI Pharma is 
a GMP-compliant, FDA-registered, licensed facility that specializes in drug formulation .and 
packaging. 
5.3 
Packaging and Labelling 
Packaging and labelling of AMPLEX will be performed in accordance with GMP and national 
regulatory requirements. 
5.3.1 
Investigational Device Packaging 
The AMPLEX kit is composed of two sterile parts: 
•
Part 1: BVF; I to 2 mm diameter granules, 5 cm3/vial, two (2) vials per kit
•
Part 2: Lyophilized B2A peptide powder, 2.8 mg/vial
An IFU is provided within the kit details the preparation of the implantable material. 
Part I bas two (2) vials per kit wherein each vial contains 5 cm3 /vial of BVF of sterile, ceramic 
granules housed in vials with external screw-top closures. Each unit is sealed in double Tyvek 
pouches and radiation sterilized. 
Part 2 is a vial that contains a white to off-white caked powder composed of highly purified B2A 
(acetate salt), mannitol (USP), and glycine (USP) under an atmosphere of nitrogen (nitrogen 
headspace gas). The vials are closed with a Daikyo VlO RB2-TR FluroTec® coated stopper and 
with an aluminum-based, flip-top closure. Part 2 is intended for use only with Part 1 vials. 
Each of the AMPLEX kit elements as described above will be packaged in a kit box. The kit box 
and the AMPLEX kit will be labeled with study specific labels, fulfilling requirements for 
investigation device. The content of the labels will be in accordance of US/Canadian requirements 
and Annex 13, Eudralex, Volume 4 when applicable. 
Each component within the kit will carry its own label delineating a description of the component. 
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 41 of 91 
All study (investigational) device accountability records will be maintained by the Investigator or 
qualified designee, stored in a secure location and reviewed during monitoring visits by the assigned 
Clinical Research Associate (CRA)/monitor. If AMPLEX is prepared, but not implanted or used for 
whatever reason, it will be discarded per the Institution's policy and the circumstances recorded in 
the device accountability log/form(s). 
5.3.2 
Non-lnvestigational Material (ABG) 
As ABG is being used as an active control reference in the clinical trial and is obtained during 
surgery, there is no packaging or labeling. 
5.4 
Conditions for Storage and Use 
The Investigator will ensure that the investigational device will be stored in appropriate conditions 
in a secure location with controlled access. The storage compartment shall be monitored regularly 
and the temperature shall be documented. 
5.4.1 
Investigational Device Storage 
The investigational device will only be dispensed to subjects who meet the eligibility criteria and 
are randomized to a treatment group in the trial. 
AMPLEX should be refrigerated (2-8 degrees Celsius / 36-46 degrees Farenheit) in a secure room 
(e.g. hospital phannacy). A temperature log should be maintained to confirm temperatures have 
not been exceeded. If stored as instructed, AMPLEX is stable for up to 1 year. 
5.5 
Treatment Compliance 
5.5.1 
Dispensing and Accountability 
AMPLEX will only be dispensed to subjects who meet the eligibility criteria and are randomized to 
the treatment group in the trial. The Investigator ( or his/her designated personnel, e.g. trial nurse) 
will maintain a device accountability log/form(s) detailing the dates and quantities of the 
investigational devices dispensed to, and used by, each subject, as well as the batch numbers. The 
monitor will verify the device accountability during the trial. 
Access to investigational devices shall be controlled and the investigational devices shall be used 
only in the clinical investigation and according to the protocol. The Sponsor shall keep records to 
document the physical location of all investigational devices from shipment of investigational 
devices to the investigation sites until return or disposal. The principal Investigator or an 
authorized designee shall keep records documenting the receipt, use, return and disposal of the 
investigational devices, which shall include: 
•
date of receipt
•
identification of each investigational device (kit lot number)
•
expiry date, if applicable
•
date or dates of use
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
•
subject identification
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 42 of 91 
•
date on which the investigational device was retumed/explanted from subject, if applicable
•
date of return of unused, expired or malfunctioning investigational devices, if applicable
•
date and manner of device destruction
All study (investigational) device accountability records will be maintained by the Investigator or 
qualified designee, stored in a secure location and reviewed during monitoring visits by the 
assigned CRA/monitor. 
If AMPLEX is prepared, but not implanted or used for whatever reason, it will be discarded per the 
institution's policy and the circumstances recorded in the device accountability log/form(s). If 
needed (e.g., due to faulty preparation, accidental contamination, etc.), and with time permitting, a 
new device may be prepared according to the same randomization treatment assignment, ( e.g., any 
given subject will be assigned a single randomization code/assignment). 
At the end of the study or as frequently as deemed appropriate, all unused study (investigational) 
device kits should be returned to the Sponsor or its designated representative unless otherwise 
instructed. 
5.6 
Return and Destruction of Medicinal Products and Auxiliary Supplies 
All opened and unused devices can be destructed at the trial site (in accordance with local 
requirements) after the device accountability has been finalized, verified by the monitor, and signed 
off by the Investigator. 
Any material remaining after B2A reconstitution and preparation will be discarded according to the 
Institution's policy and will be recorded and documented accordingly. 
At the end of the study, any remaining unopened study (investigational device) product will be 
shipped to Ferring or its representative for destruction unless authorized in writing by Perring to 
proceed otherwise. 
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
6 
TRIAL PROCEDURES 
6.1.1 
Subject Recruitment 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 43 of 91 
Each Investigator will recruit any subjects who meet the eligibility criteria regardless of the 
subjects' gender, race or ethnicity. 
6.1.2 
Screening/Pre-Operative Visit 
The potential risks and benefits associated with participation in the study will be explained to 
potential study subjects. Written informed consent must be obtained before the subject can begin 
any study-specific procedures that are not standard of care ( e.g. immunology sample collection). In 
addition, if governing laws require, all subjects must sign the appropriate authorization for use, 
collection, and disclosure of protected health information and receive a copy of their signed 
informed consent. 
The following assessments/activities wi11 be performed at the screenjng or pre-operative visit: 
•
Obtain informed consent and authorization to disclose and release protected health
information as applicable
•
Medical History:
o
Record medical history
o
Record all concomitant medications taken within the past month, including
vitamins/supplements such as glucosamine and chondroitin, and pain relief
medication includiing those that are herbal
o
Record comorbidities
•
Physical Assessment:
o
Verify inclusion/ exclusion criteria
o
Record vital signs, weight, height and BMI
o
Collect standing A/P, lateral and oblique X-rays of the hindfoot or ankle (historical
X-rays, taken up to 24 weeks prior to the planned date of surgery, will also be
accepted)
o
Collect urine sample(s) for pregnancy test from female subjects of childbearing
potential, for standard urinalysis and for microscopic urinalysis ( only if required)
o
Collect four blood samples for: 1) non-fasting chemistry (including aspartate
aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase
[APT], gamma-glutamyl transferase [GGT] bilirubin and hemaglobin [HbAlc]), 2)
hematology, 3) immunogenicity testing for B2A antibodies, and 4) immunological
testing (hepatitis B virus [HBV], hepatitis C virus [HCV], human immunodeficiency
virus [HIV]). Additional details for the collection and handling of blood samples are
provided in the SRM
o
Review with the subject the instructions for, and ask the subject to complete, the
FAAM-ADL Questionnaire and the weight-bearing pain VAS
o
Review the instructions for and ask the subject to complete the SF-12 Questionnaire
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
•
Investigator Screening Assessment:
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 44 of 91 
o
Review medical history and comorbidities
o
Record patient-reported VAS pain on weight-bearing at site where fusion is to be
performed
o
Review available relevant diagnostic imaging results evaluations (e.g. X-rays, MRI,
SPECT/CT or CT scans obtained up to 24 weeks prior to the planned date of
surgery)
o
Confirm the need for graft material and volume
o
Identify the arthrodesis site(s) / index joint(s)
6.1.3 
Day of Surgery 
Once eligibility is confirmed the subject can be randomized, but the subject will not be notified of 
randomization result until after the surgery. 
The following assessments/activities will be performed on the day of surgery: 
•
Verify subject meets eligibility criteria
•
Record date and time of hospital admission
•
Record medical history and comorbidities since screening
•
Record vitaE signs
•
Identify the arthrodesis site(s) / index joint(s)
•
Collect urine sample for pregnancy test from female subjects of childbearing potential
(within 24 hours prior to procedure)
•
Record volume of blood loss and blood use during surgery
•
Record the number and type of screws and screw systems used during surgery
•
Record operation start and end time (incision to closure)
•
Measure and record the volume of AMPLEX implanted per joint and identify the joint; and
record the amount remaining after surgery. For ABG, record the volume harvested for
treatment, implanted per joint, identify the joint, and record the amount remaining after
surgery.
•
Perform specific intraoperative data collection
•
Record any protocol deviations
•
Record all concomitant medications including (anesthesia) taken since the screening visit
•
Record any AEs experienced from time of screening
PK Assessment: 
•
A Pharmacokinetic (PK) assessment will be conducted in a sub-set of subjects to assess the
amount of B2A in blood (plasma) after surgery, on Days 1, 2, 4, 7, and 15, and will include
a baseline, pre-procedure evaluation. The sub-set of subjects will include up to
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 45 of 91 
approximately 30 AMPLEX subjects, allowing pharmacokinetic evaluation in at least 20 
AMPLEX subjects. Both genders will be represented. Blood samples will be collected and 
processed to plasma for laboratory evaluation (plasma B2A concentration). 
6.1.4 
Surgical procedure 
In addition to the below text, further detail on surgical procedure can be found in the Surgical 
Manual. 
The operative site will be prepared and draped for surgery using standard technique. The 
arthrodesis site will be prepared by decorticating any remaining arthritic cartilage down to 
subchondral bone. High speed mechanical instruments such as burrs are avoided to prevent 
excessive heat at the fusion site that may be detrimental to the biological processes required for 
fusion. The graft material should be packed in the joint space to minimize the chance of extrusion. 
Stable fixation of joint in the appropriate position is achieved using 1 to 3 internal fixation screws 
with or without supplemental fixation. Wound closure is performed using standard technique. A 
dressing is applied and the ankle and hindfoot are immobilized with a cast, splint or boot. 
Internal Fixation: 
Screws will be used for internal fixation in order to standardize the hardware. All fusion constructs 
should be comprised of at least one but not more than 3 screws. Supplemental pins and staples may 
be used. Supplemental screws and plates external to the fusion site(s) are also allowed. The 
manufacturers of the screws provide Instructions for Use and Surgical Technique for their 
respective products. These documents must be consulted for guidance on the use of instruments for 
surgical preparation, sizing of screws, and placement of the screws. 
Preparation of Graft Material: 
Graft material will be prepared during surgery using either autogenous bone or the AMPLEX 
material assigned through randomization. Graft materials are to be placed ONLY within the joint 
space. 
•
AMP LEX, Jnvestigational Treatment. AMPLEX should be prepared following the IFU
accompanying the kit. If the subject is assigned to receive AMPLEX, the lyophilized B2A
powder will be reconstituted in sterile WFI and mixed with the granules at the time of
surgery as per the IFU. Once reconstituted and mixed with granules, implant-ready
AMPLEX must be used within four hours.
•
Autogenous Bone Graft, Control Treatment. The harvested bone (calcaneus, proximal tibia,
distal tibia, iliac crest, etc.) will be cleaned of soft tissue and morselized. The volume of
ABG harvested for treatment should be measured using a syringe.
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 46 of 91 
•
The aggregate volume of AMPLEX or ABG utilized in index joints will be at the discretion
of the surgeon, provided the joint space(s) can be adequately filled with graft material
according to the following parameters:
o
Single hindfoot joint fusion: up to 5 cm3
o
Double or triple hindfoot fusion: each individual joint up to 5 cm3, but overall, not
more than l O cm3 for the full complement of joints
o
Ankle fusion: up to 10 cm3
6.1.S 
Post-Operative Care 
While in the hospital, subjects should be encouraged to mobilize out of bed by the first post­
operative day. Physical therapy for ambulation and activities of daily living should also be 
provided per standard of care. The following will be performed prior to subject's release from the 
hospital or within 1 week following the procedure: 
•
Collect A/P, lateral and oblique X-rays of the hindfoot/ankle after implant
Hospiital discharge will occur in accordance with the institutions' standard of care. Discharge 
instructions will include prescriptions for pain management. Sites should provide standard-of-care 
prophylaxis for thromboembolic disease and this may include ASA up to 325 mg bid. With the 
exception of ASA up to 325 mg bid for either cardiovascular protection and/or DVT prophylaxis, 
subjects will be instructed to avoid non-steroidal anti-inflammatory drugs (NSAIDs) and 
corticosteroids for the first 6 weeks following surgery. Subjects will be advised that the use of 
NSAIDs or systemic steroid therapy (not including topical steroid therapy) may interfere with bone 
healing. This also applies to limited use of NSAIDs for headache, dysmenorrhea, etc. 
Electromagnetic, ultrasound or osteobiologic treatments stimulating bone growth are not allowed. 
Subjects will be instructed to remain non weight-bearing for six (6) weeks, then allowed to 
progressively increase weight-bearing. During the progressively increased weight-bearing 
timeframe, a removable cast/splint or boot is worn, which is subsequently weaned after full 
weight-bearing is achieved. It is recommended that all subjects are directed to participate in a post­
operative rehabilitation program consistent with the guidelines provided in Table 2. Subjects will 
be advised against the use of tobacco products for at least six (6) months after surgery. Tobacco 
products will be defined as all tobacco products (cigarettes [including e-cigarettes], cigars, and 
chewing tobacco) and will include gum or patches that contain nicotine. Subjects will be advised 
that njcotine may increase the chances of wound infection, pseudarthrosis (nonunion) and other 
complications. 
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 47 of 91 
Table 2 
Post-operative Rehabilitation Guidance 
Average 
Examples of phase appropriate 
Phase 
Time Post-
Immobilization 
activities 
sureery 
• Gentle A/PROM of uninvolved
• Rigid immobilization (e.g.,
joints (e.g., toes, knee, hip)
Phase l 
0-2 weeks
• Limb elevation
cast)
• Crutch/ambulatory aide instruction
for strict NWB
Phase 2 
2-6 weeks
• Rigid immobilization (e.g.,
• Continued NWB instruction
cast, walking boot)
• Rigid or flexible
• Progressive WB to tolerance
Phase 3 
6-12 weeks
immobilization (e.g.,
walking boot, ankle brace)
• flexible immobilization as
• Physical Therapy rehabilitation
Phase 4 
12-24 weeks 
needed (e.g., ankle brace)
program
6.1.6 
Follow-up Visit at 2 Weeks 
The visit window is ± 3 days. 
•
Physical assessment of hindfoot/ankle, including vital signs
•
Collect two blood samples for: 1) non-fasting chemistry and 2) hematology. Additional
details for the collection and handling of blood samples are provided in the SRM
•
Subject-based Assessment:
o
If subjects are in the ABG group, ask subjects to rate their graft site pain on the VAS
•
Record adverse events
•
Record concomitant medications
6.1.7 
Follow-up Visit at 6 Weeks 
The visit window is± 14 days. 
•
Physical assessment of hindfoot/ankle, including vitati signs
•
Collect three blood samples for: I) non-fasting chemistry, 2) hematology and 3)
immunogenicity testing for B2A antibodies. Additional details for the collection and
handling of blood samples are provided in the SRM
•
Subject-based Assessment:
o
If subjects are in the ABG group, ask subjects to rate their graft site pain on the VAS
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 48 of 91 
•
Collect A/P, lateral and oblique X-rays of the hindfoot/ankle
•
Record adverse events
•
Record concomitant medications
6.1.8 
Follow-up Visit at 12 Weeks 
The visit window is± 14 days. 
•
Physical assessment of hindfoot/ankle, including vital signs
•
Collect three blood samples for: 1) non-fasting chemistry, 2) hematology and 3)
immunogenicity testing for B2A antibodies. Additional details for the collection and
handling of blood samples are provided in the SRM
•
If immune testing is positive, the subject will be reevaluated at each subsequent follow-up
visit until the response is resolved or to the end of the study
•
Collect A/P, lateral and oblique X-rays of the hindfoot/ankle
•
Perform a CT scan of the bind foot/ankle
•
Subject-based Assessment:
o
Review the instructions for and ask the subject to complete the FAAM-ADL
Questionnaire and weight-bearing pain VAS
o
If subjects are in the ABG group, ask subjects to rate their graft site pain on the VAS
•
Record adverse events
•
Record concomitant medications
6.1.9 
Follow-up Visit at 24 Weeks 
The visit window is± 30 days: 
•
Physical assessment of hindfoot/ankle, including vitaE signs
•
Collect A/P, lateral and oblique X-rays of the hindfoot/ankle
•
Perform a CT scan of the hindfoot/ankle
•
Subject-based Assessment:
o
Review the instructions for and ask the subject to complete the FAAM-ADL
Questionnaire and weight-bearing pain VAS
o
If subjects are in the ABG group, ask subjects to rate their graft site pain on the VAS
o
Review the instructions for and ask the subject to complete the SF-12 Questionnaire
•
Record adverse events
•
Record concomitant medications
6.1.10 
Follow-up Visit at 52 Weeks 
The visit window is ± 30 days: 
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 49 of 91 
•
Physical assessment of hindfoot/ankle, including vital signs
•
CoJlect A/P, lateral and oblique X-rays of the hindfoot/ankle
•
Perform a CT scan of the hindfoot/ankle
•
Subject-based Assessment:
o
Review the instructions for and ask the subject to complete the F AAM-ADL
Questionnaire and weight-bearing pain VAS
o
If subjects are in the ABG group, ask subjects to rate their graft site pain on the VAS
o
Review the instructions for and ask the subject to complete the SF-12 Questionnaire
•
Record adverse events
•
Record concomitant medications
6.1.11 
Follow-up Visit at 78 Weeks 
The visit window is ± 30 days: 
•
Physical assessment of hiodfoot/ankle, including vitaE signs
•
Collect NP, lateral and oblique X-rays of the hindfoot/ankle
•
Record adverse events
•
Record concomitant medications
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 50 of 91 
6.2 
Trial Flow Chart 
PK Assessment 
l,p to 20 SubjecLČ 
Study 
Asscssmeors 
Pre-procedure 
Day I l'ost 
Day 2 Post 
Day4 Post 
Duy 7 Pu,L 
Day IS Post 
lnfonm:d Consent 
Screening and Pre-operative 
Assessment 
2:1 Randomization 
----------1 (AE cullec1io11 ,Jart,,) 
320AMPLEX: 
(Treatment) 
1 Weck 
Follow-up Visi1 
6Weck 
follow-up \li,,it 
i 
12\Vk 
Follow-up Visi1 
24 Week 
Follow-up Visit· 
78 Weck 
Follow-up Visi1 
Study E1i1 
Figure 2 
Trial Flow Chart 
Ferring Phannaceuticals 
CONFIDENTIAL 
Fail 
160ADG 
(Control) 
l'roccdure 
i 
2 Weck 
Di,qualify 
Follow-up Visit 
6 Weck 
folluw-up \li,it 
i 
12 Weck 
Follow-1tp Visir 
24 Weck 
Follow-up Visit 
52 Weck 
Fulluw-up \li,,it 
78 Weck 
Fulluw-up Vi,it 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
7 
TRIAL ASSESSMENTS 
7.1 
Schedule of Assessments 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 51 of 91 
Table 3 
Schedule of Assessments 
Screening 
Treatment 
Follow-up 
Vi sit number 
Vl 
V2 
VJ 
V4 
VS 
V6 
V7 
Procedure 
Weeks 
-12
-
2 
6 
12 
24 
52 
V8 
78 
Days 
Days: -84 to 
Day 1 
Day 15 
Day 43 
Day85 
Day 169 
Day 365 
Day 547 
-1 
(+/- 3) 
(+/- 14) 
(+/- 14) 
(+/- 30) 
(+/- 30) 
(+/- 30) 
Informed consent 
X 
Medical History/ comorbidities 
X 
X 
Supplemental graft reqlrirement 
X 
confinnation 
Eligibility criteria verification 
X 
X 
Physical assessment of foot/hindfoot, 
X 
X 
X 
X 
X 
X 
X 
X 
vital signs 
Pregnancy test [I] (if applicable) 
X 
X 
Standard Unrinalysis [2) 
X 
Clin. labs: chemistry and 
X 
X 
X 
X 
hematology (3) 
Immunological Testing for HBV, 
X 
HCVand HfV 
Semm for 82A Ab testing [4] 
X 
X 
X 
Identification of target arthrodesis 
X 
X 
site 
Subject randomization [5] 
X 
Arthrodesis procedure 
X 
Specific intraoperative data 
X 
collection [6] 
Graft material volumes 
X 
A/P, lateral and oblique X-rays of 
Xt 
X [7] 
X 
X 
X 
X 
X 
hindfoot/ankle 
Foot and ankle CT scan 
X 
X 
X 
FAAM-ADL 
X 
X 
X 
X 
Weight bearing pain at fusion site 
X 
X 
X 
X 
VAS 
Graft Harvest site pain VAS 
X 
X 
X 
X 
X 
SF-12 
X 
X 
X 
Adverse event evaluation [8] 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
t At the screening/pre-operative visit, A/P, oblique and lateral X-rays will be collected (historical X-rays taken up to 24 weeks prior to the 
planned date of surgery will also be accepted). 
[I] Pregnancy test may be performed within 24 hours of the procedure
[2] If positive for blood, leukocytes, or nitrite, microscopic unrinalysis will be performed.
(3] HbAic is to be performed at screening for all subjects 
[41 B2A Antibody testing may continue past the 12 week follow-up visit if there is a positive test at 12 weeks. 
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 52 of 91 
(5] The subject will be randomized as close to the time of surgery as possible, with the recommendation that the randomization be 
perfonned on the day of the surgical procedure. 
[6] See Section 6.1.4 referencing the Surgical Manual. 
[7] Perform immediately following surgery or within I week following the procedure.
[8] Collected from time of informed consent. Post-treatment outcomes that are evaluated as efficacy endpoints, such as pain on weight­
bearing, harvest site pain, etc. will not be reported as AEs. 
Table 4 
Schedule of Assessments for PK Sampling 
Screening 
Treatment 
Follow-up 
Visit number 
Vl 
V2 
V3* 
V4 
vs 
V6 
V7 
vs 
P1·ocedu1·e 
Weeks 
-12 
--
2 
6 
12 
24 
52 
78 
Days 
Days -84 to 
Day l 
Day2 Day4 Day 7 Day 15 
Day 43 
Day85 
Day 169 Day 365 
Day 547 
-1 
(+/- 14) 
(+/- 14)
(+/- 30) 
(+/- 30) 
(+/- 30) 
PK assessment [I) 
X 
X 
X 
X 
X 
[I] A sub-set of up to 20 evaluable AMPLEX subjects will have a PK assessment. An additional sample of blood will be collected at 
pre-procedure and after surgery on Days I, 2, 4, 7, and 15. 
* Visit 3 will also consist of Days 2, 4 and 7, for which there will be an option for blood to be collected at home by a mobile
laboratory unit. 
7.2 
Assessments Related to Endpoints 
7.2.1 
Radiographic Assessments 
The collection and assessment of radiographic information will follow a pre-defined imaging core 
laboratory protocol. The radiographic assessments (X-ray and CT) will be read by a central core 
imaging laboratory. The assessments will be made by independent board-certified radiologists. 
The reviewers will be blinded to treatment arm and will not have access to clinical outcomes data 
when conducting the assessments. 
More specifically, radiographic assessments of osseous bridging will be performed by two 
independent radiographic reviewers (the "primary reviewers") blinded to each other's assessments. 
A third independent reviewer (the "adjudicator") will resolve disagreements between the primary 
reviewers. Each reviewer will be a US-based, board-certified, licensed and practicing radiologist 
with subspecialty training in musculoskeletal radiology. 
7.2.1.1 
X-rays 
At the screening/pre-operative visit, A/P, lateral and oblique X-rays will be collected (historical X­
rays taken up to 24 weeks prior to the planned date of surgery will also be accepted). These pre­
operative X-rays are the baseline for subsequent safety evaluation. After surgery A/P, oblique and 
lateral X-rays will be collected at the following visits: Day of Procedure (e.g., after implant or 
within I week following surgery), and 12, 24, 52 and 78 weeks post-surgery. The core imaging 
laboratory will provide qualitative (safety) assessments of screw loosening and radiolucencies 
around the screws, (new) fractures, subsidence, device migration, radiographic nonunion, osteolysis 
and/or heterotopic ossification in the area surrounding the implant site. A radiographic nonunion is 
Fening Phannaceuticals 
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B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 53 of 91 
defined on x-ray as radiographic evidence of nonunion (as defined in the REP) and the absence of 
radiographic progression of healing bone (as defined in the REP). The assessment will be 
conducted at Weeks 52 and 78. 
7.2.1.2 
Computerized Tomography (CT) and fusion success 
CTs will be collected at I 2, 24, and 52 weeks after surgery. Radiographic CT fusion success will 
be determined based on evaluation of CT slices in sagittal or coronal reconstructions. A joint will 
be considered successfully fused if there is evidence of bridging bone over 2:50% of the joint. If a 
subject undergoes fusion at more than one site, each fusion site will be assessed independently. A 
subject will be considered fused if all fusion sites (full complement of joints) independently have 
evidence of bridging bone over at least 50% of the joint in the absence of secondary surgical or 
nonsurgical interventions intended to promote fusion. By definition, immediately after surgery 
there is 0% bridging bone in the target joint. The progression of fusion over time will be assessed in 
each subject by monitoring the change in fusion status from the previous visit. 
7.2.2 
Subject self-assessments 
7.2.2.1 
FAAM-ADL Questionnaire 
The Foot and Ankle Ability Measure (F AAM) is a subject self-assessment questionnaire comprised 
of the separately scored 21-item Activities of Daily Living ADL (FAAM-ADL) and 8-item sports 
subscales.45 Each item is scored on a 5-point Likert scale anchored by 4 (no difficulty at all) and 0 
(unable to do), with higher scores representing a higher levels of function. 
In consideration of its target arthrodesis population, this study will utilize the FAAM-ADL sub­
scale as a measure of functional improvement in the composite endpoint. The FAAM-ADL 
questionnaire (included in Appendix 2) will be utilized at screening and at 12, 24 and 52 weeks 
post-surgery. The questionnaire and its instructions for use will be provided in the SRM. Prior to 
administering the F AAM-ADL, subjects will be instructed on how to complete the questionnaire. 
7.2.2.2 
Weight-bearing Pain VAS 
Weight-bearing pain at fusion site will be assessed using a VAS. Subjects will mark the location on 
a JOO-millimeter line corresponding to the amount of pain they experienced with O mm being "no 
pain" and 100 mm being "the worst pain imaginable". The weight-bearing pain VAS will be 
completed at screening and at 12, 24 and 52 weeks post procedure. The assessment and its 
instructions for use will be provided in the SRM. 
7.2.2.3 
SF-12 Questionnaire 
A validated SF-12 patient questionnaire will be completed at screening and at 24 and 52 weeks 
post-surgery. The SF-12 Health Survey includes 12 questions from the SF-36 Health Survey. 
These include: 2 questions concerning physical functioning; 2 questions on role limitations because 
of physical health problems; 1 question on bodily pain; 1 question on general health perceptions; 1 
question on vitality (energy/fatigue); 1 question on social functioning; 2 questions on role 
limitations because of emotional problems; and! 2 questions on general mental health (psychological 
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 54 of 91 
distress and psychological well-being). Scoring of individual items is identical to the SF-36 Health 
Survey. Scoring algorithms are tlhen applied to produce the physical component summary and 
mental health component summary scores. The survey and its instructions for use will be provided 
in the SRM. 
7 .2.2.4 
Graft Harvest Site Pain 
Since AMPLEX subjects will not undergo graft harvest, this is a patient reported outcome that is 
applicable to ABG subjects only. Subjects in the ABG group will be asked to assess the pain 
associated with their graft site. ABG subjects will assess the pain using a VAS. Subjects will mark 
the location on a 100-millimeter I ine corresponding to the amount of pain they experienced with 0 
mm being "no pain" and 100 mm being "the worst pain imaginable". This questionnaire will be 
completed at 2, 6, 12, 24 and 52 weeks after surgery. The assessment and its instructions for use 
will be provided in the SRM. 
7.3 
Other Assessments 
7.3.1 
Concomitant Medications 
At all study visits, subjects will be instructed to report any medications used to treat them over the 
course of the study. 
7 .3.2 
Vital Signs 
Vital signs will be performed at all study visits. On the day of Treatment, vital signs must be 
performed prior to surgery. Weight, height and BMI will be performed at screening (Visit 1). 
7.3.3 
Clinical Laboratory Testing 
Routine clinical laboratory tests (hematology and chemistry, including AST, ALT, ALP, GGT, 
bilirubin and hemaglobin Al c levels), will be performed at screening (Visit I) and follow-up 
through 12 weeks. All female subjects of childbearing potential will have urine pregnancy tests 
performed at the screening (Visit 1) and within 24 hours of the procedure (Visit 2). At the 
discretion of the Investigator, additional blood samples may be taken for safety reasons to analyze 
other clinical laboratory endpoints. All blood samples will be analyzed by a central laboratory. 
Full dletails regarding sample collection, proces.sing and shipping will be provided in the SRM. The 
lab results/reports will be provided to the site. If a laboratory result is abnormal, the Investigator 
will assess if it is clinically significant (CS) or not clinically significant (NCS). Clinically 
significant laboratory abnormalities are defined as abnormal results requiring treatment or medical 
interv·ention and should be recordled as adverse events. The severity of a clinically significant 
laboratory finding should be recorded as described; however, abnormal laboratory observations 
classified as NCS do not require an adverse event to be filed. 
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
7.3.3.1 
Standard Urinalysis 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page55of 91 
Diptstick urinalysis tests will be performed at screening (Visit 1 ), to assess blood, leukocytes, pH, 
specific gravity, nitrite, protein, glucose and urobilinogen. If dipstick urinalysis results are positive 
for blood, leukocytes or nitrite, microscopic urinalaysis will be performed. 
7.3.3.2 
Immunological Testing for HBV, BCV and HIV 
Serological testing for HBV, HCV and HIV will be performed at screening (Visit 1). Negative 
results are required for study admission. 
7 .3.4 
Antibody Monitoring 
The presence of anti-B2A antibodies will be evaluated using a tiered approach consistent with FDA 
guidance. This evaluation consists of screening and confirming for B2A-specific antibodies with 
use of a ligand bindling immunoassay. Following confirmation of the "positive" screening result an 
antibody titer will be determined. Subsequently, in confirmed ani-B2A antibody positive samples 
the BMP-2 cross-neutralization potential will be determined by a cell-based assay. Blood for 
immunogenicity testing will be collected at pre-operative/ screening visit, at 6 weeks and at 12 
weeks after surgery. For subjects testing positive for antibodies to B2A, additional blood samples 
will be obtained at each subsequent follow-up visit and analyzed until antibody titers return to 
baseline or until the end of the study. Samples will be analyzed at a GLP-compliant laboratory 
under the responsibility of the Department of Bioanalysis, IPC, Ferring Pharmaceuticals A/S. 
7 .4 
Human PK Assessment 
A Pharmacokinetic (PK) assessment will be conducted in a sll.lb-set of subjects to assess the amount 
of B2A in blood (plasma). Blood for assessment will be collected pre-procedure (baseline) and after 
surgery on Days 1, 2, 4, 7, and 15. Visit 3 will also consist of Days 2, 4 and 7, for which there will 
be an option for blood to be collected at home by a mobile laboratory unit. From the plasma 
concentration-time data of B2A, the following parameters will be estimated, if possible: AUC, 
AU Ct,% AUC extrap, Cmax, Tmax, tYi, lamda z, CL/F, Vz/F. The sub-set of subjects will include 
up to approximately 30 AMPLEX subjects, allowing pharmacokinetic evaluation in at least 20 
AMPLEX subjects. Both genders will be represented. Subjects included in the PK sub-set will 
provide written informed consent prior to the fusion procedure. 
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
8 
ADVERSE EVENTS 
8.1 
Definitions 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 56 of 91 
An adverse event (AE) is any untoward medical occurrence in a subject participating in a clinical 
trial. It includes: 
•
Any unfavorable and unintended sign, s.ymptom or disease temporally associated with the
use of the investigational device or control material, whether or not considered to be caused
by the investigational device or control material
•
Adverse events commonly observed and adverse events anticipated based on the effect of
the investigational device or control material
•
Any laboratory abnormality, vital sign or finding from physical examination assessed as
clinically significant by the Investigator
•
Any accidental injuries, reasons for any medical, nursing or pharmacy consultation, or
reasons for admission to hospital or surgical procedures
A Serious Adverse Event (SAE) is defined as any AE that: 
+
Results in death
+
Is life threatening (the subject is at immediate risk of dying from the adverse experience)
+
Results in subject hospitalization or prolongs existing hospitalization
+
Results in persistent or significant disability/incapacity
+
Is a congenital anomaly/birth defect
+
Is an important medical event that may not result in death, be life-threatening, or require
hospitalizatiion may be considered a serious adverse device effect when, based upon
appropriate medical judgment, they may jeopardize the subject or subject and may require
medical or surgical intervention to prevent one of the outcomes listed in this definition
An unanticipated adverse device effect (UADE) is defined as any serious adverse effect on health or 
safety or any life-threatening problem or death caused by, or associated with, graft material (either 
AMPLEX or ABG in the context of this protocol), if that effect, problem, or death was not previously 
identified in nature, severity, or degree of incidence in the investigational plan or application 
(including a supplementary plan or application), or any other unanticipated serious problem 
associated with a medical device that relates to the rights, safety, or welfare of subjects. 
An anticipated adverse device effect is any adverse device experience, reported in this protocol, 
contained in a report of prior investigations, Informed Consent Form and, or general investigational 
plan. 
A list of anticipated AEs is presented in Appendix 1. 
Subsequent Secondary Surgical Interventions, which are surgical interventions occurring at the 
index fusion site(s) subsequent to the completion of the index procedure, will be evaluated and 
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page57of 91 
presented separately from other adverse events. While secondary surgical interventions will not be 
classified as adverse events, the reasons for these procedures may be. An explanatory description 
will be provided as an adverse event narrative and will include: 
•
the reason for each subsequent secondary surgical intervention and
•
the action taken
•
the types and timing of these surgeries
The following are types of secondary surgical interventions at the index fusion site along with their 
definitions: 
•
Revision. A procedure that adjusts or in any way modifies or removes part of the original
implant configuration, with or without replacement of a component. A revision may also
include adjusting the position of the original configuration.
•
Removal. A procedure where all of the original system configuration is removed with or
without replacement due to, for example, mechanical failure of the graft material, pain, or
infection.
•
Reoperation. Any surgical procedure tbat does not include removal, modification, or
addition of any components to the system (e.g., drainage of a hemat:oma at the surgical site).
•
Supplemental fixation. A procedure in which additional instrumentation not under study
in the protocol is implanted.
8.2 
Collection and Recording of Adverse Events 
8.2.1 
Collection of Adverse Events 
The Investigator must monitor the condition of the subject throughout the trial from the time of 
informed consent until the last visit. 
The sources of adverse events include: 
•
The subject's response to questions about his/her health (a standard non-leading question
such as "How have you been feeling since your last visit?" is asked at each visit)
•
Symptoms spontaneously reported by the subject
•
Investigations and examinations where the findings are assessed by the Investigator to be
clinically significant changes or abnormalities
•
Other information relating to the subject's health becoming known to the Investigator (e.g.,
hospitalization)
8.2.2 
Recording of Adverse Events 
All adverse events will be coded by system organ class and preferred term using the Medical 
Dictiona1y for Regulatory Activities (MedDRA) (version effective at trial start). 
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page58of 91 
During each clinical follow-up, the Investigator or Investigator designee will determine AE 
occurrences. Each adverse event is considered to be either anticipated or unanticipated as described 
above. The site is required to report all adverse events that occur during the trial. AEs will be 
collected from the time of informed consent until the final follow up. 
Post-treatment outcomes that are evaluated as efficacy endpoints, such as pain on weight-bearing, 
harvest site pain, etc., will not be reported as AEs. Post-operative pain is, in general, anticipated, 
typically improves over time, and it will not be considered an AE. However, surgical site pain that 
is associated with a complication, or worsens over time, may be considered an AE. 
Any abnormal laboratory test results or other safety assessments ( e.g., vital signs measurements, 
etc.) considered to be clinically significant in the medical and scientific judgment of the 
Investigator are to be recorded as AEs. 
The sign and symptoms and/or clinical sequelae resulting from lack of efficacy will be reported if 
they fulfill the definition of an AE or SAE. 
Internal fixation medical devices (e.g., screws, plates, pins and staples) are being used in this study 
and are considered ancillary devices. Medical device events associated with these ancillary 
devices, including those resulting from screw loosening or malfunctions of the ancillary device, 
must be documented and reported as adverse events by the Investigator throughout the study. 
8.2.3 
Assessment of Adverse Events 
AE Severity: All AEs will be assessed for severity (see table below). Note: the term "severe" is a 
measure of intensity and that a severe AE is not necessarily serious. 
Table 5 
AE Severity Grading Scale 
Severity Grade 
Description 
Mild (l) 
Transient or mild discomfort; no limitation in activity; no medical intervention or 
therapy required. The subject may be aware of the sign or symptom but tolerates 
it reasonably well. 
Moderate (2) 
Moderate limitation in activity, minimal medical intervention/therapy required. 
Severe (3) 
Marked 
limitation 
II) 
activity, 
medical 
intervention/therapy 
required
hospitalizations possible. 
Device Related Adverse Event: Relationship to the graft material will be assigned one of the 
following: 
•
Definitely: Clear evidence event caused by graft material; strong temporal relationship and
an alternative cause is unlikely.
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 59 of 91 
•
Probably: R.easonable probability event might be caused by graft material. The event has a
temporal relationship to the study procedure(s), and follows a known pattern of response
and an alternative cause seems unlikely.
•
Possibly: Reasonable possibility event is caused by graft material. The event has a
temporal relationship to the study procedure(s) and follows a known pattern of response, but
a potential alternative cause may be present.
•
Unlikely: Evidence that there may be other causes and the relationship to the graft material,
although cannot be completely ruled out, is remote.
•
Unrelated: Cause of the event is known and the event is in no way related to any aspect of
the graft material.
•
Unknown: Causality cannot be determined.
The causality of AEs will be determined by the Investigator, and the CEC will adjudicate it. 
In addition to the graft material, the relationship to the following will also be determined for each 
AE, if possible: 
•
Ancillary Device Adverse Event: An adverse event which is determined to be a
consequence of an ancillary device and is not specifically related to the use of graft material,
but could be related to the placement of the graft material. An ancillary device is defined as
an approved medical device used in conjunction with the graft material, and used during the
study procedure (e.g., internal fixation screws, etc.)
•
Procedure-Related Adverse Event: An adverse event which is determined to be a
consequence of the arthrodesis or harvest procedure and is not specifically related to use of
the graft material or ancillary devices, but could be related to the placement of the graft
material or ancillary devices.
Every effort should be made to assess the causality of all events. If the causality cannot be 
determined, it should be classified as unknown. Events classified as "unknown" causality will be 
considered related for reporting purposes. 
8.3 
Pregnancy 
If a pregnancy occurs, U.S. Pharmacovigilance at Ferring Pharmaceuticals must be informed. 
Contact details for the follow-up on the course and outcome of the pregnancy should be included. 
The mother and the fetus must be followed-up at least until the birth of the infant and one month 
after the birth of the infant. In general, the follow-up will include the course, duration and the 
outcome of the pregnancy as wern as neonatal health. If a pregnancy results in an abnormal 
outcome (birth defect/congenital anomaly) this must be reported as a serious adverse event to U.S. 
Pharmacovigilance at Ferring Pharmaceuticals using the Safety Report Form. 
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 60 of 91 
8.4 
Collection, Recording and Reporting of Serious Adverse Events 
SAE Reporting by the Investigator 
All SAEs must be reported immediately to Perring U.S. Pharmacovigilance as soon as it becomes 
known to the Investigator and not later than within 24 hours of their knowledge of the occurrence 
of an SAE. 
The Investigator is responsible for submitting tbe completed SAE Report Form with the fullest 
possible details within 3 calendar days of his/her knowledge of the SAE to Ferring U.S. 
Phannacovigilance using the contact details below. 
Completion of the Demographics, Adverse Event Log, Medical History Log and Concomitant 
Medication Log are mandatory for initial reports and for follow-up reports if any relevant changes 
have been made since the initial report. Data entries must have been made in the eCRF for Ferring 
Global Pharmacovigilance to access the information. 
Additional information relevant to the SAE such as hospital records, results from investigations, 
(e.g., laboratory parameters that are not already uploaded in the eCRF), invasive procedures, scans 
and x-rays, and autopsy results can be faxed or scanned and e-mailed to Ferring Global 
Pharmacovigilance using the contact details in the section above. In any case this information must 
be supplied by the Investigator upon request from Ferring. On any copies provided, details such as 
subject's name, address, and hospital ID number should be concealed and instead subject number 
should be provided. 
The Investigator will supply Ferring and the IRB/REB with any additional requested information 
such as results of post-mortem examinations and hospital records. 
Expedited Reporting by Ferring 
As per Regulations, Ferring will report all adverse events that are unexpected to the relevant 
regulatory authorities within the stipulated timelines. 
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 61 of 91 
8.5 
Follow-up of Adverse Events and Serious Adverse Events 
8.5.1 
Follow-up of Adverse Events with Onset during the Trial 
During the trial, the Investigator must follow-up on each adverse event until it is resolved or until 
the medical condition of the subject is stable. 
After the subject's last visit, the Investigator must follow-up on any advers,e event classified as 
serious or considered to have a reasonable possible causality to the graft material until it is 
resolved or until the medical condition of the subject is stable. All such relevant follow-up 
information must be reported to Ferring. If the event is a chronic condition, the Investigator and 
Perring may agree that further follow-up is not required. 
8.5.2 
Collection of Serious Adverse Events with Onset after Last Trial Visit 
If an Investigator becomes aware of an SAE after the subject's last visit, and he/she assesses the 
SAE to have a reasonable possible causality to the graft material, the case will have to be reported 
to Perring, regardless how long after the end of the trial this takes place. 
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
9 
ST A TISTICAL METHODS 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 62 of 91 
DetaiJs of the statistical methodology will be provided in a separate statistical analysis plan (SAP). 
9.1 
Determination of Sample Size 
Assuming true success rates of the primary endpoint to be 60% for ABG and 62% for AMPLEX 
groups, 396 subjects are needed to maintain 85% power to demonstrate non-inferiority of 
AMPLEX to ABG with a non-inferiority margin of -12% at a type I error rate of I-sided 5% in a 
2: 1 randomization (264 for AMPLEX and 132 for ABG). To account for approximately 15% lost 
to follow-up, a total of 480 subjects (320 for AMPLEX and 160 for ABG) will be randomized. 
In this calculation, the true success rate for AMPLEX is assumed to be slightly higher than that for 
ABG because of the potential benefit for AMPLEX on the absence of significant graft harvest site 
pain component. The assumption on the true success rate for ABG is made based on the clinical 
endpoint results in DiGiovanni et al. (2013) and the Augment SSED (2015). These data indicate 
relatively high success rates for each component at Week 52, and the success rate as a composite 
endpoint is estimated as approximately 60% under the independence assumption among 
components. 
In the determination of the non-inferiority margin, retaining at least 80% of the assumed success 
rate in ABG is considered clinically meaningful, because it is inherently linked with substantial 
benefit of eliminating risks associated with ABG. Therefore, the non-inferiority margin is set to -
12%. 
In addition, the CT radiographic fusion success rate at 52 weeks for ABG is assumed to be 70% to 
75% based on 24 and 36 weeks data available in FDA Orthopaedic and Rehabilitation Devices 
Division (2011). Assuming that the true CT radiographic fusion success rate for AMPLEX is the 
same as for ABG, the power to demonstrate the non-inferiority in the CT radiographic fusion 
success as an independent test with 396 subjects is 79% to 83% at 1-sided 5% significance level 
using the non-inferiority margin of -12%. 
9.2 
Subject Disposition 
All subjects screened and randomized will be accounted for. All post-randomization 
discontinuations will be summarized by time of, and reason for, discontinuation. The number of 
subjects screened and not randomized will be presented. 
9.3 
Protocol Deviations 
The final definition of protocol viiolations will be determined prior to the database lock. The 
number and percentage of subjects with important protocol deviations will be summarized. 
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
9.4 
Analysis Sets 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 63 of 91 
9.4.1 
Modified Intention-to-Treat (mITT) Analysis Dataset 
The mITT analysis set will include all randomized subjects who have an attempted fusion of the 
index joint(s). If a subject becomes ineligible or withdraws prior to the initiation of surgery, the 
subject will not be included in the mITT analysis set. Once the surgery is initiated, all subjects will 
be included in the mITT analysis set. 
9.4.2 
Per Protocol (PP) Dataset 
The PP analysis set will consist of all randomized subjects that: [1] complete the fusion procedure 
and receive either AMPLEX or ABG as assigned, [2] meet critical study eligibility criteria, and [3] 
have no significant protocol deviations. 
9.4.3 
Safety Dataset 
The safety analysis set comprises all treated subjects and will be analyzed according to the actual 
treatment received. 
9.5 
Trial Population 
9.5.1 
Demographics and other Baseline Characteristics 
Descriptive statistics of demographics and other baseline characteristics and medical history will be 
presented for them.ITT, PP and safety analysis sets by treatment group. In addition, summary of 
demographic and baseline characteristics will be presented by trial site. 
9.5.2 
Medical History, Concomitant Medication and Other Safety Evaluations 
Medical history will be coded by system organ class (SOC) and preferred term (PT) using the most 
current version of the MedDRA and summarized by SOC, PT, and treatment group for the mITT 
and Safety analysis sets. Prior and concomitant medications will be coded by the Anatomical 
Therapeutic Chemical (ATC) classification system and preferred drug name using the World Health 
Organization Drug Dictionary (WHO-Drug). Prior and concomitant drug usage will be 
summarized by A TC classification 1st level, A TC classification 2nd level and treatment group for 
subjects in the mITT and Safety analysis sets. 
9.6 
Endpoint Assessments 
9.6.1 
General Considerations 
All efficacy analyses will be conducted for the mTTT population. The primary and key secondary 
efficacy endpoints will be analyzed by a fixed-sequence procedure according to the following order 
to maintain the overall Type 1 error rate to a one-sided 5% for non-inferiority and a one-sided 2.5% 
for superiority testings. 
1.
Non-inferiority of AMPLEX to ABG in the primary efficacy endpoint
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 64 of 91 
2.
Non-inferiority of AMPLEX to ABG in the key secondary efficacy endpoint
3.
Superiority of AMPLEX to ABG in the key secondary efficacy endpoint
4.
Superiority of AMPLEX to ABG in the primary efficacy endpoint
Testing procedure will begin with the non-inferiority in the primary efficacy endpoint, and each test 
will be conducted without adjustment of multiplicity as long as all preceding tests are significant. 
All other secondary endpoints will be presented with the point estimate ofthe treatment group 
difference and the corresponding 2-sided 90% confidence interval. 
9.6.2 
Primary Endpoint 
The primary efficacy endpoint will be the proportion of subjects who meet all of the following 
criteriia for the SPC at 52 weeks: 
o
Improvement in pain on weight-bearing at fusion site (2: 20 mm reduction from
baseline on 100 mm VAS)
o
Absence of significant graft harvest site pain ( < 20 mm on 100 mm VAS)
o
Improvement in Foot and Ankle Ability Measure Activities of Daily Living subscale
(FAAM-ADL) (2: 8 points improvement from baseline)
o
Absence of device related or procedure related SAEs (up to Week 52)
o
Absence of secondary surgical or nonsurgical interventions intended to promote
fusion (up to Week 52)
Non-inferiority of AMPLEX to ABG will be claimed if the lower bound of the 2-sided 90% CI for 
the difference of the proportions (AMPLEX minus ABG) is greater than -12.0%. The superiority 
will be claimed if the lower limit of the 2-sided 95% CI is greater than zero. The CI will be 
constructed with the normal approximation to the binomial. 
The primary efficacy analysis will be based on the mITT analysis set. A sensitivity analysis will be 
conducted for the PP analysis set. In the analysis on the mITT analysis set, subjects who do not 
receive the assigned treatment will be analyzed as randomized. 
For the primary analysis, the last observation carried forward (LOCF) approach will be used for 
subjects with missing SPC endpoint at 52 weeks. If there is no SPC endpoint assessment prior to 52 
weeks, the subject will be considered not meeting the criteria. 
The primary endpoint will also be analyzed for the subgroups defined by demographic 
characteristics, baseline comorbidities, rheumatoid arthritis, or surgical site. The treatment group 
comparisons after controlling each of these factors will be conducted by stratified analyses using 
the Mantel Haenszel method as sensitivity analyses 
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
9.6.3 
Key Secondary Endpoint 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 65 of 91 
The key secondary efficacy endpoint will be the proportion of subjects who meet the following 
criteria for the CT radiographic fusion success at 52 weeks: 
•
Radiographic evidence of fusion by CT scan (2: 50% bone bridging across the joint space for
the full complement of joints in the absence of secondary surgical or nonsurgical
interventions intended to promote fusion)
Non-inferiority and superiority will be assessed in a similar manner to the primary efficacy 
endpoint, and each test will be conducted according to the fixed-sequence procedure described in 
Section 9.6.1. 
9.6.4 
Secondary Endpoint(s) 
The following secondary efficacy endpoints will be assessed without multiplicity adjustments. 
•
Proportion of subjects achieving CT radiographic fusion success at 12 and 24 weeks (in the
absence of secondary surgical or nonsurgical interventions intended to promote fusion)
•
Change from baseline in pain on weight-bearing at fusion site at 12, 24, and 52 weeks (2:20
mm reduction from baseline on 100 mm VAS)
•
ABG harvest site pain at 2, 6, 12, 24 and 52 weeks (<20 mm on 100 mm VAS)
•
Change from baseline in FAAM-ADL at 12, 24 and 52 weeks
•
SPC at 12 and 24 weeks
•
Change from baseline in Short Form-12 (SF-12) at 24 and 52 weeks
The difference of the proportions of subjects achieving CT radiographic fusion success between 
treatment groups will be estimated with the 2-sided 90% confidence interval at 12 and 24 weeks. 
Similarly, the difference of the proportions of subjects meeting all the criteria for SPC between 
treatment groups will also be estimated at 12 and 24 weeks. 
The change from baseline in weight-bearing pain at fusion site at 12, 24 and 52 weeks will be 
analyzed by the repeated-measures ANCOV A. The proportion of subjects achieving 2:20 mm 
reduction from baseline in weight-bearing pain at fusion site will also be summarized by treatment 
group at each visit. 
The change from baseline in FAAM-ADL at 12, 24 and 52 weeks will be analyzed by a repeated­
measures analysis of covariance (ANCOVA) model that includes treatment, time, treatment-by­
time interaction, baseline score, and other relevant factors or covariates on the observed data. In 
addition, the proportion of subjects achieving 2: 8 points improvement from baseline in FAAM­
ADL will be summarized by treatment group at each visit. 
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 66 of 91 
The ABG harvest site pain at 2, 6, 12, 24 and 52 weeks will be summarized for the ABG group. 
The proportion of subjects with < 20 mm in ABG harvest site pain will also be summarized at each 
visit. 
The change from baseline in SF-12 scores at 24 and 52 weeks will be analyzed by the repeated 
measures ANCOV A. 
9.7 
Safety 
9.7.1 
General Considerations 
Safety parameters will be evaluated for the safety analysis data set. 
9.7.2 
Adverse Events 
A treatment emergent adverse event (TEAE) will be an AE that occurs at the start of surgery and 
thereafter. An AE overview summary table will be prepared for the safety analysis set. It will 
display the number and percentage of subjects reporting an AE and the number of events reported 
for each treatment group. The foUowing categories will be displayed: 
•
Unanticipated Adverse Device Effects
•
SAEs
•
Device related SAEs
•
Procedure related SAEs
•
Device related AEs
•
Procedure related AEs
•
AnyTEAEs
Number and percentage of subjects reporting the following types ofTEAEs will be summarized by 
MedDRA SOC (alphabetically) and PT (in decreasing frequency of occurrence): 
•
Unanticipated Adverse Device Effects
•
SAEs
•
Device related SAEs
•
Procedure related SAEs
•
Device related AEs
•
Procedure related AEs
•
AnyTEAEs
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
9.7.3 
Other Safety Variables 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page67of 91 
Descriptive statistics of subsidence, device migration, nonunion, osteolysis and/or heterotopic 
ossification in the area surrounding the implant site by radiographic assessment, clinical laboratory 
testing and antibody monitoring will be presented for the safety analysis set by treatment group. 
Number and percentage of subjects reporting the following events will be summarized: 
•
Any secondary surgical interventions including revisions, removals, reoperations, or
supplemental fixations
•
Secondary surgical intervention related to the graft material including revisions, removals,
reoperations, or supplemental fixations
9.8 
Pharmacokinetic Assessment 
The PK analysis will be performed by Department of Experimental Medicine, Ferring 
Pharmaceuticals A/S. The PK parameters will be calculated by non-compartmental analysis (NCA) 
using the software WinNonlin®Phoenix v. 6.4 (Pharsight Corporation, US). Plasma concentration 
values below LLOQ and missing values (e.g. no blood sample collected or no value obtained at 
analysis) will be excluded from the NCA and the number of observations adjusted accordingly. No 
formal analysis of '°outliers" is planned. 
PK parameters will be estimated based on measurements Pre procedure (baseline) to the last day of 
assessment Day 15 after fusion procedure. From the plasma concentration-time data ofB2A, the 
following parameters will be estimated, if possible: AUC, AUCt, % AUC extrap, Cmax, Tmax, tYi, 
lamda z, CL/F, V z/F. 
Actual sampling time points relative to dosing will be used for the NCA and on the individual plots 
of plasma concentration versus time. Values below LLOQ will be represented as LLOQ/2 in the 
plots. 
PK parameters will be presented with number of measurements, number of missing data, mean, 
standard deviation, median, minimum, maximum, geometric mean, and coefficient of variation (CV 
[%]) on geometric mean (for AUC and Cmax). For tmax the geometric mean and the CV(%) will 
be omitted. 
9.9 
Handling of Missing Data 
For the primary and key secondary analyses, the imputation method of LOCF will be used in 
subjects with an unknown outcome. 
Sensitivity analyses of missing data will be performed by utilizing the following imputation 
methods: 
1} "missing-equals-failure"
2} multiple imputation methods
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 68 of 91 
3} a tipping point analysis will be performed for the primary and key secondary efficacy
endpoints which will allow assessment of sensitivity without need for postulating any
missing data mechanism. For this analysis, all possible combinations of missing data from
the two arms will be considered, and the point at which significance is no longer achieved
will be identified.
The planned sensitivity analyses for the primary and key secondary endpoints will be described in 
further detail in the Statistical Analysis Plan (SAP). 
All data collected on safety or adverse events will be reported to the extent it is available, regardless 
of the active/withdrawn status of participants. 
9.10 
Pooling of Site Data 
The primary analysis will be based on the pooled results. However, the homogeneity of study 
outcomes across study centers will be examined. The primary justification for pooling is that study 
centers will be following the same protocol, using the same device system, and following the same 
Instructions for Use/Surgical Manual. Additionally, frequent contact and monitoring of the centers 
will be performed to ensure that all study centers are evaluating participants and recording study 
results in a reliable and reproducible manner. It is not anticipated that any individual study center 
will dominate the study results. Therefore, it is considered that these procedures will ensure that 
the data from these study centers can be combined and analyzed. 
To evaluate differences among centers in the study, a summary of important baseline variables, 
such as demographics, medical history and baseline clinical variables, will be presented by center. 
Additionally, variables related to procedures will also be summarized by center. 
Poolability across study centers will be tested for the primary endpoint. Details of the method will 
be specified in the SAP. 
It is also noted that the evaluation of center effect will consider OUS ( outside U.S.) versus U.S.­
based centers. Thus, another analysis of the center effect wiH consider the comparison between the 
results for these two geographical regions. 
Further explanation on poolability analyses will be described in the SAP. 
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
10 
DATA HANDLING 
Trial Code: 000226 
10.1 
Source Data and Source Documents 
Source Data - ICH Definition 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 69 of 91 
Source data are defined as all information in original records and certified copies of original records 
of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source data are contained in source documents ( original 
records or certified copies). 
Source Documents - ICH Definition 
Source documents are defined as original documents, data, and records ( e.g. hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects' diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate copies, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and at 
medico-technical departments involved in the clinical trial). 
Trial-specific Source Data Requirements - Ferring 
Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the product. These documents should be retained for a longer period, however, if 
required by local regulations. No records will be destroyed without the written consent of the 
Sponsor, if applicable. It is the responsibility of the Sponsor to inform the Investigator when these 
documents no longer need to be retained. 
10.2 
eCRF 
An eCRF system provided by an independent third-party contract research organization (CRO) will 
be used for data capture. The system is validated and access at all levels to the system is 
granted/revoked following Ferring and vendor procedures, in accordance with regulatory and 
system requirements. 
Devefopment of the primary database for the study will be performed by the Sponsor or designee. 
The Sponsor or designee will also be responsible for the verification, validation and quality control 
of the database and confirming the overall integrity of the data. 
Federal Regulations and Good Clinical Practice (GCP) Guidelines require that Investigators 
maintain information in the study patient's medical records that corroborate data collected on the 
eCRFs. In order to comply with these regulatory requirements, the following information should be 
maintained: 
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 70 of 91 
•
Medical history/physical condition of tlle study patient before involvement in the study
sufficient to verify protocol entry criteria
•
Dated and signed notes on the day of entry into the study including the study Investigator,
study name, patient number assigned and a statement that consent was obtained
•
Dated and signed notes from each study patient visit with reference to the CRFs for further
information, if appropriate (for specific results of procedures and exams)
•
Information related to adverse events
•
Study patient's condition upon completion of or withdrawal from the study
•
Discharge summaries/procedure reports
10.3 
Investigator Records
Investigators will maintain complete, accurate and current study records. All records shall, at a 
minimum, be retained for a period of time equivalent to the design and expected life of the device, 
but in no case less than 2 years from the date of release for commercial distribution by the 
manufacturer. Investigator records shall include the following materials: 
•
Correspondence: Documentation of all verbal and written correspondence with FDA,
Sponsor, the Clinical Monitor, the CEC, and other Investigators regarding this clinical study
or any patient enrolled therein.
•
Subject Recort/.,;;: Signed informed consent forms, copies of all completed CRFs and
supporting documents (laboratory reports, reports of diagnostic tests, medical records, etc.)
and records of exposure of each subject to the device. Informed consent must comply with
FDA regulations (21 CFR, part 50).
•
Protocol: A current copy of the CIP including IFU of the AMPLEX System and lb lank 
CRFs.
•
Institutional Review Boan/ (IRB)!Research Ethics Board (REB) Information: All
information pertaining to IRB/REB review and approval of this clinical study including a
copy of the IRB/REB letter approving the clinical study, a blank informed consent form
approved by the IRB/
REB, and certification from the IRB/REB Chairman that the IRB/REB 
complies with FDA regulations (21 CFR, Part 56)/regulatory body r,egulations, and that the 
IRB/REB approved the clinical study protocol based on the Report of Prior Investigations. 
•
Investigator Agreements: Copies of signed Investigator, Co-Investigator and Sub­
Investigator Agreements with accompanying curriculum vitae.
•
Other: Any other records that may be required by applicable state or federal laws.
10.4 
Investigator Reports 
The l1!1vestigator will prepare and submit the following reports: 
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 7l of 91 
•
MDR: Medical Device Reporting of all events related to the device or device malfunctions.
•
Withdrawal of /RB Approval: Withdrawal of approval shall be reported to the Sponsor or
designee within five working days. The Investigator will provide a written report of the
reason(s) approval was withdrawn.
•
Progress Reports: The Investigator will submit progress reports to the Sponsor or designee
in the form of completed CRFs. The same forms will be used at all investigative centers for
the recording of data on the findings of follow-up evaluations and complications. In
addition, the Investigator may be asked to submit progress reports to the Sponsor or
designee and the reviewing IRB that include the number of study subjects, a summary of
follow-up data and complications and a general description the study progress.
•
Final Report: The Investigator shall submit a final report within three months of
termination or completion of the study or that Investigator's participation in the study, to the
Sponsor or designee and the IRB/REB.
•
Other Reports: Upon the request of Regulatory Agency/FDA, the reviewing IRB/REB, or
the Sponsor or designee, the Investigator will provide accurate and timely information about
any aspect of the clinical study.
•
Emergency Protocol Deviations: The Investigator shall notify the Sponsor or designee and
the reviewing IRB/REB of any deviation from the study protocol intended to protect the life
or physical well-being of a patient in an emergency. Such notice shall be given as soon as
possible.,
10.5 
Data Management 
A data management plan will be created under the responsibility of the Global Biometrics 
Department of Perring Pharmaceuticals A/S. The data management plan will be issued before data 
collection begins and will describe all functions, processes, and specifications for data collection, 
cleaning and validation. 
The data management plan will describe captured methods, who is authorized to enter the data, 
decisions about ownership of data, source data storage, which data will be transferred (including 
timing of transfers), the origin and destination of the data and who will have access to the data at all 
times. 
10.6 
Provision of Additional Information 
On request, the Investigator will provide Perring with additional data relating to the trial, duly 
anonymized and protected in accordance with applicable requirements. 
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
11 
MONITORJNG PROCEDURES 
11.1 
Periodic Monitoring 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 72 of 91 
The monitor will contact and visit the Investigator periodically to ensure adherence to the protocol, 
International Conference of Harmonization-Good Clinical Practice (ICH-GCP), standard operating 
procedures and applicable regulatory requirements, maintenance of trial-related source records, 
completeness, accuracy and verifiability of eCRF entries compared to source data, verification of 
drug accountability and compliance to safety reporting instructions. 
The Investigator wi 11 permit the monitor direct access to all source data, including electronic 
medical records, and/or documents in order to facilitate data verification. The Investigator will co­
operate with the monitor to ensure that any discrepancies that may be identified are resolved. The 
Investigator is expected to be able to meet the monitor during these visits. 
11.2 
Audit and Inspection 
The Investigator will make all the trial-related source data and records available at any time to 
quality assurance auditor(s) mandated by Ferring, or to domestic/foreign regulatory inspectors or 
representatives from IRBs/REBs who may audit/inspect the trial. 
The main purposes of an audit or inspection are to assess compliance with the trial protocol and the 
principles ofICH-GCP including the Declaration of Helsinki and all other relevant regulations. 
The subjects must be informed by the Investigator and in the Informed Consent Documents that 
authorized Ferring representatives and representatives from regulatory authorities and IRBs/REBs 
may wish to inspect their medical records. During audits/inspections the auditors/inspectors may 
copy relevant parts of the medical records. No personal identification apart from the 
screening/randomization number will appear on these copies. 
The Investigator should notify Ferring without any delay of any inspection by a regulatory authority 
or IRB/REB. 
11.3 
Confidentiality of Subject Data 
The Investigator will ensure that the confidentiality of the subjects' data will be preserved. In the 
eCRF or any other documents submitted to Perring, the subjects will not be identified by their 
names, but by an identification system, which consists of an assigned number in the trial. 
Documents that are not for submission to Ferring, e.g. the confidential subject identification code 
and the signed Informed Consent Documents, will be maintained by the Investigator in strict 
confidence. 
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 73 of 91 
12 
CHANGES JN THE CONDUCT OF THE TRIAL 
12.1 
Protocol Amendments 
Any change to this protocol will be documented in a protocol amendment, issued by Ferring, and 
agreed upon by the Investigator and Ferring prior to its implementation. Amendments may be 
submitted for consideration to the approving IRB(s)/REB(s) and Regulatory Authorities, in 
accordance with local regulations .. Changes to the protocol to eliminate immediate hazard(s) to trial 
subjects may be implemented prior to IRB(s)/REB(s) approval/favorable opinion. 
12.2 
Deviations from the Protocol 
If deviations from the protocol occur, the Investigator must infonn the monitor, and the 
implications of the deviation must be reviewed and discussed. Any deviation must be documented, 
either as an answer to a query in the eCRF, in a protocol deviation report or a combination of both. 
A log of protocol deviation reports will be maintained by Ferring. Protocol deviation reports and 
supporting documentation must be kept in the Investigator's File and the Trial Master File. 
Investigators must report protocol deviations to the Sponsor or designee on a routine basis (e.g., in 
accordance with interim on-site monitoring activities and/or ongoing remote correspondence). Any 
protocol deviations that affect the rights, safety or well-being of the subject or the scientific 
integrity of the clinical investigation, including those which occur under emergency circumstances 
must be reported to the Sponsor or designee and to IRB/REB within 24 hours, if required by 
IRB/REB or national regulations. The Sponsor or designee should document unreported protocol 
deviations that are identified during monitoring visits. 
12.3 
Premature Trial Termination 
Both the Investigator (with regard to his/her participation) and Ferring reserve the right to terminate 
the trial at any time. Should this become necessary, the procedures will be agreed upon after 
consultation between the two parties. In terminating the trial, Ferring and the Investigator will 
ensure that adequate consideration is given to the protection of the best interests of the subjects. 
Regulatory authorities and IRBs/REBs will be infonned. 
In addition, Ferring reserves the right to terminate the participation of individual trial sites. 
Conditions that may warrant termination include, but are not limited to, insufficient adherence to 
protocol requirements and failure to enter subjects at an acceptable rate. 
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
13 
REPORTING AND PUBLICATION 
13.1 
Clinical Trial Report 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page74of 91 
The data and information collected during this trial will be reported in a clinical trial report 
prepared by Ferring or its designee and submitted for comments and signature to the signatory 
Investigator( s). 
13.2 
Confidentiality and Ownership of Trial Data 
Any confidential information relating to the investigational device or the trial, including any data 
and results from the trial will be the exclusive property of Ferring. The Investigator and any other 
persons involved in the trial will protect the confidentiality of this proprietary information 
belonging to Ferring. 
13.3 
Publications and Public Disclosure 
13.3.1 
Publication Policy 
At the end of the trial, one or more manuscripts for joint publication may be prepared in 
collaboration between the Investigator(s) offered authorship and Ferring. In a multi-site trial based 
on the collaboration of many sites, any publication of results must acknowledge all sites. Results 
from multi-site trials must be reported in entirety in a responsible and coherent manner and results 
from subsets should not be published in advance or without clear reference to the primary 
publication of the entire trial. 
Authorship is granted based on the International Committee of Medical Journal Editors (ICMJE) 
criteria (see current official version: http/www.ICMJE.org). The total number of authors is based 
on the guideline from the relevant journal or congress. In the event of any disagreement in the 
content of a publication, both the fuvestigator's and Ferring's opinion will be fairly and sufficiently 
represented in the publication. 
Any external CRO or laboratory involved in the conduct of this trial has no publication rights 
regarding this trial. 
If the Investigator wishes to independently publish/present any results from the trial, the draft 
manuscript/presentation must be submitted in writing to Ferring for comment prior to sulbmission. 
Comments will be given within four weeks from receipt of the draft manuscript. This statement 
does not give Ferring any editorial rights over the content of a publication, other than to restrict the 
disclosure of Ferring's intellectual property. If the matter considered for publication is deemed 
patentable by Ferring, scientific publication wa! not be allowed until after a filed patent application 
is published. Under such conditions the publication will be modified or delayed at the 
Investigator's discretion, to allow sufficient time for Ferring to seek patent protection of the 
invention. 
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page75of 91 
13.3.2 
Public Disclosure Policy 
ICMJE member journals have adopted a trials-registration policy as a condition for publication. 
This policy requires that all clinical trials be registered in a public, clinical trials registry. Thus, it is 
the responsibility of Ferring to register the trial in an appropriate public registry, e.g. 
www.clinicaltrials.gov which is a website maintained by the National Library of Medicine (NLM) 
at the U.S. NationaD Institutes of Health (NIH). 
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
14 
ETHICAL AND REGULATORY ASPECTS 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page76of 91 
14.1 
Institutional Review Board (IRB) or Research Ethics Board (REB) 
An IRB/REB will review the protocol and any amendments and advertisements used for 
recruitment. The IRB/REB will review the Subject Information Sheet and the Informed Consent 
Form, their updates (if any), and any written materials given to the subjects. A list of all 
IRBs/REBs to which the protocol has been submitted and the name of the committee chairmen will 
be included in the Clinical Trial Report. 
14.2 
Regulatory Authority 
The regulatory permission to perform the trial will be obtained in accordance with applicable 
regulatory requirements. All ethical and regulatory approvals must be available before a subject is 
exposed to any trial-related procedure, including screening tests for eligibility. 
14.3 
End-of-Trial and End-of-Trial Notification 
The Sponsor may terminate the study at any time. If the study is terminated prior to the completion 
of expected enrollment for any reason, all participating centers will be notified within five working 
days. All subjects already enrolled will continue to be followed for the planned course of study 
descriibed in this protocol. The study shall be terminated following the final follow-up visit of the 
last enrolled patient. 
The Sponsor reserves the right to terminate study site participation and remove appropriate study 
materials at any time. Specific instances that may precipitate such termination include but are not 
limited to the following: 
•
Failure to meet minimum patient enrollment requirements
•
Failure to comply with protocol specified procedures and documentation
•
Failure to comply with GCP
The site Investigator may also discontinue study participation with suitable written notice to the 
Sponsor. 
14.4 
Ethical Conduct of the Trial 
This trial will be conducted in accordance with the ethical principles that have their origins in the 
Declaration of Helsinki, in compliance with the approved protocol, ICH-GCP and applicable 
regulatory requirements. 
Each participating institution must provide for the review and approval of this protocol and the 
associated informed consent documents and recruitment material by an appropriate IRB/REB. Any 
amendments to the protocol or consent materials must also be approved before they are placed into 
use. 
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 77 of 91 
14.S 
Subject Information and Consent
Informed consent is a process that is initiated prior to the individual's agreeing to participate in the
study and continues throughout the individual's study participation. Extensive discussion ofrisks
and possible benefits of this therapy will be provided to the subjects and their families. Consent
forms describing in detail the study interventions/products, study procedures, and risks are given to
the Sll!bject and written documentation of informed consent is required prior to starting intervention/
administering study product. Consent forms will be IRB/REB-approved and the subject will be
asked to read and review the document.
Upon reviewing the document, the Investigator will explain the research study to the subject and 
answer any questions that may arise. The subject will sign the informed consent document prior to 
any procedures being done specifically for the study. The subject should have the opportunity to 
discuss the study with their surrogates or think about it prior to agreeing to participate, unless study 
timeframes do not allow for such discussions. The subjects may withdraw consent at any time 
throughout the course of the trial. A copy of the informed consent document will be given to the 
subjects for their records. The rights and welfare of the subjects will be protected by emphasizing 
to them that the quality of their medical care will not be adversely affected if they decline to 
participate in this study. 
14.S.1 Subject Unable to Read or Write
Informed consent shall be obtained through a supervised oral process if a subject or legally 
authorized representative is unabfo to read or write. An independent witness shall be present 
throughout the process. The written informed consent form and any other information shall be read 
aloud and explained to the prospective subject or his/her legally authorized representative and, 
whenever possible, either party shall sign and personally date the informed consent form. The 
witness also signs and personally dates the informed consent form attesting that the information 
was accurately explained and that informed consent was freely given. 
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
14.5.2 Emergency Consent 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 78 of 91 
For clinical investigations involving emergency treatments, when prior informed consent of the 
subject is not possible because of the subject's medical condition, the informed consent of the 
subject's legally authorized representative, if present, shall be requested. When it is not possible to 
obtain prior informed consent from the subject, and the subject's legally authorized representative is 
not available, the subject may still be enrolled if a specific process has been described in the 
protocol. 
Arrangements shall be made to inform the subject or legally authorized representative, as soon as 
possible, about the subject's inclusion in the clinical investigation, and about all aspects of the 
clinical investigation. 
The subject shall be asked to provide informed consent for continued participation as soon as 
his/her medical condition allows. The principal Investigator may enroll a subject without obtaining 
the informed consent of the subject or his/her legally authorized representative only when the 
following conditions are fulfilled: 
•
the prospective subject fulfills the emergency conditions and is obviously in a life­
threatening situation;
•
no sufficient clinical benefits are anticipated from the currently available treatment;
•
there is a fair possibility that the life-threatening risk to the prospective subject can be
avoided if the investigational device is used;
•
anticipated risks are outweighed by the potential benefits of applying the investigational
device;
•
the legally authorized representative cannot be promptly reached and informed.
14.5.3 New Information 
If new information becomes available that can significantly affect a subject's future health and 
medical care, then that information shall be provided to the Sl!.lbject(s) affected in written form. If 
relevant, all affected subjects shall be asked to confirm their continuing informed consent in 
writing. 
14.6 
Subject Information Card 
The subject will be provided with a Subject Information Card bearing the following information: 
•
That he/she is participating in a clinical trial (Trial Code: 000226).
•
That he/she is treated with (AMPLEX or ABG).
•
The name and phone number of the Investigator.
•
Name and address of Ferring (if required by local regulations).
The subject will be asked to return the Subject Information Card at the last trial visit, if applicable. 
Fening Phannaceuticals 
CONFIDENTIAL

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
14.7 
Compliance Reference Documents 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 79 of 91 
This clinical investigation shall be conducted in accordance with the ethical principles that have 
their origin in the Declaration of Helsinki, International Standard Organization (ISO 14155:2011) 
and any regional or national regulations. 
The clinical investigation shall not begin until the required approval/favorable opinion from the 
IRB/REB or regulatory authority has been obtained, if appropriate. 
Any additional requirements imposed by the IRB/REB or regulatory authority shall be followed. 
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 80 of 91 
15 
LIABILITIES AND INSURANCE 
15.1 
ICH-GCP Responsibilities 
The responsibilities of Ferring, the monitor and! the Investigator are defined in the ICH-GCP 
consolidated guideline, and applicable regulatory requirements in the country where the trial takes 
place. The Investigator is responsible for adhering to the ICH-GCP responsibilities of 
investigators, for dispensing the investigational device in accordance with the approved protocol or 
an approved amendment, and for its secure storage and safe handling throughout the trial. 
15.2 
Liabilities and Insurance 
In case of any damage or injury occurring to a subject in association with the investigational device 
or the participation in the trial, Ferring has contracted an insurance which covers the liability of 
Perring, the Investigator and other persons involved in the trial in compliance with the laws in the 
countries involved. 
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
16 
ARCHIVING 
16.1 
Investigator File 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 81 of 91 
The Investigator is responsible for maintaining all the records, which enable the conduct of the trial 
at the site to be fully understood, in compliance with ICH-GCP. The trial documentation including 
all the relevant correspondence should be kept by the Investigator in accordance with investigative 
site and local regulatory requirement. All records shall, at a minimum, be retained for a period of 
time equivalent to the design and expected life of the device, but in no case less than 2 years from 
the date of release for commercial distribution by the manufacturer. 
The Investigator is responsible for the completion and maintenance of the confidential subject 
identification code which provides the sole link between named subject source records and 
anonymous eCRF data for Ferring. 
No trial site document may be destroyed without prior written agreement between the Investigator 
and Ferring. Should the Investigator elect to assign the trial documents to another party, or move 
them to another location, Ferring must be notified. If the Investigator retires and the documents can 
no longer be archived by the site, Ferring can arrange having the Investigator File archived at an 
external archive. 
16.2 
Trial Master File 
Ferring will archive the Trial Master File in accordance with ICH-GCP and applicable regulatory 
requirements. 
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
17 
REFERENCES 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 82 of 91 
References: 
1.
Glazebrook M, Daniels T, Younger A, et al. Comparison of health-related quality of life
between patients with end-stage ankle and hip arthrosis. J Bone Joint Surg Am. Mar
2008;90(3):499-505.
2.
Abidi NA, Anastassopoulos K, Ackerman S. Economic Evaluation of Direct Costs
Associated with Harvesting Autogenous Bone Graft in Foot and Ankle Fusion Surgery.
AOFAS; July, 2010, 2010; Wahington, DC.
3.
Abidi NA, Gruen GS, Conti SF. Ankle arthrodesis: indications and techniques. The Journal
of the American Academy of Orthopaedic Surgeons. May-Jun 2000;8(3):200-209.
4.
Perlman MH, Thordarson DB. Ankle fusion in a high risk population: an assessment of
nonunion risk factors. Foot Ankle Int. Aug 1999;20(8):491-496.
5.
Valderrabano V, Horisberger M, Russell I, Dougall H, Hintermann B. Etiology of ankle
osteoarthritis. Clin Orthop Re/at Res. Jul 2009;467(7): I 800-1806.
6.
Coughlin MJ, Grimes JS, Traughber PD, Jones CP. Comparison of radiographs and CT
scans in the prospective evaluation of the fusion of hindfoot arthrodesis. Foot Ankle Int. Oct
2006;27(10):780-787.
7.
Charnley J. Compression arthrodesis of the ankle and shoulder. J Bone Joint Surg Br. May
1951)3B(2): 180-191.
8.
Mann RA, Rongstad KM. Arthrodesis of the ankle: a critical analysis. Foot Ankle Int. Jan
1998; 19(1 ):3-9.
9.
Easley ME, Trnka HJ, Schon LC, Myerson MS. Isolated subtalar arthrodesis. J Bone Joint
Surg Am. May 2000;82(5):613-624.
10.
Frey C, Halikus NM, Vu-Rose T, Ebramzadeh E. A review of ankle arthrodesis:
predisposing factors to nonunion. Foot Ankle Int. Nov 1994)5(11):581-584.
11.
Haddad SL, Coetzee JC, Estok R, Fahrbach K, Banel D, Nalysnyk L. Intermediate and long­
term outcomes of total ankle arthroplasty and ankle arthrodesis. A systematic review of the
literature. J Bone Joint Surg Am. Sep 2007;89(9):1899-1905.
12.
Baumhauer JF, Pinzur MS, Daniels TR, et al. Survey on the need for bone graft in foot and
ankle fusion surgery. Foot Ankle Int. Dec 2013;34(12):1629-1633.
13.
Femyhough JC, Schimandle JJ, Weigel MC, Edwards CC, Levine AM. Chronic donor site
pain complicating bone graft harvesting from the posterior iliac crest for spinal fusion.
Spine. Dec 1992; 17(12): 1474-1480.
14.
Hill NA, Wilson HJ, Chevres F, Sweterlitsch PR. Triple arthrodesis in the young child. Clin
Orthop Relat Res. May-Jun 1970;70: 187-190.
15.
Kurz LT, Garfin SR, Booth RE, Jr. Harvesting autogenous iliac bone grafts. A review of
complications and techniques. Spine. Dec 1989;14(12):1324-1331.
16.
Summers BN, Eisenstein SM. Donor site pain from the ilium. A complication of'lumbar
spine fusion. J Bone Joint Surg Br. Aug 1989;71(4):677-680.
17.
Baumhauer J, Pinzur MS, Donahue R, Beasley W, DiGiovanni C. Site selection and pain
outcome after autologous bone graft harvest. Foot Ankle Int. Feb 2014;35(2):104-107.
18.
Schmidt ER, Townsend J. Unusual complication of subacute osteomyelitis following tibial
bone graft: report of a case. J Oral Maxillofac Surg. Jun 2008;66( 6): 1290-1293.
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 83 of 91 
19.
DiGiovanni CW, Lin SS, Baumhauer JF, et al. Recombinant human platelet-derived growth
factor-BB and beta-tricalcium phosphate (rhPDGF-BB/beta-TCP): an alternative to
autogenous bone graft . .J Bone Joint Surg Am. Jul 3 2013;95(13): 1184-1192.
20.
Glazebrook M, Younger A, Wing K, Lalonde KA. A prospective pilot study of B2A-coated
ceramic granules (Amplex) compared to autograft for ankle and hindfoot arthrodesis. Foot
Ankle Int. Aug 2013;34(8): 1055-1063.
21.
Melkerson MN. K063527. Rockville, MD: FDA; 2007.
22.
Franco-Vidal V, Daculsi G, Bagot d'Arc M, et al. Tolerance and osteointegration of
TricOs(TM)/MBCP((R)) in association with fibrin sealant in mastoid obliteration after canal
wall-down technique for cholesteatoma. Acta Otolaryngol. Apr 2014;134(4):358-365.
23.
Lee JH, Jung UW, Kim CS, Choi SH, Cho KS. Histologic and clinical evaluation for
maxillary sinus augmentation using macroporous biphasic calcium phosphate in human.
Clin Oral Implants Res. Aug 2008;19(8):767-771.
24.
Mangano C, Perrotti V, Shibli JA, et al. Maxillary sinus grafting with biphasic calcium
phosphate ceramics: clinical and histologic evaluation in man. Int J Oral Maxillofac
Implants. Jan-Feb 2013;28(1):51-56.
25.
Rouvillain JL, Lavalle F, Pascal-Mousselard H, Catonne Y, Daculsi G. Clinical,
radiological and histological evaluation of biphasic calcium phosphate bioceramic wedges
filling medial high tibial valgisation osteotomies. Knee. Oct 2009;16(5):392-397.
26.
Wagner W, Wiltfong J, Pistner H, et al. Bone formation with a biphasic calcium phosphate
combined with fibrin sealant in maxillary sinus floor elevation for delayed dental implant.
Clin Oral Implants Res. Sep 2012;23(9): 1112-1117.
27.
Cunningham BW, Atkinson BL, Hu N, et al. Ceramic granules enhanced with B2A peptide
for lumbar interbody spine fusion: an experimental study using an instrumented model in
sheep. J Neurosurg Spine. Apr 2009;10(4):300-307.
28.
Glazebrook M, Younger A, Zamora PO, Lalonde K. B2A peptide Bone Graft Substitute:
Literature Review, Biology and Use for Hind Foot Fusions,. Current Orthopaedic Practice.
2013; Sept-Dec, 24(5):482-486.
29.
Lin X, Elliot JJ, Carnes DL, et al. Augmentation of osseous phenotypes in vivo with a
synthetic peptide. J Orthop Res. Apr 2007;25(4):531-539.
30.
Lin X, Guo H, Takahashi K, Liu Y, Zamora PO. B2A as a positive BMP receptor
modulator. Growth/actors. Jun 2012;30(3): 149-157.
31.
Liu Y, Lin X, Takahashi K, Zamora PO. B2A, a receptor modulator, increases the growth of
pluripotent and preosteoblast cells through bone morphogenetic protein receptors. Growth
factors. Dec 2012;30(6):410-417.
32.
Sardar Z, Alexander D, Oxner W, et al. Twelve-month results of a multicenter, blinded,
pilot study of a novel peptide (B2A) in promoting lumbar spine fusion . .J Neurosurg Spine.
Apr 2015;22(4):358-366.
33.
Kirmeier R, Payer M, Lorenzoni M, Wegscheider WA, Seibert FJ, Jakse N. Harv,esting of
cancellous bone from the proximal tibia under local anesthesia: donor site morbidity and
patient experience . .J Oral Maxillofac Surg. Nov 2007;65(11):2235-2241.
34.
Budiman-Mak E, Conrad KJ, Mazza J, Stuck RM. A review of the foot function index and
the foot function index - revised. J Foot Ankle Res. 2013;6(1):5.
35.
Mundi R, Chaudhry H, Mundi S, Godin K, Bhandari M. Design and execution of clinical
trials in orthopaedic surgery. Bone Joint Res. May 2014;3(5):161-168.
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 84 of 91 
36.
Pinsker E, Daniels TR. AOF AS Position Statement Regarding the Future of the AOF AS
Clinical Rating Systems. Foot & Ankle International. 2011 ;32(09):841-842.
37.
Sciences NUsDoMS. PROMIS Global Health Scale vl. l.pdf.
38.
Sciences NUsDoMS. PROMIS SF vl O - Phys Fune 12a.pdf.
39.
Sciences NUsDoMS. PROMIS SF vl.O - Pain Interference-SF8a.pdf.
40.
Sciences NUsDoMS. PROMIS-29 Profile v2.0.pdf.
41.
Epstein NE, Silvergleide RS. Documenting fusion following anterior cervical surgery: a
comparison of roentgenogram versus two-dimensional computed tomographic findings. J
Spinal Disord Tech. Jun 2003;16(3):243-247.
42.
Epstein NE, Silvergleide RS, Black K. Computed tomography validating bony ingrowth
into fibula strut allograft: a criterion for fusion. Spine J. Mar-Apr 2002;2(2): 129-133.
43.
Glazebrook M, Beasley W, Daniels T, et al. Establishing the relationship between clinical
outcome and extent of osseous bridging between computed tomography assessment in
isolated hindfoot and ankle fusions. Foot Ankle Int. Dec 2013;34(12): 1612-1618.
44.
Administration USDoHaHSFaD. Clinical Trial Imaging Endpoint Process Standards:
Guidance for Industry. In: (CDER) CfDEaR, (CBER) CfBEaR, eds2015.
45.
Martin R.L. IJJ, Burdett R.G., Conti S.F., Van Swearingen J.M. Evidence of validity for the
Foot and Ankle Ability Measure (FAAM). Foot & Ankle International. 2005;26(11):968-
983.
46.
Hung M, Baumhauer, J., Brodsky, J., et. al. Psycometric comparison of the PRO MIS
physical function CAT with the FAAM and FFI for measuring patient-reported outcomes.
Foot & Ankle International. 2014;35:592-599.
47.
Administration USDoHaHSFaD. Proposed Summary Of Safety And Effectiveness Data
(SSED): Augment™ Bone Graft.
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
18 
APPEN.DICES 
Ferring Phannaceuticals 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 85 of 91 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 86 of 91 
Appendix 1 
Anticipated Adverse Events 
Safety assessments involving AEs and SAEs are critical in the clinical assessment of new medical 
devices. Clinical trials evaluating medical devices often involve surgical OT other procedures. As a 
result, AEs and SAEs can result from the medical device, the procedure itself, or the underlying 
medical condition. All AEs and SAEs will be reported regardless of cause. Nevertheless, since 
some AEs and SAEs impact on the primary efficacy assessment, Device-relatedness will be 
determined by the Investigator and adjudicated by the CEC. However, the relatedness of a number 
of AEs and SAEs are known. This table is provided as a guidance in assessing the better-known 
complications of arthrodesis surgery. 
Adverse events associated with any surgical procedure could include: 
Likely: 
•
pain (not reported as an AE if related to graft site or harvest site)
•
swelling
•
adverse reaction to anesthesia including nausea, confusion, vomiting and elevations in
liver enzymes
Less Likely: 
•
soft tissue injury (swelling, warm to touch and/or pain to affected area)
•
surgical site wound infection (drainage or pus at surgical site)
•
cellulitis (inflammation of the soft tissue, especially below the skin characterized by
fever, swelling, redness and pain)
•
failure of the tissue to heal properly ( wound breakdown or opening)
•
other wound problem (fluid pocket formation)
•
other infection (fever, aches and/or pain)
•
hemorrhage (severe bleeding)
•
nerve damage (weakness, tingling, and or numbness)
•
muscular damage
•
swelling, pain and/or redness at affected area
•
arrhythmia (abnormal heart rhythm)
Rare but serious: 
•
anesthesia complication (drug allergy, difficulty breathing, cardiac (heart) or systemic
effect that could be life threatening)
•
heart attack
•
stroke
•
pulmonary (lung) complications
o
pneumonia, (lung inflammation caused by infection)
o
atelectasis (shortness of breath caused by partial collapse of the lung)
o
respiratory distress (shortness of breath or respiratory failure)
o
pulmonary edema ( excess water in the lung)
•
pulmonary embolus (clogging of lung blood vessels by a blood clot)
•
need for blood transfusion (risk of disease transmission)
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page87of 91 
•
bad reaction to blood transfusion (fever, itching, heart failure or systemic illness)
•
septicemia (life-threatening infection in the blood)
•
seizures/convulsions
•
changes in mental status
•
death
Adverse events associated with foot/ankle fusion surgery include: 
Liikely: 
•
pain ( evaluated as an efficacy assessment, not reported as an AE)
•
swelling
Less likely: 
•
nerve injury (numbness sensation, tingling of affected area, decreased strength)
•
adjacent joint degeneration ( degeneration of the joint(s) next to the fusion at a later time
requiring surgery)
•
lack of pre-operative pain/symptoms reduction (signs and symptoms that were present
before surgery remain the same after surgery)
•
failure to achieve desired or any foot/ankle fusion (incomplete fusion of the bone)
•
heavy surgical or post-surgical bleeding
•
deep vein thrombosis (swelling or pain in the legs from a blood clot)
•
paraesthesia (sensation of pricking, tingling and/or creeping on the skin)
•
muscle and/or ligament injury
Rare but serious: 
•
fracture (bone breaks) of the tibia (leg), or bones of the foot
•
osteolysjs (resorption and/or dissolution of bone tissue)
Adverse events associated with foot/ankle instrumentation include: 
Liikely: 
•
pain and discomfort associated with implanted instrumentation ( only of it can be
differentiated from graft site pain)
Less Likely: 
•
misplaced, wrong sizing, loosened, broken or migrated implants (screws)
•
implant displacement or migration ( change of position)
•
wear debris ( accumulation of fragments)
Rare but serious: 
•
foreign body reaction to the implant (fever, swelling, and or discomfort)
•
local or systemic allergic reaction (fever, aches and/or pain)
•
damage to local structures
Fening Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 88 of 91 
Adverse events associated with the study product include: 
•
Allergic reaction (local or systemic response)
•
Ectopic bone growth (bone forming outside of normal bone growth areas)
•
Abnormal cell growth (growth of tissue or c,ells beyond the norm)
•
Negative effects on pregnancy or fetus
•
Immune response (bodily response against foreign material)
•
Significant increase in liver enzyme measures
Adverse events associated with harvesting autologous bone graft include: 
•
pain at the graft harvest site ( evaluated as an efficacy assessment, not reported as an AE)
•
swelling
•
fracture at the graft harvest site
•
soft tissue injury (swelling, warm to touch and/or pain to affected area)
•
harvest site wound infection (drainage or pus at surgical site)
•
cellulitis (inflammation of the soft tissue, especially below the skin characterized by
fever, swelling, redness and pain)
•
failure of the tissue to heal properly (wound breakdown or opening)
•
other wound problem (fluid pocket formation)
•
other infection (fever, aches and/or pain)
•
hemorrhage (severe bleeding)
•
nerve damage ( weakness, tingling, and or numbness)
•
muscular damage
•
phlebitis thromboembolus (swelling, pain and/or redness at affected area)
Ferring Phannaceuticals 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 89 of 91 
Appendix 2 
Foot and Ankle Ability Measure Activities of Daily Living (FAAM-ADL) 
Questionnaire 
Ferring Phannaceuticals 
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B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Fening Phannaceuticals 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 90 of 91 
CONFIDENTIAL 

B2A Peptide, FE 999318 
Implant 2.8 mg 
AMPLEX® Amendment 2 
Fening Phannaceuticals 
Trial Code: 000226 
Date: 14Mar2018 
E-Protocol Amendment-22219; Ver. 1.0
Supersedes: Ver. Protocol Amendment 1.0 
Page 91 of 91 
CONFIDENTIAL