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rhBMP-2 soaked Absorbable rhBMP-2 soaked Absorbable Collagen Sponge (ACS) for the Collagen Sponge (ACS) for the treatment of Open Tibial Shaft treatment of Open Tibial Shaft
Fractures Fractures
Clinical SummaryClinical Summary
Points to consider
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Clinical Summary of Clinical Summary of International InvestigationInternational Investigation
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Clinical ReviewClinical Review
Study Design
Effectiveness
Safety
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Clinical ReviewClinical Review
STUDY DESIGN
• Confounding Variables
• Patient Assessment
• Study Endpoints
• Data Analysis
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Confounding VariablesConfounding Variables
• Technique for IM nail insertion• All fracture types considered equal• Isolated fractures grouped with
multiple injuries• Gustilo I ≠ Gustilo II ≠ Gustilo IIIA• Not all patients received a full
sponge to the fracture site• Large centers ≠ small centers
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Distribution of Patients by Distribution of Patients by CountryCountry
Country # sites
Control .75 mg/ml
1.5 mg/ml
Total
Australia 6 18 18 12 48
Belgium/
Netherlands
8 8 12 12 32
Canada 4 5 10 15 30
France 4 8 6 11 25
Germany 12 35 22 26 83
Israel 4 5 13 10 28
Finland/
Norway
3 13 8 8 29
So.Africa 5 47 50 41 138
U. K. 3 11 12 14 37
TOTALS 49 150 151 149 450
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Clinical Aspects of PoolingClinical Aspects of Pooling• Multiple centers • Over 50% of patients from 2 countries• Different experiences:
• Few patients from many sites pooled with many patients from few sites
• Different philosophies regarding optimal treatment :
reamed vs. unreamed nails• Different interpretations of healing, delayed
healing• Cultural and Geographic differences
• Applicability to US trauma populations
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Assessment MethodsAssessment Methods
ClinicalFracture site tendernessRadiographic unionWeight bearing status
Independent Radiographic
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Patient AssessmentPatient Assessment
PAIN
• No scale used for comparison
• Differentiation between fracture site tenderness and soft tissue injury difficult
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Criteria For Radiographic Union for Criteria For Radiographic Union for Independent Radiology PanelIndependent Radiology Panel
A fracture was considered united when:• 3 of 4 cortices demonstrated cortical bridging
and/or complete disappearance of fracture lines• This definition includes:
• 3 of 4 cortices demonstrate bridging• 3 of 4 cortices demonstrated disappearance of fracture
lines• 2 of 4 cortices demonstrate cortical bridging and at least
1 of the remaining 2 cortices demonstrate disappearance of fracture lines
• 1 of 4 cortices demonstrated cortical bridging and at least 2 of the remaining 3 cortices demonstrated disappearance of fracture lines
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Independent and Investigator Independent and Investigator ReviewReview
Gustillo Grade IIIA
Unreamed locked nail
0.75 mg/ml rhBMP
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DefinitionsDefinitions
Healed Fracture:
• Absence of tenderness upon manual palpation of the fracture site
• Radiographic fracture union as assessed by the investigator
• Full weight bearing status
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DefinitionsDefinitions
Delayed Union:
“A fracture is considered a delayed union if insufficient fracture healing was observed as determined by the investigators radiographic and clinical assessment”
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Number of Patients with SI recommended & Number of Patients with SI recommended & Patients meeting criteria of Delayed unionPatients meeting criteria of Delayed union
SOC 0.75 1.5 Total
Total w/SI
41 28 24 93
# of criteria met3 criteria 12 18 7 24
(26%)
2 criteria 19 18 11 48(52%)
1 criterion
10 5 6 21(23%)
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Primary EndpointPrimary Endpoint
Secondary Interventions :
How was the decision made?
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Study Design:Study Design:Control GroupControl Group
What is the standard of Care?• Depends on
Fracture typeInjury severityBone lossContaminationConcomitant injuries
Different prognoses for different types
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Relevance of EndpointsRelevance of Endpoints
Primary Endpoint• Rate of Secondary Interventions
– Recommended & Performed– Recommended & Not Performed– Not Recommended but Performed– Self Dynamizations (screw breakages)
Secondary Endpoints• Healing rate at 6 months• 50% probability of healing• CCRE
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What is important?What is important?
• How many healed?
• What is the incidence of nonunion?
• What are the complications and incidence?
• Incidence of Infection?
• Time to healing for majority of the patients?
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Combined Clinical & Radiographic Combined Clinical & Radiographic Endpoint Endpoint (CCRE)(CCRE)
• Independent review paired with investigator review
• Clinical assessment compared to purely radiographic assessment
• Patients with SI evaluated differently than patients without SI
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Treatment of Missing Treatment of Missing DataData
• Inconsistent• Three examples
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The DilemmaThe Dilemma
• Investigators unblinded
• Investigators determined pain, weight bearing status and radiologic healing
• Investigators determined when to perform secondary intervention
• The CCRE is 50% dependent on investigators determination
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The DilemmaThe Dilemma• No time course/interval to delineate “delayed
healing” from “healing”
• No radiographic/clinical criteria to separate healing fracture vs. delayed healing
• How patients with delayed healing fractures were recommended for secondary intervention is imprecise.
• Extent to which all the investigators used the same criteria for determining a secondary intervention is unknown
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ResultsResults
Effectiveness
• Primary Endpoint• Rate of Fracture Healing• Time to event Analysis• Probability of 50% healing• Nonunion
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Primary EndpointPrimary Endpoint
Standard of Care
0.75 mg/ml rhBMP-2/ ACS
group
1.5 mg/ml rhBMP-2/
ACS group
SI 66
(44%)
51
(35%)
38
(26%)
Recommended
& Performed
38
(25%)
25
(17%)
19
(13%)
Exclude Self dynamization
31% 25% 21%
No SI 84
(56%)
98
(65%)
111
(74%)
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Rate of Fracture HealingRate of Fracture Healing
Investigator Radiology Panel
SOC 0.75 mg/ml
1.5 mg/ml
SOC 0.75
mg/ml
1.5 mg/ml
26 wks
36 % 40 % 55 % 20 % 25 % 33 %
39 wks
48 % 51 % 64 % 38 % 41 % 50 %
50 wks
51 % 58 % 70 % 47 % 52 % 64 %
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Probability of a Fracture Healing by Probability of a Fracture Healing by InvestigatorInvestigator
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Time To Healing by InvestigatorTime To Healing by Investigator
Treatment Days to Healing Probability of Healing
Standard of Care 141 25%
184 50%
275 75%
0.75 mg/ml rhBMP-2/ACS
128 25%
187 50%
273 75%
1.5 mg/ml rhBMP-2/ACS
102 25%
147 50%
273 75%
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Time to Independent Radiographic Time to Independent Radiographic Assessment of Fracture UnionAssessment of Fracture Union
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Time to Fracture Healing by Independent Radiology Time to Fracture Healing by Independent Radiology PanelPanel
Treatment Days to Healing Probability of Healing
Standard of Care 189 25%
275 50%
351 75%
0.75 mg/ml rhBMP-2/ACS
186 25%
272 50%
351 75%
1.5 mg/ml rhBMP-2/ACS
182 25%
271 50%
353 75%
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NonunionNonunion
SOC 0.75 mg/ml
1.5 mg/ml
Inv Rad Inv Rad Inv Rad
Overall
12 months
49% 53% 42% 48% 30% 38%
Patients w/ SI
12% 9% 13%
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Time to Fracture healing by Investigator Time to Fracture healing by Investigator Assessment : Patients with Secondary Assessment : Patients with Secondary
InterventionsInterventions
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SafetySafety
Serology• Anti-rhBMP antibodies• Anti Type I Bovine collagen antibodies
Hardware failure
Laboratory Results
Heterotopic Ossification
Infection
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SerologySerology
Antibodies formed to:
Standard of Care
0.75 mg/ml rhBMP-2/ACS
1.5 mg/ml rhBMP-2/ACS
rhBMP-2 1
(1%)
3
(2%)
9
(6%)
Bovine Type I
Collagen
9
(6%)
22
(16%)
29
(20%)
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Hardware FailureHardware Failure
SOC .75 mg/ml 1.3 mg/mlTotal Patients 32 (22%) 25 (17%) 16 (11%)
Total Events 48 33 25
Nail breakage 0 2 0
Screw Breakage
48 31 24
Pts reamed Nail screw breakage
7/39 (18%) 8/48 (17%) 2/59 (3.4%)
Pts unreamed nail screw breakage
25/108 (23%)
17/97 (18%)
14/86 (16%)
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Laboratory resultsLaboratory results
Liver function Tests elevated in rhBMP-2 treated groups
• Elevated Amylase
• Hypomagnesemia
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Heterotopic OssificationHeterotopic Ossification
SOC 0.75 mg/ml 1.5 mg/ml
Patients 4 5 8
Hypertrophic Callus
3 2 1
Soft tissue callus 0 1 2
HO of tibia fracture
0 1 0
Synostosis 1 0 1
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Infection RateInfection Rate
SOC .75 mg/ml 1.5 mg/ml
Total 30% 23% 25%
Leg/Tibia 29% 25% 24%
Gustilo I 18% 17% 19%
Gustilo II 20% 19% 20%
Gustilo IIIA/B
48% 30% 33%
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CONCLUSIONSCONCLUSIONS
• Definitions for assessment unclear• Assessments based on investigators• Clinical relevance of endpoints• Control group as standard of care an
issue• Pooling across different sites and
applicability to US population an issue• Outcomes Interpretations differ• Safety questions