rhBMP-2 soaked Absorbable Collagen Sponge (ACS) for the treatment of Open Tibial Shaft Fractures Clinical Summary

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rhBMP-2 soaked Absorbable Collagen Sponge (ACS)
for the treatment of Open Tibial Shaft Fractures
Clinical Summary

• Points to consider

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Clinical Summary of International Investigation
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Clinical Review

• Study Design
• Effectiveness
• Safety

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Clinical Review

• STUDY DESIGN
• Confounding Variables
• Patient Assessment
• Study Endpoints
• Data Analysis

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Confounding 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 Country
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 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 Methods

• Clinical
• Fracture site tenderness
• Radiographic union
• Weight bearing status
• Independent Radiographic

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Patient 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 Independent
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 Review

• Gustillo Grade IIIA
• Unreamed locked nail
• 0.75 mg/ml rhBMP

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Definitions

• 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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Definitions

• 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 Patients
meeting criteria of Delayed union
SOC SOC 0.75 1.5 Total
Total w/SI 41 41 28 24 93
of criteria met of criteria met of criteria met of criteria met of criteria met of criteria met
3 criteria 3 criteria 12 18 7 24 (26)
2 criteria 2 criteria 19 18 11 48 (52)
1 criterion 1 criterion 10 5 6 21 (23)
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Primary Endpoint

• Secondary Interventions
• How was the decision made?

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Study DesignControl Group

• What is the standard of Care?
• Depends on
• Fracture type
• Injury severity
• Bone loss
• Contamination
• Concomitant injuries
• Different prognoses for different types

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Relevance 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?

• 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 Endpoint (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 Data

• Inconsistent
• Three examples

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The 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 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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Results

• Effectiveness
• Primary Endpoint
• Rate of Fracture Healing
• Time to event Analysis
• Probability of 50 healing
• Nonunion

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Primary 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 Healing
Investigator Investigator Investigator Radiology Panel Radiology Panel 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 Investigator
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Time To Healing by Investigator
Treatment Days to Healing Probability of Healing
Standard of Care 141 25
Standard of Care 184 50
Standard of Care 275 75

0.75 mg/ml rhBMP-2/ACS 128 25
0.75 mg/ml rhBMP-2/ACS 187 50
0.75 mg/ml rhBMP-2/ACS 273 75

1.5 mg/ml rhBMP-2/ACS 102 25
1.5 mg/ml rhBMP-2/ACS 147 50
1.5 mg/ml rhBMP-2/ACS 273 75
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Time to Independent Radiographic Assessment of
Fracture Union
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Time to Fracture Healing by Independent Radiology
Panel
Treatment Days to Healing Probability of Healing
Standard of Care 189 25
Standard of Care 275 50
Standard of Care 351 75

0.75 mg/ml rhBMP-2/ACS 186 25
0.75 mg/ml rhBMP-2/ACS 272 50
0.75 mg/ml rhBMP-2/ACS 351 75

1.5 mg/ml rhBMP-2/ACS 182 25
1.5 mg/ml rhBMP-2/ACS 271 50
1.5 mg/ml rhBMP-2/ACS 353 75
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Nonunion
SOC SOC 0.75 mg/ml 0.75 mg/ml 1.5 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
Assessment Patients with Secondary Interventions
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Safety

• Serology
• Anti-rhBMP antibodies
• Anti Type I Bovine collagen antibodies
• Hardware failure
• Laboratory Results
• Heterotopic Ossification
• Infection

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Serology
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 Failure
SOC .75 mg/ml 1.3 mg/ml
Total 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 results

• Liver function Tests elevated in rhBMP-2 treated
  groups
• Elevated Amylase
• Hypomagnesemia

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Heterotopic 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 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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CONCLUSIONS

• 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