PROVASA Amputation

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					  Intra-arterial administration of Bone-
marrow mononuclear cells in patients with
         critical limb ischemia –
    a randomized placebo-controlled
              trial PROVASA
  D.H.Walter, H. Krankenberg, J. Balzer, C. Kalka,
   I. Baumgartner, M. Schlüter, T.Tonn, F.Seeger
       S.Dimmeler, E.Lindhoff-Last, A.M.Zeiher

         MVZ Prof. Mathey, Prof. Schofer, Hamburg,
       Cardiology - Angiology and Radiology, Frankfurt
                       Inselspital Bern
                  Blutspendedienst Hessen



          ClinicalTrials.gov number : NCT00282646
I do not have any potential conflict of interest
                           PROVASA
                           Background
Intra-arterial Application of Bone-Marrow Mononuclear Cells


  Intracoronary


                              Bone-marrow
                                 (50 ml,
                             Local anesthesia)




                                                  Isolation of
                                                 mononuclear      *

                                                 cells (Ficoll)
                                                                      *
                                                   *
                                                 BSD Hessen               Critical limb
                                                 GMP Facility             ischemia
REPAIR AMI                                                                Rutherford
Schächinger V et al.                                                      4-6
                       In PAOD: no randomized placebo
NEJM 2006
                           controlled trials available
                           PROVASA
                   Study Flow Chart
 Randomized-start,
 placebo controlled,          40 Patients
multicenter trial with a
  cross-over phase
                                    R
                                   1:1
   Baseline           BMC                  Placebo


   3 Months (open-label)         BMC


                             (Optional BMC)
   6 Months                  Extended Protocol


                             Mean 30.2 months
   Long-term F/U
                              (6-57 months)
                     PROVASA
                     Endpoints
• Primary Endpoint
  • Change in ankle-brachial index (ABI) at 3 and 6
    months

• Secondary Endpoint
  • Wound healing

  • Pain reduction

  • Amputation-free survival
                 PROVASA
       Inclusion/Exclusion Criteria
• Patients with Fontaine III or IV
  who were not candidates for interventional
  or surgical revascularization or who failed to
  respond to interventional or surgical
  procedures.
• PAOD or thrombangitis obliterans (TAO)


• Exclusion:
  prior PTA or Bypass < 3 months
• Creatinine > 2.0 mg/dl at time ot treatment
                      PROVASA
             Patient Characteristics
                               BMC      Placebo
                                                   P
                              N=19       N=21
Age, years                   64.4 ±15   64.5 ±16   NS
Men                          16 (84%)   13 (62%)   NS
Hx of smoking                10 (53%)   10 (48%)   NS
   Current smoker            4 (21%)     1 (5%)    NS
Diabetes                     10 (53%)   10 (48%)   NS
   IDDM                      9 (47%)    6 (29%)    NS
Hypertension                 14 (74%)   14 (67%)   NS
Hyperlipidemia               15 (79%)   16 (76%)   NS
Kidney dysfunction           7 (37%)    6 (29%)    NS
Hx of CAD                    10 (53%)   10 (48%)   NS
Prior MI                     6 (32%)    4 (21%)    NS
Heart failure (LVEF ≤ 35%)   3 (16%)     1 (5%)    NS
                      PROVASA
      PAD/Procedural Characteristics
                               BMC      Placebo
                                                    P
                              N=19       N=21
Femoropopliteal occlusion    6 (32%)    7 (33%)    NS
Infrapopliteal disease       13 (68%)   14 (67%)
Buerger’s disease (TAO)      3 (16%)    5 (24%)    NS
Mediasclerosis               5 (26%)    3 (14%)    NS
Rutherford category                                NS
   4 (rest pain)             4 (21%)    6 (29%)
   5 (minor tissue loss)     12 (63%)   14 (67%)
   6 (gangrene)              3 (16%)     1 (5%)
Prior PTA > 3 months prior   3 (16%)    10 (48%)   0.04
Prior peripheral surgery     3 (16%)    9 (43%)    NS
Prior minor amputation       3 (16%)    2 (10%)    NS
BMC therapy @ 3 months       14 (74%)   19 (90%)   NS
BMC therapy > 6 months        5 (26%)   6 (29%)    NS
                            PROVASA
                             Results
• Ankle-brachial index (1ry EP)
  in 26 patients with complete serial measurements
              1.20
                            Pooled data
                                                       IQR
              1.00
 Median ABI




              0.80

              0.60

              0.40                        0.80
                              0.71
                     0.65
              0.20                               P*=0.040
                            P**=0.014
              0.00                                * Repeated measures
                     BL        M3         M6        ANOVA
                                                 **Holm test (post hoc)
                             All pts
                             BMC
                                    PROVASA
                                     Results
• Ankle-brachial index (1ry EP)
  in 26 patients with complete serial measurements
              1.20                                            IQR

              1.00
                                                    0.85
 Median ABI




              0.80                                         P†=0.836
                             0.66
                                                0.70
                     0.64
              0.60

                                                                BMC     (n=11)
              0.40
                                                                Placebo (n=15)

              0.20

              0.00
                            BL        M3       M6

                 Randomized-Start    All pts
                                     BMC
                   PROVASA
      The Primary Endpoint Dilemma
• ABI values were not useful as primary endpoint


• Changes in ABI do not correlate well with ulcer
  healing and limb salvage

• In patients with thrombangiitis obliterans
  (TAO) as well as in patients with extensive
  mediasclerosis, ABI values do not reflect the
  degree of distal ischemia and tissue necrosis.
                        5                              PROVASA
                                     Ulcer Healing- quantitative Analysis

                        4                                   P=0.009

                                               P=0.5                  P=0.09
Mean Ulcer Area (cm²)




                        3



                        2                                                                  SE



                                                                                      Placebo (n=12)
                        1
                                                                                      BM-MNC (n=10)

                                          P=0.014                       P=0.2

                        0                               P=0.059

                               Baseline                   M3                    M6

                            Randomized-Start           All BM-MNC                    Figure 3A
                                                    PROVASA
                                      Ulcer Area- Absolute Reduction


                                            Placebo (n=12)    1x BM-MNC            2x BM-MNC
                                                             (n=10 ) + (n = 11)      (n=19)
Mean Reduction of Ulcer Area (cm²)

                                       0
                                                 Placebo       1x BM-MNC           2x BM-MNC

                                     -0.5



                                      -1



                                     -1.5
                                                              P=0.16
                                                             vs Placebo
                                      -2



                                     -2.5
                                                                                   P=0.018
                                                                                  vs Placebo
                                      -3
                                    PROVASA
Patients with Complete Ulcer Healing
                                                              P=0.037
    Mean time to ulcer                                  All BMC vs. Placebo
    healing 10.9 months                            18
                                                                         17

7                                                  16

                                        6
6                   Placebo                        14

                    BMC
                                                   12
5

                                                   10
                                    4
4       NS
                                                    8
    3        3
3
                                                    6
                           2                  2
2
                                                    4
                                                           3

1                                                   2



0                                                   0
        3M                     6M       > 6-24 M         Placebo        BMC


                 All pts
                 BMC
                 PROVASA
                Ulcer healing

• No difference in complete ulcer healing
 within 3 months between BMC vs Placebo

• Complete healing of ulcers 20/30 patients
 (66.6%)

• 20/21 (95%) complete healing in patients
 with stable ulcers, 17/21 (81%) after
 repeated BMC !
                                     PROVASA
                            Pain Analysis-Serial Values
             7                               P=0.002
                                    P=0.3
                                   P=0.13                P=0.004
                                                         P=0.02
             6


             5
Pain scale




             4


             3                                                                SE

             2
                                                                        Placebo (n=15)

             1                    P=0.009                P=0.343        BM-MNC (n=10)
                                              P=0.014
             0
                       Baseline                M3                  M6
                      BL                       M3                  M6


                 Randomized-Start           All BM-MNC
                                  PROVASA
                Pain Analysis-Absolute Reduction


                    Placebo (n=15)    1x BM-MNC            2x BM-MNC
                                     (n=15 ) + (n = 10)      (n=10)

               0
                        Placebo         1x BMC              2x BMC
             -0.5


              -1
Pain scale




             -1.5


              -2


             -2.5
                                     P=0.1 vs
                                      Placebo
              -3


             -3.5


              -4


             -4.5                                          P=0.002
                                                          vs Placebo
                                          PROVASA
                       Amputation-free survival

                                                     6 M : 76%
Event-free survival




                                          • No difference within 3
                           All pts
                                            months
                           BMC             (BMC vs Placebo)

                                          • Maj. amputations in
                                            patients with advanced
                                            lesions/gangrene




        Pts at risk   40       29    28
Cell Number and Functional
    Capacity (Migration)
                       350
                                          Cell number
                       300
Number of Cells x106
                       250
                                          p =0.003
                       200

                       150

                       100

                        50

                         0
                             Healing                    Non-healing

                       140
                                       Functional capacity
                       120

                       100
  Migration




                        80
                                          p =0.016
                        60

                        40

                        20

                         0
                             Healing                 Non-healing
                  Multivariate Analysis
Clinical Improvement (Healing or Pain Reduction)
                          Exp (B)
  Factor           P                  95% CI
                          Hazard

  Age              0.7     1.01      1.01 - 1.07


  Ulcer size       0.5      0.9      0.65 - 1.25

                                                     Repeated BM-MNC
  EF              0.08     1.09      0.99 - 1.20
                                                      administration as well
  Pain at
                  0.12     0.82      0.65 - 1.05
                                                      as the number and
  baseline
                                                      functionality of
  Creatinine <
                  0.11     6.13       0.66 - 56
                                                      administered BM-MNC
  1.4 mg/dl
                                                      were significant
  Buerger’s
                   0.8     1.26      0.17 - 9.0       independent predictors
  disease (TAO)
                                                      for clinical improvement
  Cell number     0.003    1.02     1.008 - 1.038

  Repeated
  BM-MNC (≥ 2     0.018    6.17       1.35 - 28
  applications)

  Cell function   0.049    0.99      0.98 – 1.00
                    PROVASA
                Conclusions (1)
• Intraarterial administration of BM-MNC
  significantly promotes ulcer healing and reduces
  rest pain until 3 months versus Placebo

• Successful ulcer healing associated with improved
  limb salvage requires repeated administration
  of functionally competent BM-MNC

• Patients with thrombangiitis obliterans generally
  responded well, critically ill patients with extensive
  gangrene and impending amputation did not
  derive any benefit.
                    PROVASA
                 Conclusions (2)
• Thus, large scale randomized trials are warranted
  to assess the clinical effect of repeated BM-MNC
  administration in patients with critical limb
  ischemia with stable ulcers and/or rest pain.

• Complete ulcer healing occurred at a mean of 10.9
  months after BM-MNC administration

• To assess potential clinical benefits of cell therapy
  in patients with critical limb ischemia, a follow-up
  period of at least 18 months will be required.
 Frankfurt               Institut für
Kardiologie:         Transfusionsmedizin          Hamburg             Bern
                         BSD Hessen:
D. Walter (Coordinator)                        H. Krankenberg       C. Kalka
                           T. Tonn
A. Zeiher (PI)                                   M. Schlüter     I.Baumgartner
S. Dimmeler                                D. Walter (Coordinator)



Angiologie:
 A. Kopalla
E. Lindhoff-Last

Radiologie:
  J. Balzer,
 PROVASA
Back-up slides
                      Responders

•   Younger age
•   Better ejection fraction
•   Smaller ulcer size (< 2.3 cm² , p =0.038)
•   Less rest pain at baseline
•   Better renal function (creatinine < 1.4 mg/dl)
•   TAO (all 8 TAO) responders versus 18 of 32 (56%)
    atherosclerotic PAOD improved clinically by BM-
    MNC treatments (P=0.02 TAO vs. PAOD).

• Patients with gangrene (Rutherford 6) did not
    respond at all.
                                             P=0.14

                                P=0.032                 P=0.018
              60


              50
TCO2 (mmHg)




              40


              30


              20                                                       Placebo (n=10)
                                 P=0.058                 P=0.52
                                                                       BM-MNC (n=6)
                                               P=0.17
              10


               0
                     Baseline                M3                   M6


               Randomized-Start            All BM-MNC
                                             PROVASA
                                  Ulcer Healing- quantitative Analysis


                         3.5


                          3
Mean Ulcer Area (cm²)




                         2.5


                          2

                                                                          Placebo
                         1.5                                              BMC


                          1


                         0.5


                          0

                               Baseline    M3           M6   Last Visit




                        Randomized-Start   All BM-MNC

				
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