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Do we still need corticosteroids for maintenance immunosuppression after renal transplantation? Con

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Title: Do we still need corticosteroids for maintenance immunosuppression after renal transplantation? Con


1
Do we still need corticosteroids for maintenance
immunosuppression after renal transplantation? Co
n
  • Burkhard Tönshoff
  • University Childrens Hospital
  • Heidelberg, Germany

2
The Steroid Problem Multifaceted toxicity
  • Poor growth
  • Cushingoid habitus, acne as risk factors for
    non-adherence
  • Calcium loss, bone demineralization
  • Hypertension
  • Lipid abnormalities, chronic graft
    atherosclerosis
  • Diabetes mellitus
  • Depression-mood swings
  • Cataracts

Non-immune triggers of CR
3
Treatment strategies to minimize glucocorticoids
in pediatric renal transplantation
  • Steroid avoidance
  • Early steroid withdrawal
  • Late steroid withdrawal (gt1 year posttransplant)
  • The success of corticosteroid withdrawal may
    depend in part upon the effectiveness of the
    remaining agents that constitute the
    immunosuppressive regimen and the right patients
    selection (one size does not fit all)

4
NIH Multicenter Randomized Study of Steroid-Free
vs. Steroid-Based Rx n130 Stanford protocol
ATC 2008
  • 130 unsensitized primary pediatric renal
    transplant recipients randomized 11 to
  • Steroid-free arm Daclizumab 10 mg/kg over 9
    doses Tacrolimus MMF
  • Steroid-based arm Daclizumab 5 mg/kg over 4
    doses Tacrolimus MMF Steroids 24.1 of
    steroid-free and 27.5 of steroid-based patients
    were African Americans.

5
1 Year Results Sarwal et al, ATC 2008
Steroid-free N60 Steroid-based N70 P value
Patient survival 100 100 n.s.
Graft survival 96.7 98.6 n.s.
D Height SDS 0.34 SDS 0.34 SDS n.s.
BPAR 23.3 21.4 n.s
Calculated GFR ml/min/1.73 m² 90.0 90.6 n.s.
Percent first hospitalization 55 70 n.s.
Neoplasms 0 6.3 n.s.
PTDM 0 4.5 n.s.
6
Overview of strategies for steroid minimization
  • Steroid avoidance
  • Early steroid withdrawal
  • Late steroid withdrawal

7
European Study TWIST study design
8
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9
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10
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11
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12
Overview of strategies for steroid minimization
  • Steroid avoidance
  • Early steroid withdrawal
  • Late steroid withdrawal

13
Multicenter, open-label, prospective, randomized
study on late steroid withdrawal in children
with stable renal function on a maintenance
immunosuppressive therapy with CsA and MMF
  • Burkhard Tönshoff, Britta Höcker, Lutz Weber
  • University Childrens Hospital
  • Heidelberg, Germany
  • on behalf of the German Study Group on Pediatric
    Renal Transplantation

14
Rationale
  • Many centers at least in Europe practice late
    steroid withdrawal in selected pediatric renal
    transplant recipients, but this approach has
    never been rigorously tested in a controlled
    prospective clinical trial.
  • We therefore undertook this first prospective
    randomized open-label multicenter trial
    (investigator-initiated) to address this
    question.

15
Inclusion and exclusion criteria
  • Inclusion criteria
  • Age lt 18 years
  • Bone age 15 years in boys and 13 years in
    girls
  • Time posttransplant 12 24 months
  • First or second RTx, LD or CD
  • Triple immunosuppression at study entry CsA,
    MMF, steroids
  • Written informed consent
  • Exclusion criteria
  • Irreversible AR of an previous graft within 6
    months prior to study entry
  • PRA gt 80 within 12 months prior to study entry
  • Steroid-resistant AR, gt 2 AR after RTx or gt 1 AR
    within the last 6 months
  • GFR lt 40 mL/min1.73 m²
  • Serum creatinine increase gt 20 within the last
    6 months
  • Biopsy-proven chronic rejection
  • Noncompliance
  • Other immunosuppressants
  • Growth hormone therapy

16
Patient characteristics (n41)
Parameter Steroid withdrawal (n 23) Control group (n 18) Statistical significance
Gender 7 girls 16 boys 7 girls 11 boys n.s.
Prepubertal (n 20) 13 7 n.s.
Pubertal (n 21) 10 11 n.s.
Age at transplantation yr 8.4 4.7 9.8 3.2 n.s.
Living/cadaveric RTx 18 CD 5 LD 13 CD 5 LD n.s.
Age at study entry yr 10.0 4.4 11.5 3.1 n.s.
Time period between grafting and study entry yr 1.53 0.48 1.65 0.42 n.s.
Graft function CCr at study entry mL/min1.73 m² 105 37 94 20 n.s.
Body Mass Index SDS 0.80 0.22 0.37 0.35 n.s.
CsA dose mg/kgday 5.5 2.2 5.6 2.1 n.s.
CsA trough level µg/mL 107 43 107 34 n.s.
MMF dose mg/m²day 944 369 948 221 n.s.
Prednisone dose mg/m²day 4.4 1.5 4.6 1.3 n.s.
17
Primary endpoint Longitudinal growth 2-year
data (n 28)
n 14








n 14

plt0.05 vs. control group plt0.005 vs. control
group plt0.05 vs. baseline plt0.005 vs.
baseline
Steroid withdrawal Control group
18
Change in body mass index 2-year data (n 28)
n 14







n 14




plt0.05 vs. control group plt0.01 vs.
control group plt0.001 vs. control group
plt0.05 vs. baseline
Steroid withdrawal Control group
19
Body Mass Index

Before steroid withdrawal
One year after steroid withdrawal
? Steroid withdrawal ? Control group ? Andreas S.
P 0.008 versus baseline
20
Antihypertensive drugs





0
9
3
6
15
12
Time months
Steroid withdrawal Control group
plt0.005 vs. baseline
21
Serum cholesterol


0
9
15
Time months
plt0.01 vs. baseline
Steroid withdrawal Control group
22
Allograft function 2-year data (n 28)
n.s.
n 14
n 14
Steroid withdrawal Control group
23
Drop-outs and treatment failure
Drop-out reason / treatment failure Steroid withdrawal (5/23 (22)) Control group (3/18 (17))
Switch to mTOR inhibitor 2 (month 1 and 6) 0
MMF discontinuation 1 (month 18) 1 (month 18)
Consent withdrawal 0 2 (month 0)
Assumed AR 1 (month 12) 0
Allograft loss due to noncompliance 1 (month 33) 0
24
Histology (n 41)
Histology Steroid withdrawal (n 23) Control group (n 18)
Number of biopsies 6 (26) 4 (22)
BPAR BPAR BPAR
? Borderline 0 1 (month 9)
? Banff IIa 0 1 (month 21)
CAN CsA nephrotoxicity 5 1
CsA nephrotoxicity 1 0
Unspecific changes 0 1
25
Summary Late steroid withdrawal study
  • In this study, late steroid withdrawal (gt 1 year
    posttransplant) in selected pediatric renal
    transplant recipients on CsA and MMF over an
    observation period of 2 years was
  • Safe No increased rate of ARE, no difference in
    calculated GFR and proteinuria
  • Allowed significant catch-up growth Height gain
    1 SDS in 2 years
  • Improved cardiovascular risk factors Decrease of
    serum cholesterol, blood pressure, BMI

26
Steroid withdrawal and cardiovascular risk
factors
  • Obesity, hyperlipidemia and arterial hypertension
    are well-known cardiovascular risk factors and
    closely associated with steroid therapy.
    Cardiovascular events are among the main causes
    of death for both pediatric (N Engl J Med 350,
    2004) and adult (Am J Kidney Dis 38, 2001) renal
    transplant recipients in the long-run.
  • Vanrenterghem et al. (Transplantation 85, 2008)
    recently showed that an increased long-term total
    steroid dose is associated with increased
    cardiovascular morbidity.

27
Steroid withdrawal and compliance/adherence
  • Moreover, the improvement of body disfigurement
    attributable to a marked cushingoid appearance,
    at least in individual patients, potentially
    enhances their adherence to taking
    immunosuppressive drugs (Transplantation 26,
    1990), an essential prerequisite for long-term
    allograft survival.
  • Thus, a hidden cost of steroid-related
    side-effects may be increased graft loss.

28
Renal transplant function as primary endpoint?
  • Theoretically, safety should be the primary
    endpoint and adequately powered to show at least
    non-inferiority of the proposed regimen.
  • In order to assess the feasibility of a
    non-inferiority study, we calculated the sample
    size to provide 90 power to detect
    non-inferiority of GFR, in the steroid-withdrawal
    group compared to the standard-steroids group.

29
Renal transplant function as primary endpoint?
  • If one considers a difference in GFR of 5 after
    one year of steroid-free IS to be non-inferior
    with a 15 coefficient of variation based on
    values from former studies performed with a
    standard-steroid regimen, at least 196 patients
    per treatment arm would be necessary for
    between-group comparisons made at an adjusted
    significance level of 5.
  • Given the small number of pediatric renal
    transplant patients available, such a study would
    be impossible to conduct.

30
The impact of steroid-free IS on graft function
and survival Evidence from other studies
  • Long-term follow-up studies on late ( 1 year
    post-transplant) steroid withdrawal with an
    observation period of up to four years in
    pediatric renal transplant recipients
    (Transplantation 78, 2004) and up to 7 years in a
    large group (n 1110) of adult Caucasian
    patients (AJT 5, 2005) indicate that the rates of
    acute rejection and renal dysfunction did not
    differ between steroid-free and
    steroid-continuation groups.

31
Long-Term Prospective Study of Steroid Withdrawal
in Kidney and Heart Transplant Recipients
81.9 vs. 75.3, p 0.0001
88.8 vs. 84.3, p 0.0016
91.8 vs. 87.9, p 0.0091
  • Steroids were withdrawn no earlier than 6 months
    post-transplant.
  • 94 CsA, 97 Caucasian

Opelz G et al, Am J Transpl 5 720, 2005
32
The impact of steroid-free IS on graft function
and survival Evidence from other studies
  • Recently, the 5-year results of a randomized
    double-blind placebo-controlled trial of early
    corticosteroid cessation vs. chronic
    corticosteroids in adults on TAC and MMF revealed
    that no significant differences existed in
    allograft survival or graft function 5 years
    post-transplant, but steroid withdrawal provided
    cardiovascular risk and bone disease benefits
    (Woodle S, ATC meeting 2008).
  • It is important to note that these differences
    were found despite the low prednisone dose of 5
    mg per day in the steroid maintenance group after
    6 months post-transplant.

33
Conclusions
  • Late (gt 12 months post-transplant) steroid
    withdrawal is feasible in low immunological risk
    patients on newer immunosuppressive drugs (MMF,
    TAC).
  • Late steroid withdrawal has the advantage over
    steroid avoidance that immunological high-risk
    patients and those with unstable graft function
    can easily be identified beforehand and be
    excluded from steroid-free immunosuppression.
  • Early steroid withdrawal in patients receiving
    antilymphocyte induction therapy is promising.
  • Long-term follow up is required to decide which
    strategy (steroid avoidance, early steroid
    withdrawal or late steroid withdrawal) is
    superior for both graft survival and patient
    outcome.

34
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35
Randomized Prospective Steroid Withdrawal Study
German Study Group on Pediatric Renal
Transplantation
2nd study phase (uncontrolled)
1st study phase (controlled)
Branch A steroid withdrawal
Patients at least 1 year after kidney
transplantation with stable transplant
function Immunosuppre-ssion with CsA, MMF, Predn.
Randomi-zation
0 3 6 9 12 15
18 21 24 27 months
Branch B control group, daily steroids
optional steroid withdrawal
27 30 33 36 39 42
36
Randomized Prospective Steroid Withdrawal Study
German Study Group on Pediatric Renal
Transplantation
2nd study phase (uncontrolled)
1st study phase (controlled)
Branch A steroid withdrawal
Patients at least 1 year after kidney
transplantation with stable transplant
function Immunosuppre-ssion with CsA, MMF, Predn.
Randomi-zation
0 3 6 9 12 15
18 21 24 27 months
Branch B control group, daily steroids
optional steroid withdrawal
27 30 33 36 39 42
37

Steroid-free Protocol Immunosuppression Dosing
Tacrolimus 0.15 mg/kg/dose Trough levels
(ng/ml) bid Weeks 0-1 12-14
Mo 3 5-7 Year 1 3-5
MMF 600-450 mg/m²/dose bid 300
mg/m2/dose, bid Trough levels 2-4
mg/dl
38
Conclusion
  • In this study, late steroid withdrawal (gt 1 year
    posttransplant) in selected pediatric renal
    transplant recipients on CsA and MMF over an
    observation period of 2 years was
  • safe no difference in calculated GFR and
    proteinuria
  • allowed significant catch-up growth height gain
    1 SDS in 2 years
  • improved cardiovascular risk factors decrease of
    serum cholesterol, blood pressure, BMI
  • Long-term follow up is required to decide which
    strategy (steroid avoidance, early steroid
    withdrawal or late steroid withdrawal) is
    superior for both graft survival and patient
    outcome in pediatric renal transplant recipients.

39
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40
Protocol
  • Safety and efficacy of antithymocyte globulin or
    alemtuzumab preconditioning, steroid avoidance
    and reduced CNI immunosuppression in 34 children
    after RTx.
  • ATG (n8) or alemtuzumab (n26), followed by
    low-dose twice a day tacrolimus monotherapy with
    consolidation to once daily dosing by 6 months
    and once every other day dosing by 12 months.
  • Follow-up ranged from 0.52.9 years (mean 1.33
    years), with a minimum of 6 months.

41
Results
  • Both ATG and alemtuzumab were well tolerated.
    Lymphopenia occurred routinely and resolved after
    36 months.
  • Acute cellular rejection in 9, related to
    medical nonadherence in two patients and resulted
    in one graft loss at 1.5 years.
  • AE Transient neutropenia in 10 children (none
    with serious infection), and autoimmune hemolytic
    anemia in two.
  • GFR stable (88 mL/min/1.73 m² at latest
    follow-up. 91 catch-up growth.

42
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43
Primary endpoint Longitudinal growth 1-year
data (n 36)
n 20





n 16
plt0.05 vs. control group plt0.01 vs. control
group plt0.001 vs. baseline
Steroid withdrawal Control group
44
Serum triglycerides
n.s.
0
9
15
Time months
Steroid withdrawal Control group
45
Change in blood pressure 1-year data (n 36)
n 20




n 16



plt0.01 vs. control group plt0.001 vs.
control group plt0.05 vs. baseline
Steroid withdrawal Control group
46
Blood pressure 2-year data (n 28)
n 14




n 14
Steroid withdrawal Control group
plt0.05 vs. control group
47
Hemoglobin





0
9
3
6
15
12
Time months
plt0.01 vs. control group plt0.001 vs. control
group plt0.05 vs. baseline
Steroid withdrawal Control group
48
Leucocytes

0
9
3
6
15
12
Time months
Steroid withdrawal Control group
plt0.05 vs. control group
49
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50
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51
Adverse events
Clinical event Steroid withdrawal (n 23) Steroid withdrawal (n 23) Control group (n 18) Control group (n 18)
Clinical event Event per patient Number of patients () Event per patient Number of patients ()
Opportunistic infections 1.0 4 (17.4) 1.8 5 (27.8)
Diarrhea 1.6 7 (30.4) 1.6 7 (38.9)
Respiratory tract infections Upper RTI Pneumonia 4.1 1.0 18 (78.3) 5 (21.7) 5.3 1.0 12 (66.7) 1 (5.6)
Urinary tract infections 3.6 5 (21.7) 2.8 4 (22.2)
Other infections 2.4 15 (65.2) 2.4 9 (50.0)
M. Addison 1.0 1 (4.3) 0 0
Pseudotumor cerebri 1.0 1 (4.3) 0 0
Gingival hyperplasia 1.0 4 (17.4) 1.0 1 (5.6)
Hypertrichosis 1.0 2 (8.7) 1.0 2 (11.1)
52
Methods. In a retrospective case-control study,
covering a mean follow-up period of 46 2.3
months and 40 patients aged 11.4 4.9 years, we
analyzed the safety and efficacy of steroid
withdrawal in pediatric renal transplant
recipients receiving CsA micoroemulsion, MMF, and
low-dose prednisone treatment.
53
Graft function
P lt 0.05 P lt 0.01 vs. baseline
54
Conclusions Glucocorticoids
  • Late withdrawal Feasible in pediatric renal
    transplant recipients with stable graft function.
    Facilitated by maintenance therapy with newer
    immunosuppressive drugs (tacrolimus, MMF).
  • Early withdrawal IL2r antibody, steroids, CNI
    and Rapamycin are too immunosuppressive in
    at-risk population. Lesson Balance must not
    be too far on the complication side.
  • Steroid avoidance (Stanford experience)
    successful, substantial benefits for children
    following kidney transplantation, but requires
    further validation in controlled randomized
    trials.

55
Change in body mass index 1-year data (n 36)
n 20






n 16




Steroid withdrawal Control group
plt0.05 vs. control group plt0.05 vs. baseline
56
Allograft function 1-year data (n 36)
n.s.
n 20
n 16
Steroid withdrawal Control group
57
Histology (n 41)
Histology Steroid withdrawal (n 23) Control group (n 18)
Number of biopsies 6 (26) 4 (22)
BPAR BPAR BPAR
? Borderline 0 1 (month 9)
? Banff IIa 0 1 (month 21)
CAN CsA nephrotoxicity 5 1
CsA nephrotoxicity 1 0
Unspecific changes 0 1
58
Proteinuria 1-year data (n 36)
n.s.
0
15
Time months
Steroid withdrawal Control group
59
Proteinuria 2-year data (n 28)
n.s.
0
27
15
Time months
Steroid withdrawal Control group
60
Longitudinal growth 1-year data in prepubertal
patients (n 18)
n 11






n 7
Steroid withdrawal Control group
plt0.01 vs. control group plt0.05 vs. baseline
61
Longitudinal growth 1-year data pubertal
patients (n 18)
n.s.
n 9
n 9
Steroid withdrawal Control group
62
Study endpoints
  • Primary endpoint
  • Longitudinal growth
  • Secondary endpoints
  • Alleviation of cardiovascular risk factors
  • Arterial hypertension
  • Hyperlipidemia
  • Body Mass Index
  • Safety aspects
  • Patient and graft survival
  • Allograft function (CCr according to Schwartz)
  • Acute rejection episodes
  • Proteinuria
  • Myelosuppression

63
Longitudinal growth 1-year data (prepubertal
patients n 10)
Time months
64
Height SDS 1-year data (n 36)
n 20



n 16
plt0.05 vs. baseline
Steroid withdrawal Control group
65
Height SDS 2-year data (n 28)

n 14


n 14
plt0.05 vs. baseline
Steroid withdrawal Control group
66
Body mass index 1-year data (n 36)
n 20

n 16




Steroid withdrawal Control group
plt0.05 vs. baseline
67
Body mass index 2-year data (n 28)
n 14


n 14



Steroid withdrawal Control group
plt0.05 vs. baseline
68
Blood pressure 1-year data (n 36)
n 20

n 16



Steroid withdrawal Control group
plt0.05 vs. baseline
69
Blood pressure 2-year data (n 28)
n 14

n 14
Steroid withdrawal Control group
plt0.05 vs. control group
70
Standard vs Novel Extended Daclizumab Induction

0
1
2
3
4
5
6
12
Months post-txp
Protocol biopsies
Total dose 10 mg/kg vs 5 mg/kg 6 months versus 2
months coverage
1mg/kg every 2 weeks x 4 3 weeks x 1 4 weeks x 3
Ext-Dac
Safety Data for Extended Use Nussenblatt et al,
PNAS, 1999, 96(13), 7462
2mg/kg
71
Complete Steroid Avoidance vs Steroid Taper?
  • Steroid ELIMINATION is the best option to improve
    growth
  • Lower daily dosing growth/-
  • Alternate day dosing growth, AR, compliance-
  • Steroid Withdrawal growth , AR, graft loss
  • Stronger Rx (maintenance/ induction) may allow
    safe steroid avoidance from the start
  • Steroid avoidance may promote graft acceptance
  • No steroids immunologically safer- steroid
    dependancy hypothesis?
  • Steroids inhibit Fas dependant peripheral
    tolerance
  • Steroids break experimental tolerance

72

STANFORD STEROID FREE PROTOCOL
  • Sarwal et al, Rapid Comm., Transplantation, 2001
  • n10, 6 month analysis
  • Sarwal et al, Transplantation, 2003
  • n50, 2 year analysis

Months post-txp
Protocol biopsies
Rx
Daclizumab
Tacrolimus
MMF
73

STEROID FREE PROTOCOL Immunosuppression Dosing
Tacrolimus 0.15mg/kg/dose Trough levels
(ng/ml) bid Weeks 0-1 12-14
Mo 3 5-7 Year 1 3-5
MMF 600-450 mg/m2/dose bid 300
mg/m2/dose, bid Trough levels 2-4
mg/dl
74
Single Center Study Analysis November 1999- July
2005
  • 77 Steroid-Free (SF) pediatric transplant
    recipients
  • Efficacy and Dosing study
  • Follow-up Range16-66 months Mean 40 months
  • 77 Steroid-Based (SB) historical (1/3) and
    prospective (2/3) pediatric transplant controls
  • Pre-requisite for Inclusion 100 graft survival
    at 2 years and no DGF
  • Matched for age, sex, race, cause of ESRD,
    pre-txp dialysis, mean HLA match, CMV, EBV, Blood
    pressure, HCT, WBC, Lipids
  • Immunosuppression
  • -Tacrolimus 100
  • - Induction 100 (Daclizumab 65)

75
Graft Survival at 3 Years
  • Graft survival
  • 95 in SF vs. 71 in SB (p0.001)
  • Death censored graft survival
  • 100 in SF vs. 87 in SB (p0.0011)

76
Acute Rejection Improved in SF!
  • Acute Rejection (AR) in both groups
  • 1 year AR 6 in SF vs 22 in SB (p0.0005)
  • Late AR (gt 1 yr) 2 in SF vs. 8 in SB (p0.01)
  • Sub-clinical AR in SF (405 protocol biopsies)-
    data not available in SB
  • Banff ungradable
  • 13
  • No steroid pulsing, graft function stable,
    follow-up biopsy clear-? significance
  • Incidental drug toxicity at 1 year 25
  • 48 in first 20 patients vs 18 in last 20
    patients

77
ALLOGRAFT FUNCTION Schwartz method in ml/min/1.73
m2
Steroid-free Steroid-based p value
Pre-transplant 13.55.9 14.57.9 0.48
6 months 99.431.9 85.329 0.03
12 months 90.722.8 76.426.1 0.01
24 months 103.439.5 74.131.8 0.009
36 months 48 months 92.727.3 89.424.6 72.225.6 69.730.3 0.01 0.01
78
HYPERTENSION- less severe in SF
Steroid-Free
Steroid-Based
p value
Pre-transplant Hypertension 60 67.4 0.1
Post-transplant Hypertension at 1 year 12.5 91.6 lt0.0001
New-onset Hypertension post-transplant 4 36.3 lt0.0001
Post-transplant Hypertension at 1 year with 2 drugs 4 27.7 lt0.0001

79
Hyperlipidemia Less in SF
80
Growth - Improved ? Height z-score in SF
Improved growth by 0.75-1.68 height SDS
(p0.0011) in SF 0-15 yrs age confirmed with 565
matched NAPRTCS SB 0-15 yr old patients
81
German Study Group on Pediatric Renal
Transplantation German Working Group for
Pediatric Nephrology (APN)
Contributing investigators
  • J Drube, L Pape, G Offner - Hannover
  • U John, J Misselwitz - Jena
  • H Fehrenbach - Memmingen
  • M Pohl - Freiburg
  • M Zimmering, J Gellermann, U Querfeld - Berlin
  • G Klaus Marburg
  • S Fründ, M Bulla - Münster

82
TWIST-Study
  • INVESTIGATOR MEETING FG-506-02-43 TWIST
    STUDY London, 01st August 2008
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