1. IMPROVED GASTROINTESTINAL TOLERABILITY IN RENAL TRANSPLANT PATIENTS CONVERTED FROM LOW-DOSE MMF TO AN EQUIMOLAR DOSE OF ENTERIC-COATED MYCOPHENOLATE SODIUM (MYFORTIC®)
E. Minetti, MP. Scolari, ML. Perrino, S. Stefoni, S. Marchini, B. Giacon, P. Passerini, E. Sestigiani, D. Dissegna, G. Tisone and
M. Salvadori
for the CERL080AIT01 Study Group
7th New Trends in Immunosuppression Meeting
Berlin, February 16-19, 2006

2. Increased risk of rejection2-3 & graft loss4
Background
Although MMF has provided proven graft protection, up to 40% of patients experience distressing GI problems1
GI side effects are dose dependent1 , can be reduced by dose reduction/interruption/discontinuation
subtherapeutic dosing
Increased risk of rejection2-3 & graft loss4
Mycophenolic acid administered as mycophenolate mofetil (MMF, Cellcept®), is a widely used antiproliferative agent as part of combined immunosuppressive therapy following renal transplantation and offers both short-term (3, 4) and long-term (5, 6) efficacy benefits. However, the side-effect profile notably gastrointestinal (GI) complications (7), can limit its clinical benefits. These GI side effects which have a reported incidence of up to 40% are dose dependant and can lead to dose reduction or interruption increasing the risk of acute rejection or graft loss as reported in two retrospective analysis conducted by Pelletier and Knoll et al.
1. European MMF Cooperative Study Group. Lancet 1995; 345:
2. Pelletier RP. Am J Transplant 2002; S3: 467
3. Knoll GA et al. J Am Soc Nephrol 2003; 14: 2381
4. Hardinger KL et al. Transpl Int 2004; 17:

3. Aims of the MMF to EC-MPS conversion study
To assess:
safety and efficacy of equimolar conversion from MMF (dose < 2 g/day) to EC-MPS
the incidence and severity of GI adverse events before and after conversion
the impact of gastrointestinal (GI) symptoms on GI-specific Quality of Life (QoL)

4. Evaluation criteria
Serum creatinine, hematobiochemistry and vital signs
Physicians’ assessment of presence/severity of GI symptoms (16-item check list)
Patient reported outcomes:
GI specific Quality of life (GIQLI)
Visual-analog scale (100 mm) for upper and lower GI symptoms
Picture of VAS

5. Study design Multicenter, open-label, longitudinal, single arm study.
Enrollment Equimolar Conversion End of study
Observational Phase
MMF
Treatment Phase
EC-MPS
W W W W W16
GI check list X X X X X
SCr, BP X X X X X
GIQLI X X X
VAS X X X X X
This study was

6. Inclusion/exclusion criteria
Kidney transplant at least 6 months previously with:
MMF dose < 2 g/day in combination with CsA
Stable renal function and no acute rejection in the last two months
Serum creatinine  2,5 mg/dl
Absence of anemia or cytopenias

7. Patient Characteristics
No of patients
Recipient age: year (SD)
Male sex
Time since tx: months (SD)
1st transplant
Deceased donor
CsA mean dose (mg/kg/day)
140
50.912.2
88 (63%)
53.243.3
127 (91%)
130 (93%)
2.60.85

8. MMF dose at conversion and reason for previous MMF dose reduction
Reasons for previous MMF dose reduction
N° of patients
MMF dose
% of patients
5. Slide should describe inclusion and exclusion criteria
mg/day
Patients may have more than one reason for MMF dose reduction

9. Safety of conversion: hematobiochemistry and vital signs
MMF (W8)
EC-MPS (W16)
Serum creatinine (mg/dL)
1.56  0.44
1.57  0.42
Blood pressure: systolic
diastolic
133.8  14.7
82.2  8.28
135.3  16.4
82.2  8.75
Hb (mg/dL)
13.0  1.73
13.0  1.88
WBC count (1012/L)
6.68  2.09
6.88  2.23
Platelet count (1012/L)
222.4  55.6
226.9  55.7

10. Percentage of patients with GI Symptoms according to check list%
Upper GI
MMF W8
EC-MPS W16
p<0.05
Lower GI

11. GIQLI total Score before and after conversion
GIQLI total score (max score=144) NS
p< 0,0022
Improvement
1) Eypasch E, et al (1995). Br J Surg; 82(2):

12. Presence and severity of GI-symptoms
None
Mild
Moderate/Severe
22.1%
20.3%
36.8%
conversion
45.7%
32.2%
43.9%
MMF W8
p<0.0001
EC-MPS W16

13. Mean Values of GI-Symptom VASmm
MMF
EC-MPS NS NS
P<0.05
P<0.05
Improvement
W0 W8 W16
W0 W8 W16

14. Conclusions
The presence of GI complications in MMF treated patients and their impact on GI specific HRQoL seems to be underestimated
Equimolar conversion from MMF to myfortic:
is safe in maintenance renal transplant patients
Decreases the frequency and severity of GI symptoms
improves Patient Reported Outcomes (GIQLI and VAS) significantly

15. Participating centers
MILANO, Osp. Niguarda G. Civati, E. Minetti
BOLOGNA, Pol. S. Orsola S. Stefoni, MP. Scolari
PADOVA, Osp. Policlinico E. Ancona, P. Rigotti
BOLZANO, Osp. Centrale W. Huber, B. Giacon
MILANO, Osp. Policlinico PG. Messa, G. Montagnino
BOLOGNA, Pol. S.Orsola A. Santoro
SIENA, Pol. Le Scotte M. Carmellini, A. Bernini
PALERMO, Osp. Civico V. Sparacino
UDINE, Osp. S. Maria M. G. Mioni, D. Montanaro
VICENZA, Osp. S. Maria Ronco, S. Chiaramonte
ROMA, Osp. S. Eugenio G. Tisone
FIRENZE, Pol. Careggi M. Salvadori

16. Possible questions and backup
Gastroprotection would protect upper GI but you showed a reduction of diarrhea also: how could you explain that?

17. Patient disposition MMF Myfortic No. enrolled Discontinued
Withdrew consent
Adverse event
Protocol violation
Unsatisfactory therap. Effect
Lost to follow-up
Study phase completion
MMF
162 22 7 2 10 1
140
Myfortic 6 -
134
4. slide should describe study design including all visits

18. Myfortic treatment discontinuation backup
Pat.
02/07
02/22
08/15
12/01
14/07
14/09
Age
53/M
50/M
54/F
57/M
53/F
71/F
Dose
360
720
1080
Reason AE
Adverse Event
Anxiety, limbs formication
Headache, erythema, meteorism
Herpes Zoster
Nausea, eructation, acid reflux
GI symptom worsening
Pre-existing bladder cancer

19. Other drug-related AE backup
Pat.
02/09
02/11
05/01
05/07
08/11
Age
43/F
65/F
49/F
59/M
52/F
Type AE
Inf.
Event
Headache, abdominal pain
Leucopenia
Abdominal distension
Diarrhea
Polioma virus, irritability
Dose changes
Dose reduction
No change

20. GIQLI weighted subscales before and after conversion
MMF W8
EC-MPS W16
P<0.0001 NS NS NS NS

21. GI symptoms severity and QoL (GIQLI total score) after MMF and EC-MPS treatment
Bubble size indicate the
% of pts in each category
GIQLI
MMF W8
EC-MPS W16
Deterioration Improvement
none
mild
mod./
severe
none
mild
mod./
severe
Highest GI symptom severity

22. Study rationale
The standard dose of MMF after renal transplantation is 2 g/day
Many patients suffer from GI adverse events, so the dose of MMF needs to be reduced or withdrawn1
The new formulation of sodium mycophenolate (EC-MPS, myfortic®) has been shown to be effective and safe in de novo and also in maintenance patients converted from MMF to EC-MPS on equimolar basis 2,3
1) Knoll GA et al (2003). J Am Soc Nephrol;
2) Budde K et al. (2004). Am J Transplant;
3) Salvadori M et al. (2004). Am J Transplant;