Early Termination of a Trial of Mycophenolate Mofetil for
Treatment of Interstitial Cystitis/Painful Bladder Syndrome:
Claire C. Yang,* David A. Burks,† Kathleen J. Propert, Robert D. Mayer,‡
Kenneth M. Peters,§ J. Curtis Nickel,? Christopher K. Payne,¶ Mary P. FitzGerald,**
Philip M. Hanno,†† Toby C. Chai,‡‡ Karl J. Kreder,§§ Emily S. Lukacz,??
Harris E. Foster, Liyi Cen, J. Richard Landis, John W. Kusek,¶¶ Leroy M. Nyberg
and the Interstitial Cystitis Collaborative Research Network
From the Departments of Urology, University of Washington (CCY), Seattle, Washington, Henry Ford Hospital (DAB), Detroit, Michigan, and
William Beaumont Hospital (KMP), Royal Oak, Michigan, Department of Biostatistics and Epidemiology (KJP, LC, JRL) and Division of
Urology (PMH), University of Pennsylvania, Philadelphia, Pennsylvania, Departments of Urology, University of Rochester (RDM), Rochester,
New York, Queen’s University (JCN), Kingston, Ontario, Canada, and Stanford University (CKP), Stanford and Department of Reproductive
Medicine, University of California-San Diego (ESL), La Jolla, California, Departments of Obstetrics and Gynecology, and Urology (MPF),
Loyola University, Maywood, Illinois, Division of Urology, University of Maryland (TCC), Baltimore and National Institute of Diabetes and
Digestive and Kidney Diseases (JWK, LMN), Bethesda, Maryland, Department of Urology, University of Iowa (KJK), Iowa City, Iowa, and
Department of Surgery (Urology), Yale University (JRL), New Haven, Connecticut
Purpose: We evaluated the efficacy and tolerability of mycophenolate mofetil
in patients with treatment refractory interstitial cystitis/painful bladder syn-
Materials and Methods: A total of 210 patients with interstitial cystitis/
painful bladder syndrome were to be randomized into a multicenter, placebo
controlled trial using a 2:1 randomization. Participants in whom at least 3
interstitial cystitis/painful bladder syndrome specific treatments had failed
and who had at least moderately severe symptoms were enrolled in a 12-week
treatment study. The primary study end point was the global response as-
sessment. Secondary end points were general and disease specific symptom
questionnaires, and voiding diaries.
Results: Only 58 subjects were randomized before a black box warning regarding
mycophenolate mofetil safety was issued by the manufacturer in October 2007.
The trial was halted, and interim analysis was performed and presented to an
independent data and safety monitoring board. Six of the 39 subjects (15%)
randomized at study cessation were considered responders for mycophenolate
mofetil compared to 3 of 19 controls (16%, p ? 0.67). Secondary outcome measures
reflected more improvement in controls.
Conclusions: In a randomized, placebo controlled trial that was prematurely
halted mycophenolate mofetil showed efficacy similar to that of placebo to treat
symptoms of refractory interstitial cystitis/painful bladder syndrome. The results
of this limited study cannot be used to confirm or refute the hypothesis that
immunosuppressive therapy may be beneficial to at least a subgroup of patients
with interstitial cystitis/painful bladder syndrome. Despite study termination
lessons can be gleaned to inform future investigations.
Key Words: urinary bladder; cystitis, interstitial; fetus; drug toxicity;
CyA ? cyclosporine
FSFI ? Female Sexual Function
GRA ? global response assessment
IC ? interstitial cystitis
MCS ? Mental Component Score
MMF ? mycophenolate mofetil
PBS ? painful bladder syndrome
PCS ? Physical Component Score
Submitted for publication June 21, 2010.
Study received institutional review board ap-
proval at all study sites.
Supported by National Institute of Diabetes and
Digestive and Kidney Diseases Cooperative Agree-
ments U01 DK65209, U01DK65255, U01DK65213,
U01DK65214, U01DK65215, U01DK65178,
U01DK65190, U01DK65192, U01DK65255,
U01DK65267, U01DK65271 and U01DK65202.
Supplementary material for this article can be
obtained at http://depts.washington.edu/uroweb/
* Correspondence: Department of Urology,
Box 356510, University of Washington, Seattle,
† Financial interest and/or other relationship
with Astellas, GlaxoSmithKline and Bayer.
‡ Financial interest and/or other relationship
with Bioform, Taris/Lipella, AbbeyMoore, Pfizer
THE JOURNAL OF UROLOGY®
© 2011 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
Vol. 185, 901-906, March 2011
Printed in U.S.A.
§ Financial interest and/or other relationship with Medtronic, Boston Scientific, Uroloplasty, Johnson & Johnson, Celgene, Allergan and Pfizer.
? Financial interest and/or other relationship with Merck, GlaxoSmithKline, Pfizer, Ortho Women’s Health, Farr Labs, Watson, Medtronic, NeurAxon, Genyous Biomed, Merck, Glaxo-Smith Kline,
Allergan, Watson, Pfizer, American Medical Systems, Astellas, Ortho McNeil and Taris.
¶ Financial interest and/or other relationship with Astellas, Allergan, Afferent, Celgene, Pfizer and Medtronic.
** Financial interest and/or other relationship with Astellas and Ferring.
†† Financial interest and/or other relationship with Astellas, Pfizer, Watson, Trillium and Tarus.
‡‡ Financial interest and/or other relationship with Pfizer, Allergan and National Institutes of Health.
§§ Financial interest and/or other relationship with Pfizer, Astellas and Medtronic.
?? Financial interest and/or other relationship with Pfizer, Watson, Novartis, Proctor and Gamble, Intuitive Surgical and Elsevier.
¶¶ Financial interest and/or other relationship with deCode Genetics.
INTERSTITIAL cystitis/PBS is a syndrome character-
ized by debilitating pain, pressure or discomfort re-
lated to bladder filling, usually accompanied by uri-
nary frequency to relieve pain and the urge to void.
Treatments to date have been empirical and inade-
quate, and there remains a pressing need for an effec-
tive oral treatment for IC/PBS. To our knowledge the
pathogenesis of the disorder is still undefined and a
number of theories based on clinical and experimental
observations have been advanced. A case for immune
dysregulation in at least a subset of patients with
IC/PBS can be made based on epidemiological, his-
topathological and clinical response criteria.1–6
If the etiology of IC/PBS is in part due to an induced
autoimmune/inflammatory disorder, immunosuppres-
sant therapy is a reasonable consideration for a treat-
ment trial. Methotrexate used in a small open label
study showed no significant effect on voiding patterns7
but 2 open label trials from Finland showed that CyA
produced short-term8and long-term9pain resolution,
decreased frequency and increased voided volume. A
well tolerated and significantly more effective than
pentosan polysulfate sodium (active control)10for con-
trolling symptoms in patients with severe IC/PBS.
MMF is commonly used in transplant recipients as an
antirejection agent combined with CyA and corticoste-
roids. While to our knowledge it has not been used for
inflammatory and autoimmune disorders, such as in-
flammatory uveitis,11systemic lupus erythematosis12
and lupus nephritis,13and Wegener’s granulomatosis.14
We performed a randomized, double-blind, placebo
controlled clinical trial of MMF in patients with IC/PBS
in whom previous therapy for this syndrome failed. The
agent was chosen since it was an immunosuppressant
drug with a reasonable safety profile. Also, CyA was not
of a placebo. Primary trial objectives were to compare 2
gm MMF daily to placebo for effects on overall IC/PBS
symptoms and well-being in patients with refractory IC/
PBS, and assess the medication safety profile.
Participants and Study Design
Men and women older than 18 years were recruited from
11 urology/urogynecology clinics in the United States and
Canada. All study sites obtained local institutional review
board approval. Eligibility required fulfillment of all of
certain criteria, including 1) persistent symptoms of uri-
nary frequency and pain rated at least 4 on a scale of 0 to
10, 2) failure of at least 24 weeks of active treatment with
a minimum of 3 standard forms of therapy or combination
of therapies for IC/PBS, 3) cystoscopic diagnosis of IC/PBS
in the past with findings of glomerulations and/or ulcer-
ations, and 4) screening cystoscopy within the 24 weeks
before study entry to evaluate for an unevaluated patho-
logical condition. There were additional exclusion criteria.
Except for medications listed in the exclusion criteria sub-
jects were allowed to continue on the current medication
Eligible participants were randomized to MMF or
matching placebo in a 2:1 ratio. For the first 14 days
subjects were instructed to ingest 1 gm MMF by mouth
daily. Subjects discontinuing the study drug during this
introduction/tolerability phase were followed until the
primary end point visit at 12 weeks. After successful
completion of this phase the full dose phase of 2 gm
daily in 2 divided doses was continued for 10 more
weeks. Laboratory values, including complete blood
count and liver enzymes, and physical symptoms were
closely monitored for adverse events at regular inter-
vals throughout the study. All subjects were treated and
followed for up to 16 weeks after randomization, includ-
ing 12 weeks of study treatment and 4 weeks after
treatment. Participants who withdrew before comple-
tion of the intervention phase were asked to complete
all outcome measures.
The primary efficacy outcome measure was GRA at 12
weeks. The GRA queries, “As compared to when you
started the current study, how would you rate your overall
pelvic symptoms now?” with 7 response categories. Partic-
ipants who indicated that they were moderately or mark-
edly improved were considered intervention responders.
Participants with missing GRAs were considered nonre-
sponders and included in the denominator to assess re-
Secondary measures obtained at baseline and 12 weeks
included a 24-hour voiding diary, ratings of pain and fre-
quency on a 10-point scale, and responses to validated
symptom questionnaires, including the McGill Pain Ques-
tionnaire,15O’Leary-Sant Interstitial Cystitis Symptom
and Problem Indexes,16SF-12® Health Status Question-
naire with separate calculation of PCS and MCS,17FSFI18
or Sexual Health Inventory for Men,19as appropriate, and
Hospital Anxiety and Depression Scale.20
The study was powered to detect a difference in GRA
response rates between 20% for placebo to 45% for MMF,
EARLY TERMINATION OF MYCOPHENOLATE MOFETIL FOR INTERSTITIAL CYSTITIS
a difference of 25%. Based on previous IC/PBS studies the
placebo response was estimated at 20%.21To achieve 90%
power to detect this 25% difference using 2:1 randomiza-
tion and 2-sided p ? 0.05 a minimum of 180 participants
was required. Sample size was increased by 15% to ac-
count for clinical center variation, that is 210 participants,
including 140 on MMF and 70 on placebo. Stratified per-
muted block randomization with variable block sizes by
clinical site was done to ensure balance across treatment
Standard descriptive statistics were used to summarize
baseline characteristics and study outcome measures at
each followup visit overall and in each treatment group.
The balance of baseline measures across the 3 treatment
groups was compared using appropriate k-sample tests,
including the Kruskal-Wallis and Fisher exact tests. Pri-
mary analysis compared GRA response rates using the
exact conditional test version of the Mantel-Haenszel test
to control for clustering by clinical center.22The pooled
rate difference and 95% CI across clinical centers were
calculated using the metan routine in Stata®, version
10.23For secondary efficacy outcomes changes from base-
line to 12 weeks were calculated in subjects with data at
each time point, not representing intent to treat analysis.
Comparisons of these changes between treatment groups
are also shown as the 95% CI, which was calculated using
standard normal based methods, not adjusting for cluster-
ing by clinical center.
Study recruitment began in April 2007. A black box
warning for MMF was issued by Roche Pharmaceu-
ticals on October 31, 2007.24The warning addressed
the change of the drug classification by the United
States Food and Drug Administration from a preg-
nancy category C (risk of fetal harm cannot be ruled
out) to category D (positive evidence of fetal risk).
The manufacturer recommendation was for female
subjects of child bearing potential to be contacted
immediately and for all subjects to be recounseled and
reconsented with specific attention to the require-
ments for 2 methods of effective contraceptive use be-
ginning 4 weeks before the study, use throughout the
study and for 6 weeks after stopping MMF. The
black box warning also addressed the risk of suscep-
tibility to infection and the possible development of
lymphoma. As a result of these warnings, study drug
delivery and all subject enrollment were suspended
on November 15, 2007, to remain in place until an
amended protocol and consent form were approved
by the institutional review board at each study site.
Slow recruitment of study participants up to this
point prompted the study data and safety monitor-
ing board to request interim analysis in January
2008, which identified observed decreased efficacy of
MMF compared to placebo. Due to a lack of treat-
ment efficacy, increased safety concerns due to the
black box warning and difficulty recruiting eligible
study participants the data and safety monitoring
recommended to the study sponsor (National Insti-
tute of Diabetes and Digestive and Kidney Diseases)
early termination of the study. This recommenda-
tion was accepted and the study was terminated on
February 4, 2008. The final analysis that we report
was performed in April 2008.
The figure shows the Consolidated Standards of
Reporting Trials. Table 1 lists baseline demographic
data by treatment arm on all 58 randomized sub-
jects. There were no differences in the distribution of
demographic characteristics between the 2 treat-
ment arms. Table 1 also shows select baseline symp-
tom scores. Overall baseline symptoms were moder-
ate to severe, that is 72% of subjects presented with
severe pain (7 to 10) and 79% presented with severe
frequency. Treatment groups were comparable
across all baseline measures evaluated.
GRA response rates in the MMF and placebo groups
were 15.4% and 15.8%, respectively (p ? 0.67). Table 2
shows the CI for the difference in response rates,
adjusted for center variability. The primary end
point was the 12-week response rate and the second-
ary end point was the change from baseline to 12
weeks. Responders were considered those reporting
markedly or moderately improved on GRA. Consis-
tent with intent to treat analytic strategies partici-
pants who did not provide data at 12 weeks (only 1,
who was on placebo) were considered treatment non-
responders. Given the single subject who did not
complete the study, additional noncompleter analy-
sis would not have changed the conclusions. Eight
subjects on placebo and 14 on MMF were not on drug
at the primary end point due to study suspension, as
Total Contacted: n=796
Randomized: n=58 (Target n=271)
Arm A (n=39)
Arm B (n=19)
Withdrawal (reason not specified): n=1
Ineligible: (“pre-screening failure”) n=570
Declined to participate:*
e t se r e t n i t oN
Does not consider study beneficial
Concerns about research process
Not bothered enough by symptoms
= n (
) 08 d
Did not complete pre-screening
due to study suspension: n=10
Consented: (“Agreed to participate”)
Did not complete screening
due to study suspension
*6 participants declined to participate
for multiple reasons
Consolidated Standards of Reporting Trials diagram shows flow
of subjects through study phases by treatment arm.
EARLY TERMINATION OF MYCOPHENOLATE MOFETIL FOR INTERSTITIAL CYSTITIS
described. When these subjects were excluded from
analysis, ie removed from the intent to treat process,
the responder rates were 2 of 25 on MMF (8%) and 3
of 11 (27.3%) on placebo.
Table 2 also lists changes in select symptom out-
comes from baseline to 12 weeks by treatment arm
and provides the CI for these differences. This anal-
ysis does not strictly represent intent to treat anal-
ysis since it was based only on subjects with com-
plete data. No comparisons for these secondary end
points were statistically significant at the more
stringent p ? 0.01 typically used for statistical com-
parisons of secondary end points. At the primary
end point 19 subjects (50%) in the treatment arm
were not receiving study drug due to study suspen-
sion (14) or drug tolerability (5).
Table 3 shows the cumulative numbers of partic-
ipants with at least 1 adverse event subdivided by
the primary body system or specific itemized catego-
ries for each treatment arm. Overall at least 1 mild,
at least 1 moderate and at least 1 severe adverse
event was reported by 16 (28%), 15 (26%) and 16
(28%) of the 58 study participants, respectively.
Table 2. Primary and select secondary symptom outcomes
No. SubjectsMMF No. SubjectsPlacebo % Difference (95% CI)*
No. subjects randomized/analyzed
No. primary end point (%)†
Mean ? SD secondary end points:
IC Symptom Index
IC Problem Index
Total McGill Pain Questionnaire
Hospital Anxiety ? Depression Scale
?0.5 ? 2.0
?0.7 ? 2.0
?1.0 ? 2.1
?0.8 ? 3
?0.7 ? 3
?2.5 ? 8
0.0 ? 10
?0.9 ? 6
?1.4 ? 8.8
0.0 ? 6
?1.9 ? 2.1
?1.8 ? 1.9
?1.9 ? 2.1
?1.8 ? 4
?1.7 ? 4
0.6 ? 10
?4.6 ? 10
2.9 ? 6
?6.7 ? 11.4
?4.9 ? 7
(?8.2, 2.1) 37
4.6 (?1.3, 10.5)
5.4 (?0.8, 11.5)
4.9 (1.5, 8.3)
* Positive secondary end point values indicate greater improvement in placebo group.
† Patients with missing GRA were considered nonresponders and included in denominator to assess response rate using intent to treat analysis.
Table 1. Baseline characteristics by treatment group
No. female (%)
Mean ? SD age
No. race (%):
Multirace, Asian, other
No. ever diagnosed with
Mean ? SD yrs:
Since diagnosis, if applicable
Since initial symptom onset†
Mean ? SD Score (range
Mean ? SD IC index:
Mean ? SD SF-12:
Mean ? SD total FSFI
Mean ? SD total McGill Pain
51.3 ? 10.3
51.8 ? 11.6
6.4 ? 4.1
13.8 ? 12.0
6.3 ? 5.9
14.4 ? 14.4
6.9 ? 1.5
7.1 ? 1.8
7.7 ? 1.4
7.2 ? 1.2
7.1 ? 1.7
7.4 ? 1.8
15.7 ? 3
12.9 ? 3
15.1 ? 3
12.8 ? 3
34.9 ? 10
42.6 ? 11
14.0 ? 10
21.5 ? 10.4
34.8 ? 11
38.3 ? 13
11.5 ? 9
21.5 ? 11.3
* Baseline symptom scores represent average of measurements made at 2
baseline visits with data missing on at most 1 subject per arm for all measures
except initial symptom onset and voiding frequency.
† Data missing on 8 subjects per arm.
‡ Data missing on approximately 9 subjects per arm.
Table 3. Significant cumulative adverse events by body
system and treatment group
At least 1 adverse event
Constitutional symptoms (primarily fatigue,
Gastrointestinal (primarily nausea, constipation,
Neurological (primarily dizziness, anxiety)
Pain, primarily headache
Benign viral syndromes
* Subject may be in more than 1 category.
EARLY TERMINATION OF MYCOPHENOLATE MOFETIL FOR INTERSTITIAL CYSTITIS
Thus, 47 of 58 participants (81%) reported at least 1
adverse event. There was no statistically significant
difference in overall adverse event rates between the
MMF and control treatment arms (87% vs 68%,
p ? 0.09). There were 2 reported serious adverse
events in the treatment arm. Neither event required
unmasking of treatment and each subject continued
on study. One event was determined to be unrelated
to treatment (narcotic withdrawal) and 1 was deter-
mined to be possibly related to treatment (asthma
The etiology and pathophysiology of IC/PBS remain
obscure. The rationale for selecting MMF for this trial
was based on evidence that immune system dysregu-
lation/autoimmunity has a role in the perpetuation of
IC/PBS symptoms. The evidence includes the age and
sex distribution of patients with IC/PBS, which is sim-
ilar to those of known autoimmune diseases,25the
clinical concordance of IC/PBS with other established
autoimmune diseases26and the efficacy of immuno-
suppressive drugs for IC/PBS,7,10,27mostly in small
case series. However, scientific investigation of blad-
der tissue has failed to produce any strong indication
that autoimmune complexes are consistently associ-
ated with IC/PBS.
Sairanen et al performed a randomized, con-
trolled trial showing that 75% of patients responded
to CyA compared to only 19% on pentosan polysul-
fate.10These compelling data led to our interest in
assessing immunotherapy in a well designed, pla-
cebo controlled study. We believed that the risks of
immunosuppressive therapy were outweighed by
the morbidity experienced by patients with a severe
albeit benign disease. We tried to perform such an
investigation with CyA but were unable to have
placebo pills made. Ultimately MMF was chosen
based on strongly positive data presented as an ab-
stract at a 2003 National Institutes of Health Inter-
stitial Cystitis research meeting (unpublished data).
Unfortunately, as described, the study was inter-
rupted by unforeseeable events and then appropri-
ately halted due to futility analysis. It should be
emphasized that 19 of the 39 subjects randomized to
the study drug were not receiving it at the primary
end point, including 14 due to study suspension,
strongly biasing the study toward a negative result
and limiting the interpretation of tolerability and
other data related to drug ingestion. However, re-
sults in aggregate do not indicate that further inves-
tigation of the specific drug MMF would be fruitful.
What lessons can we take away from this effort
that will inform future investigators? 1) MMF was
reasonably well tolerated. Risks of immunosuppres-
sive therapy include general risks of cytopenia, in-
fection and promotion of malignancy as well as spe-
cific risks unique to individual drugs. Overall 87% of
subjects on the active agent experienced an adverse
event compared to 68% on placebo with grade 3
adverse events in 31% vs 21%. There were no grade
3 infectious events and no significant cytopenia.
These data suggest that further research in immu-
nosuppressive therapy is reasonably safe with a
need for specific precautions related to the drug to be
studied. Notably long-term risks, such as malig-
nancy, cannot be assessed in a short-term trial.
2) Recruitment was difficult. A much higher propor-
tion of interested and otherwise eligible patients were
excluded from study than in other randomized trials
for IC/PBS. This was primarily due to the exclusion
criteria mandated for prior malignancies or premalig-
nant conditions, including cervical dysplasia, colon
polyps and any skin cancer, including basal cell can-
cer. Projected risks were largely based on experience
with these drugs in the transplant community, in
which triple therapy including steroids is standard.
There are inadequate data on the risk of immunosup-
pressive agents as monotherapy. It is conceivable that
risks to subjects who receive monotherapy are much
difficult to investigate immunosuppressive therapy
until other studies of the drugs used as monotherapy
allow for relaxed exclusion criteria.
3) The rationale for selecting MMF was based on
less than solid reasoning. Although an immunosup-
pressant agent (CyA) was effective for IC/PBS symp-
toms, it does not necessarily follow that another
immunosuppressant drug (MMF) would also be ef-
fective. CyA and MMF inhibit T-cell function but
through different mechanisms.28Immunosuppression
medications have multiple immune and nonimmune
effects, which are not all defined for each agent. There
is no compelling evidence that IC is a purely T-cell
mediated condition and, thus, the immunosuppres-
sant mechanism(s) of MMF may not be effective for
IC/PBS. However, although MMF is not the ideal
of other immunosuppressant medications.
In a multicenter, randomized, placebo controlled
trial that was prematurely halted MMF showed ef-
ficacy similar to that of placebo to treat refractory
IC/PBS symptoms. The results of this limited study
cannot be used to confirm or refute the hypothesis
that immunosuppressive therapy may be beneficial
to at least a subgroup of patients with IC/PBS. De-
spite the study termination lessons can be gleaned
to inform future investigations.
EARLY TERMINATION OF MYCOPHENOLATE MOFETIL FOR INTERSTITIAL CYSTITIS
APPENDIX Download full-text
Study Group Participants
In addition to the authors, the Interstitial Cystitis Collaborative Research Network Study Group includes the following institutions and individuals: Robert Mayer,
Edward Messing, Elizabeth Betty Smith, Kay Rust and Jay Reeder, University of Rochester (8 subjects randomized at center); Eleanor Anton, Cheryl Wolfert and Loni
Lampkins, William Beaumont Hospital (8); Alvaro Morales, Laurel Emerson, Lesley Carr, Joseph Downey, Janet Clark-Pereira and Sylvia Robb, Queen’s University
(7); Rajesh Shinghal, Rodney Anderson, Debra Clay and Anna Ramakrishnan, Stanford University (7); Linda Brubaker, Judy Senka, Lucia Radukanu, Janet Rindels
and Grace Bucher, Loyola University Medical Center (6); Diane K. Newman, Sylvia Salazar, Jennifer Milado and Gia Deleon, University of Pennsylvania (6); Susan
Keay, Rosanna Dinh, Rupali Sangrampurkar, Judith Murray and Lisa Radebaugh, University of Maryland (4); Michael O’Donnell, Susan Lutgendorf, Mary Eno and
Kelly O’Berry, University of Iowa (4); Jane Miller, Jean Kalhoff, Sharon Downing and Robert F. Bale, Jr., University of Washington (3); Charles Nager and Marianne
Chenoweth, University of California-San Diego (3); Kandis Rivers, Samina Romero, Michelle Peabody and Jill Sullivan, Henry Ford Hospital (2); Keith Mickelberg,
Ted Barrell, Shannon Chuai and Rosemary Madigan, Data Coordinating Center, University of Pennsylvania School of Medicine; Christopher Mullins and Mary Harris,
National Institute of Diabetes and Digestive and Kidney Diseases; and Vickie Ratner, Interstitial Cystitis Association.
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