Campath, calcineurin inhibitor reduction and chronic
allograft nephropathy (3C) study: background,
rationale, and study protocol
Authors: Richard Haynes1, Colin Baigent1, Paul Harden2, Martin Landray1, Murat
Akyol3, Argiris Asderakis4, Alex Baxter1, Sunil Bhandari5, Paramit Chowdhury6,
Marc Clancy7, Jonathan Emberson1, Paul Gibbs8, Abdul Hammad9, Will Herrington1,
Kathy Jayne1, Gareth Jones10, Nithya Krishnan11, Michael Lay1, David Lewis1, Iain
Macdougall12, Chidambaram Nathan13, James Neuberger14, Chas Newstead15, Ravi
Pararajasingam16, Carmelo Puliatti17, Keith Rigg18, Peter Rowe19, Adnan Sharif20, Neil
Sheerin21, Sanjay Sinha22, Chris Watson23, Peter Friend24
Publication date (Electronic): 6 May 2013
Source: PMC ID: 3674985
Journal: Transplantation Research
Publisher: BioMed Central
License: This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in any medium, provided the
original work is properly cited.
Author and article information
 Clinical Trial Service Unit & Epidemiological Studies Unit, Richard Doll
Building, Old Road Campus, Roosevelt Drive, Headington Oxford OX3 7LF, UK
 Oxford Kidney Unit, Churchill Hospital, Headington, Oxford OX3 7LJ, UK
 Royal Infirmary of Edinburgh, Little France Crescent, Edinburgh EH16 4SA, UK
 University Hospital of Wales, Heath Park, Cardiff CF4 4XW, UK
 Hull Royal Infirmary, Anlaby Road, Hull HU3 2JZ, UK
 Guy’s Hospital, St Thomas Street, London SE1 9RT, UK
 Western Infirmary, Dumbarton Road, Glasgow G11 6NT, UK
 Queen Alexandra Hospital, Cosham, Portsmouth PO6 3LY, UK
 Royal Liverpool University Hospital, Prescot Street, Liverpool L7 8XN, UK
 Royal Free Hospital, Pond Street, London NW3 2QG, UK
 University Hospitals Coventry and Warwickshire NHS Trust, Clifford Bridge
Road, Coventry, West Midlands CV2 2DX, UK
 King’s College Hospital, Denmark Hill, London SE5 9RS, UK
 Northern General Hospital, Herries Road, Sheffield S5 7HU, UK
 NHS Blood and Transplant, Stoke Gifford, Bristol BS34 8RR, UK
 St James’s University Hospital, Beckett Street, Leeds LS9 7TF, UK
 Manchester Royal Infirmary, Oxford, Manchester M13 9WL, UK
 Royal London Hospital, Whitechapel, London E1 1BB, UK
 City Hospital, Hucknall Road, Nottingham NG5 1PB, UK
 Derriford Hospital, Derriford Road, Plymouth PL6 8DH, UK
 Queen Elizabeth Hospital, Edgbaston, Birmingham, West Midlands B15 2TH,
 Freeman Hospital, High Heaton, Newcastle-upon-Tyne NE7 7DN, UK
 Oxford Transplant Centre, Churchill Hospital, Headington, Oxford OX3 7LJ, UK
 Addenbrooke’s Hospital, Cambridge CB\2 2QQ, UK
 Churchill Hospital, Headington, Oxford OX3 7LJ, UK
The 3C Study Collaborative Group
Richard Haynes: email@example.com.
Colin Baigent: firstname.lastname@example.org.
Paul Harden: email@example.com.
Martin Landray: firstname.lastname@example.org.
Murat Akyol: email@example.com.
Argiris Asderakis: firstname.lastname@example.org.
Alex Baxter: email@example.com.
Sunil Bhandari: firstname.lastname@example.org.
Paramit Chowdhury: email@example.com.
Marc Clancy: firstname.lastname@example.org.
Jonathan Emberson: email@example.com.
Paul Gibbs: firstname.lastname@example.org.
Abdul Hammad: email@example.com.
Will Herrington: firstname.lastname@example.org.
Kathy Jayne: email@example.com.
Gareth Jones: firstname.lastname@example.org.
Nithya Krishnan: email@example.com.
Michael Lay: firstname.lastname@example.org.
David Lewis: email@example.com.
Iain Macdougall: firstname.lastname@example.org.
Chidambaram Nathan: Chidambaram.email@example.com.
James Neuberger: firstname.lastname@example.org.
Chas Newstead: email@example.com.
Ravi Pararajasingam: firstname.lastname@example.org.
Carmelo Puliatti: email@example.com.
Keith Rigg: firstname.lastname@example.org.
Peter Rowe: email@example.com.
Adnan Sharif: firstname.lastname@example.org.
Neil Sheerin: email@example.com.
Sanjay Sinha: firstname.lastname@example.org.
Chris Watson: email@example.com.
Peter Friend: firstname.lastname@example.org.
Journal ID (nlm-ta): Transplant Res
Journal ID (iso-abbrev): Transplant Res
Title: Transplantation Research
Publisher: BioMed Central
ISSN (Electronic): 2047-1440
Publication date (Collection): 2013
Publication date (Electronic): 6 May 2013
Copyright statement: Copyright ©2013 Haynes et al.; licensee BioMed Central Ltd.
Subject: Clinical Trial Protocol
Randomized controlled trial
Kidney transplantation is the best treatment for patients with end-stage renal failure,
but uncertainty remains about the best immunosuppression strategy. Long-term graft
survival has not improved substantially, and one possible explanation is calcineurin
inhibitor (CNI) nephrotoxicity. CNI exposure could be minimized by using more
potent induction therapy or alternative maintenance therapy to remove CNIs
completely. However, the safety and efficacy of such strategies are unknown.
The Campath, Calcineurin inhibitor reduction and Chronic allograft nephropathy (3C)
Study is a multicentre, open-label, randomized controlled trial with 852 participants
which is addressing two important questions in kidney transplantation. The first
question is whether a Campath (alemtuzumab)-based induction therapy strategy is
superior to basiliximab-based therapy, and the second is whether, from 6 months after
transplantation, a sirolimus-based maintenance therapy strategy is superior to
tacrolimus-based therapy. Recruitment is complete, and follow-up will continue for
around 5 years post-transplant. The primary endpoint for the induction therapy
comparison is biopsy-proven acute rejection by 6 months, and the primary endpoint
for the maintenance therapy comparison is change in estimated glomerular filtration
rate from baseline to 2 years after transplantation. The study is sponsored by the
University of Oxford and endorsed by the British Transplantation Society, and 18
centers for adult kidney transplant are participating.
Late graft failure is a major issue for kidney-transplant recipients. If our hypothesis
that minimizing CNI exposure with Campath-based induction therapy and/or an
elective conversion to sirolimus-based maintenance therapy can improve long-term
graft function and survival is correct, then patients should experience better graft
function for longer. A positive outcome could change clinical practice in kidney
ClinicalTrials.gov, NCT01120028 and ISRCTN88894088
Main article text
Kidney transplantation is well established as the best treatment for patients with end-
stage renal failure . Despite significant advances in short-term graft survival over
the past two decades, these have not been matched by improved long-term graft
survival . Long-term graft survival has many implications both for individual
patients (who generally enjoy a better quality of life than when on dialysis) and for
healthcare providers (after the initial cost surrounding the operation, the cost of
maintaining a graft is less than that of dialysis). The 1-year graft survival rates are
now more than 90%, so there is considerable interest in strategies that can maximize
the life span of renal transplants.
There are many potential causes of late graft failure, with the most common being
interstitial fibrosis/tubular atrophy (IF/TA) . IF/TA is believed to be the end result
of various types of graft damage, including preservation damage, rejection,
calcineurin inhibitor (CNI) toxicity, hypertensive vascular disease, and viral infection.
Functional studies significantly underestimate the incidence of histological graft
injury, with one study showing that 94% of grafts had histological evidence of IF/TA
at one year . This same study concluded that much of the chronic damage is due to
CNI toxicity, even though the levels of these drugs in the study had been maintained
within the target range. For this reason, many recent studies have focused on reducing
exposure to CNIs, and these have generally shown that this strategy produces better
medium-term outcomes (for example, graft function at 1 year) . There are two
potential strategies to minimize CNI exposure: more potent induction therapy could
be used safely to allow dose reduction or avoidance of CNIs, or CNIs could be
replaced by a different class of immunosuppressant that is less likely to damage the
Campath is a potent induction agent
Campath (alemtuzumab) is a humanized monoclonal antibody directed against CD52,
and causes depletion of lymphocytes. It was first studied in kidney transplantation as a
potential treatment for acute rejection. In a small non-randomized pilot study of 12
patients, it appeared to be effective, but was associated with severe infective episodes
. The dosage was revised from seven daily doses of 10 mg each to five daily doses
of 6 mg each, and no further severe infections occurred in the five patients who
received the less potent regimen. It has since been used as induction therapy in many
centers; over 1,500 transplants in the USA received Campath induction during the 2-
year period of 2003 to 2004 .
Until recently there have been very few data on the safety and efficacy of Campath
from randomized controlled trials. A systematic review of Campath as induction
therapy identified five studies comparing Campath with interleukin-2 receptor
antagonist induction, and identified a significant reduction in the risk of acute
rejection (relative risk (RR) = 0.54; 95% confidence interval (CI) 0.37 to 0.79), but no
effect on short-term graft survival (RR = 1.06; 95% CI 0.64 to 1.78) . However,
there were only 659 patients in total included in these trials, so substantial uncertainty
remains over the efficacy and safety of Campath. The largest trial to date was the
INTAC (Induction with TACrolimus) trial, which compared Campath with
basiliximab in 335 low-risk patients (defined by non-black ethnicity, first transplant,
and panel reactive antibody (PRA) level <20) . At 1 year, the rate of biopsy-proven
acute rejection was 3% in participants allocated Campath versus 22% in those
allocated basiliximab (P<0.001). There was a small excess risk of serious infection in
participants allocated Campath (57 versus 38 events, P = 0.02), but not of any
infection (129 versus 123 events, P = 0.17). However, the INTAC trial did not
attempt to spare CNI after Campath: all participants received the same maintenance
immunosuppression of tacrolimus (target trough concentration 7 to 14 ng/ml for 6
months then reducing to 4 to 12 ng/ml), mycophenolate mofetil (2 g/day) and
corticosteroids (1 g or less prednisolone equivalent during the first 5 days), so
substantial uncertainty remains over the safety and efficacy of Campath as part of a
Sirolimus as a potential replacement for calcineurin inhibitors
Sirolimus is a macrocyclic lactone, and has a different mechanism of action to CNIs.
It blocks the mammalian target of rapamycin pathway, thus inhibiting cellular
proliferation. Sirolimus has been used in a variety of strategies for kidney
transplantation. It was initially used de novo (in conjunction with ciclosporin) but is
not as effective as CNIs during the high-risk post-operative period, and the doses
required to prevent rejection (including a high loading dose) were associated with
unacceptable adverse effects . Trials of late conversion to sirolimus failed to show
any benefit , but more recently trials of early (that is, within 3 to 6 months post-
transplant) conversion to sirolimus have shown potential. The CONCEPT study
randomized 192 kidney-transplant recipients to remain on a ciclosporin-based
regimen or to switch to a sirolimus-based regimen at 3 months after transplantation.
The patients allocated to sirolimus had better graft function at 1 year compared with
the ciclosporin-allocated group (Cockcroft-Gault glomerular filtration rate 68.9 versus
64.4 ml/min, P=0.017) with no significant excess of acute rejection . A similarly
designed study using everolimus (initiated at 4.5 months post-transplant) in 300
patients also showed a highly significant increase in eGFR at 1 year after transplant
(eGFR 71.8 versus 61.9 ml/min/1.73m2, P<0.0001) . The benefits appear to be
durable in the medium term , but whether these translate into differences in
clinical outcomes such as graft failure remains uncertain.
Campath and sirolimus in tolerance
The combination of Campath and sirolimus may enable exposure to CNIs to be
reduced or eliminated. This could be favorable because CNIs are nephrotoxic and
may interfere with tolerogenesis . It is known that ischemia-reperfusion injury
occurring during organ implantation enhances the activation of the immune system
. Depleting induction agents profoundly reduce the number of circulating
lymphocytes capable of mounting an immune response during this period. It has been
suggested that by the time the peripheral lymphocytes return, the graft may have
recovered from the injury, and will therefore be immunologically quiescent .
Studies examining the use of Campath followed by either tacrolimus  or sirolimus
 monotherapy have had encouraging results, consistent with (but not yet proving)
the concept of donor-specific hyporesponsiveness suggested by Calne when he
proposed the term prope (almost) tolerance .
Sirolimus is also potentially tolerogenic; it increases the number of CD4+ cells with a
regulatory phenotype (Treg cells) . Treg cells dampen the effector response to
antigenic challenge and are a crucial element of peripheral tolerance. Furthermore, in
addition to its effects on tolerance-promoting Treg cells, sirolimus facilitates the
deletion of effector alloreactive T cells . In combination, Campath and sirolimus
have been shown to induce donor-specific hyporesponsiveness, as assessed by in vitro
tests . This is obviously encouraging, and merits further investigation.
Based on these observations, we have designed a clinical trial with the purpose of
testing whether Campath and/or sirolimus can improve long-term outcomes after
Basic protocol overview
The 3C Study is an open-label, randomized multi-center trial comparing 1) Campath-
based and basiliximab-based induction therapy strategies; and 2) from about 6 months
after transplantation, sirolimus-based and tacrolimus-based maintenance therapy
strategies. The study is planned to take about 7 years, with recruitment of the 852
participants taking 2 years, followed by a 5-year follow-up period.
Participants will be randomly allocated to receive either Campath-based or
basiliximab-based induction therapy before transplantation. All participants will then
receive 6 months of tacrolimus-based maintenance therapy before being randomized
again (if they remain willing and eligible) to either sirolimus-based or tacrolimus-
based long-term maintenance therapy (Figure 1).
Flowchart showing study treatments and randomizations, including proposed
The 3C Study includes all patients eligible for kidney transplantation, including those
receiving kidneys from deceased donors (brain or circulatory death) and living
donors, as well as highly sensitized (defined as calculated reaction frequency >85%)
and previously transplanted recipients. The specific inclusion criteria are recipients of
a kidney-only transplant aged over 18 years.
Patients will be excluded if they: are pregnant; are receiving multi-organ transplants
(including kidney-pancreas transplants); have previously been treated with Campath;
have active infection including HIV or viral hepatitis; have a history of anaphylaxis to
humanized monoclonal antibodies; have a history of malignancy (except non-
melanoma skin cancer) that was diagnosed or recurred in the previous 5 years; have
lost a previous kidney transplant within 6 months not due to technical reasons; or have
a medical history that might limit their ability to take trial treatments for the duration
of the study.
Participants are eligible for the maintenance therapy randomization (sirolimus or
tacrolimus) if: 1) at about 6 months after transplantation, their urine protein excretion
rate is below 800 mg/day (urine protein:creatinine ratio <80 mg/mmol or
albumin:creatinine ratio <50 mg/mmol); and 2) they have not had biopsy-proven
acute rejection (Banff grade >1) in the previous 30 days.
The primary aims of the 3C Study are to assess the differences in 1) biopsy-proven
acute rejection among participants allocated Campath-based versus basiliximab-based
induction therapy (assessed at 6 months); and 2) graft function among all those
allocated tacrolimus-based versus sirolimus-based maintenance therapy (assessed at 2
years after transplantation).
Secondary aims include assessments of the study treatments (Campath versus
basiliximab, and tacrolimus versus sirolimus) on: 1) graft-related outcomes (including
graft survival, rates of biopsy-proven rejection); and 2) safety outcomes (including
infection [particularly opportunistic infections], malignancy and overall survival).
Randomization and treatment scheme
Participants will be randomized by an internet-based system before transplantation.
After the participant is registered on the internet-based system, they are assigned a
unique identifier (participant ID), and once randomized, the assigned treatment group
is displayed on the screen. Participants assigned Campath-based induction will
receive Campath 30 mg (intravenously or subcutaneously) after reperfusion of the
transplant (and a further 30 mg 24 hours later if they are ≤60 years old). Before the
first dose of Campath, patients will be given 500 mg methylprednisolone and 10 mg
chlorphenamine intravenously, but no further steroids will be given. Maintenance oral
immunosuppression will consist of mycophenolate sodium (360 mg twice daily) and
tacrolimus (starting at 2 mg twice daily from day 3, aiming for target trough
concentration 5 to 7 ng/ml). After 12 months, the mycophenolate sodium dose will be
reduced to 180 mg twice daily. Participants assigned basiliximab-based induction will
receive 20 mg basiliximab intravenously pre-operatively and on day 4, oral
mycophenolate sodium (540 to 720 mg twice daily) and oral tacrolimus (0.05 to 0.10
mg/kg twice daily, aiming for target trough concentration 5 to 12 ng/ml). Patients will
be given 500 mg methylprednisolone intravenously pre-reperfusion and maintenance
oral corticosteroids, starting at 15 to 20 mg prednisolone, to be reduced or withdrawn
completely in accordance with local practice (avoiding complete withdrawal 5 to 7
months post-transplantation; that is, around the time of the maintenance therapy
Participants can enter the maintenance-therapy randomization between 5 to 7 months
after transplantation, assuming no exclusion criteria apply. Participants allocated
tacrolimus-based maintenance therapy will continue their current therapy and the
target trough concentration is 5 to 7 ng/ml in all participants. Participants assigned
sirolimus-based maintenance therapy will stop tacrolimus after an evening dose and
start sirolimus the next morning at 3 mg daily (unless they weigh <60 kg, when 2 mg
daily will be used). Target trough concentration is 6 to 12 ng/ml for the first 6 months,
then reducing to 5 to 10 ng/ml. Advice will be given on mouth, care and a short
course of low-dose prednisolone can be used to cover the conversion period if the
local investigator considers it necessary. Mycophenolic acid levels are not routinely
monitored in the UK, so are not specified in this protocol.
Both randomizations use a minimization algorithm that ensures balance for recipient
age, ethnicity, type of transplant, human leukocyte antigen mismatch, sensitization
status (and for maintenance randomization, allocated induction therapy).
Other treatments (including cytomegalovirus and Pneumocystis prophylaxis) will be
left to the discretion of the local investigator. A summary of the treatment scheme and
flow of participants through the trial is shown in Figure 1.
Follow-up and documentation
During the first year after transplantation, all participants will be followed up at
discharge after transplantation and at 1, 3, 6, 9, and 12 months after transplantation.
Data will be collected on all serious adverse events (which include all episodes of
rejection and opportunistic infection for the purposes of this study), current
medication (including doses of immunosuppressive drugs), non-serious adverse
events considered to be related to one of the study treatments, along with blood
pressure and weight, and relevant laboratory values (including serum creatinine, full
blood count, lipid profile, and urine protein/albumin to creatinine ratio). Data will also
be collected on healthcare usage and quality of life to allow health economic analyses
to be conducted.
On a yearly basis, all participants will be sent an annual questionnaire to collect
information on serious adverse events, study treatments, healthcare usage, and quality
of life. In addition, all participants will be flagged with a number of national registries
so that their routinely collected data can be used for long-termfollow-up. These
registries include the UK Transplant Registry (which collects data on graft survival
and function), Office for National Statistics (which collects data on death), National
Health Service (NHS) Information Centre (which collects data on cancer), and the
Hospital Episode Statistics registry (which collects data on all hospital admissions).
The primary endpoint of the induction therapy comparison will be biopsy-proven
acute rejection during the first 6 months after transplantation. The Banff classification
definition (including those of the various subtypes) will be used. The histological
appearances of cellular rejection after depleting induction with alemtuzumab are
usually typical (despite the profound lymphopenia) . All reports of rejection
(including events that may yield a diagnosis of rejection (for example, transplant
biopsy) will be adjudicated by trained clinicians, blinded to study treatment
allocation, at the coordinating center. The date of the rejection will be the date of the
The primary endpoint of the maintenance therapy comparison will be change in graft
function (estimated using the four-variable Modification of Diet in Renal Disease
(MDRD) formula ) from 6 months to 2 years after transplantation.
Secondary endpoints for both comparisons will include safety outcomes (including
infection and cancer) and long-term outcomes (including graft and patient survival).
The 3C Study is an investigator-initiated trial. Preliminary investigator meetings were
organized by the University of Oxford, which is the sponsor of the study. The trial is
funded by grants from the UK National Health Service Blood and Transplant
Research and Development fund, Pfizer (Collegeville, PA, USA), and Novartis UK.
Major kidney transplant centers from the UK (18 sites in total) will be participating in
the study. Such a collaboration is required in order to recruit the planned number of
kidney-transplant patients needed to provide statistically reliable and clinically
Study drugs will be purchased by participating hospitals, and the Campath will be
relabeled by local hospital pharmacies in accordance with the EU Clinical Trial
Directive. The other investigation medicinal products (basiliximab, tacrolimus, and
sirolimus) will be exempt from the EU Clinical Trial Directive requirements for
labeling and accountability, as they will be used within the terms of the marketing
authorization. All treatments will be used on an open-label basis.
Before recruitment started, all sites were visited by the sponsor in order to train the
relevant staff in the study procedures. Recruitment rates and completeness of follow-
up data will be monitored closely by the sponsor. Sites will be monitored during
recruitment and follow-up through a combination of on-site visits from the sponsor
and central statistical monitoring. An independent data monitoring committee (DMC)
has been convened (see below).
Ethics and safety
The most recently approved version of the protocol is version 5, which was approved
by the Nottingham 2 Research Ethics Committee on 28 February 2012. Trust
management approval has been granted by each transplant center. The 3C Study
complies with the principles of Good Clinical Practice. Written informed consent will
be obtained from each participant before randomization, after a discussion with the
local investigator or their nominated deputy. Unblinded interim analyses of all
relevant data will be reviewed twice a year by the independent DMC, which can
advise the study steering committee if the study protocol needs to be amended in any
way, or if they recommend early termination of the study.
The sample size for the 3C Study was determined by the maintenance therapy
allocation. A meta-analysis of the effect of conversion to sirolimus-based
maintenance therapy showed an improvement in eGFR of 6.4 ml/min/1.73m2 (95% CI
1.9 to 11) in the group assigned to sirolimus . The trials included in that meta-
analysis varied in duration, with most patients followed up for 1 year. If these
differences were maintained, it would be reasonable to anticipate a 10 ml/min/1.73m2
difference in eGFR 2 years after conversion to sirolimus (that is, median follow-up at
least 2.5 years after transplantation). We assumed that the adherence to sirolimus
therapy would be around 75% (that is, approximately 25% of patients allocated
sirolimus in randomized trials discontinue it ), and further it was estimated that
about two-thirds of participants would be willing and eligible to be randomized at 6
months after transplantation. Thus, of 800 patients entering the study, about 530 (two-
thirds) would be re-randomized at 6 months. This number of participants would
provide excellent power (>90%) with α = 0.05 and good power (>80%) with α = 0.01
to detect such a difference (even if adherence to allocated treatment was only 75%). If
the self-correlation between baseline eGFR (that is, before re-randomization at 6
months) and eGFR 2 years later is >0.5, then comparing the change from baseline in
eGFR will provide even better power for these analyses.
Having 800 patients would also provide good power (90%) with α = 0.05 to detect a
halving in the acute rejection rate at 6 months (from 15% to 7.5%), which is the
primary comparison in the induction-therapy comparison.
The primary endpoint of the induction-therapy comparison (biopsy-proven acute
rejection occurring before maintenance-therapy randomization or at 6 months post-
transplant (whichever occurs first) will be compared using the log-rank test, with
average event rate ratios derived using standard methods . Secondary endpoints of
the induction-therapy comparison will be analyzed in an exploratory manner, as there
is a potential for bias in endpoints that occur after the maintenance-therapy
randomization (if inclusion in the maintenance-therapy comparison is not balanced
between the two induction-therapy groups).
The statistical analysis of the primary endpoint of the maintenance treatment will
depend on the self-correlation of eGFR at baseline (that is, at randomization into the
maintenance comparison) and at 2 years. This will be performed by investigators
blinded to treatment allocation and, if the self-correlation is >0.5, the analysis will be
of the difference in the mean change from baseline between the two groups using
analysis of covariance methods, as this will provide greater power for the analysis
(analyses of other datasets suggests this is likely, but if the self-correlation is less than
0.5 then the analysis will be of the difference in mean eGFR at 2 years). All analyses
will be intention to treat, and will include all randomized participants who are
transplanted. The small number of participants who are randomized but not
transplanted will be censored at day 0 for the purposes of analysis.
Secondary endpoints for which time-to-event data are available will be compared with
the log-rank test, whereas other categorical endpoints will be compared with χ2 tests.
Continuous variables will be compared with t-tests (after logarithmic transformation if
necessary for skewed variables). Tertiary endpoints (that is, subgroup analyses of the
primary endpoint in different types of participants) will be interpreted cautiously, as
the power to detect true differences between subgroups will be limited. Subgroups
will be compared by testing for heterogeneity of the treatment effect across
Late graft loss (that is, more than 1 year after transplantation) is a major issue for
kidney-transplant recipients. Despite improvements in short-term graft survival, long-
term graft survival has not improved substantially . The commonest reason for
such late graft failure is IF/TA. Data from serial protocol biopsies previously
suggested that CNI nephrotoxicity was an important cause of IF/TA , although this
has been debated more recently [28,29]. Previous CNI minimization studies have not
been large enough or of sufficient duration to detect benefits in terms of long-term
graft function and survival. Two potential strategies to reduce exposure to CNIs are
Campath as a more potent induction therapy, and conversion to a sirolimus-based
maintenance regimen. Given the favorable effects of both treatments on markers of
tolerance , the 3C Study has been designed to test both strategies to investigate
whether they could improve both short-term and long-term outcomes.
The 3C Study deliberately includes a wide range of kidney-transplant recipients. as all
transplants are vulnerable to the nephrotoxic effects of CNIs, and it is important to
ensure that the results will be applicable to as many kidney-transplant recipients as
possible. Many previous trials have only included low-risk transplant recipients, and
therefore uncertainty remains about the applicability of such treatments to higher-risk
recipients. Using broader exclusion criteria and conducting a small number of
carefully pre-specified subgroup analyses will provide reliable information about
whether any effect of either strategy is modified by certain baseline characteristics.
One such key subgroup analysis will be whether there is an interaction between the
two randomizations; for example, whether induction therapy based on Campath
modifies the treatment effect (possibly by improving compliance) of sirolimus-based
The protocol is intended to be pragmatic and easy to implement at local transplant
centers. Considerable effort has been made to make the control treatment as similar to
current European practice as possible to ensure that centers would be willing to
deliver it to participants and to ensure that the results will be relevant to current
practice. Prednisolone withdrawal, precise mycophenolate dosing, and infection
prophylaxis will be left to the local investigator’s discretion, in order to limit the
effects of the study on routine practice and thus facilitate recruitment. 852 participants
have been randomized into the study (of whom 355 have been re-randomized into the
maintenance comparison at the time of submission). The safety analysis (once all
participants have completed the 1-year follow-up) will therefore be conducted in early
An important and novel aspect of the 3C Study design is linkage with registries. In the
UK, data will be routinely collected on patient survival and certified cause of death
(by the Office for National Statistics), cancer incidence (by the NHS Information
Centre), hospital admission or outpatient evaluation (by the Hospital Episode
Statistics registry), and transplant function, rejection and survival (by the UK
Transplant registry). Specific approval to flag all 3C Study participants with these
registries has been obtained, and these will therefore provide a cost-efficient means of
collecting data on all the relevant outcomes for the lifetime of the participant (unless
they withdraw consent). It will therefore be possible to investigate the very long-term
effects of the study treatments reliably at reasonable cost. For example, graft failure
and cancer (with the possible exception of post-transplant lymphoproliferative
disorder) will be uncommon during the first few years after transplantation, when
most studies cease follow-up. However, the 3C Study will continue follow-up for
many more years, and therefore will accrue substantially more events and thus allow
more reliable conclusions to be drawn.
3C Study: Campath Calcineurin inhibitor reduction and Chronic allograft
nephropathy; CNI: Calcineurin inhibitor; eGFR: Estimated glomerular filtration rate;
IF/TA: Interstitial fibrosis/tubular atrophy; MDRD: Modification of Diet in Renal
Disease; NHS: National Health Service
The 3C Study has received funding from Pfizer and Novartis and a NHS Blood and
Transplant Research and Development grant. PF has received honoraria from
Novartis and Pfizer. PG has received honoraria from Roche and Novartis. KR has
received honoraria from Astellas. AA, MA, SB, PC, AH, IM, GJ, NK, JN, CNa, CNe,
CP, RP, AS, NS, PR, and CW have no conflicts of interest to declare. The Clinical
Trial Service Unit has a staff policy of not accepting honoraria or other payments
from the pharmaceutical industry, except for the reimbursement of costs to participate
in scientific meetings.
RH contributed to the study design, coordination, approval processes, and acquisition
of data, and drafted the manuscript. PF initiated the study concept and design, and
reviewed the paper. CB and ML contributed to the study design and coordination. PH,
MA, AA, AB, SB, PC, MC, JE, PG, AH, WH, KJ, GJ, NK, ML, DL, IM, CNa, CNe,
JN, RP, CP, KR, PR, AS, NS, SS, and CW contributed to the design, acquisition of
data, and revision of the manuscript. All authors read and approved the final
We thank Ms Ruth Davis (study administrator) for coordinating the trial. We also
thank the staff at each of the sites who have recruited and cared for the trial
participants. The most important acknowledgement is to the participants in the 3C
Professor Peter Friend (Chair)
Dr Richard Haynes (Clinical Coordinator)
Professor Colin Baigent
Dr Paul Harden
Dr Martin Landray
Mr Murat Akyol
Mr Argiris Asderakis
Dr Alex Baxter
Professor Sunil Bhandari
Dr Paramit Chowdhury
Mr Marc Clancy
Mr Paul Gibbs
Mr Abdul Hammad
Dr Will Herrington
Mrs Kathy Jayne
Dr Gareth Jones
Dr Nithya Krishnan
Dr Michael Lay
Dr David Lewis
Professor Iain Macdougall
Mr Chidambaram Nathan
Professor James Neuberger
Dr Chas Newstead
Mr Ravi Pararajasingam
Mr Carmelo Puliatti
Mr Keith Rigg
Dr Peter Rowe
Dr Adnan Sharif
Professor Neil Sheerin
Mr Sanjay Sinha
Mr Chris Watson
Data monitoring committee
Professor Sir Peter Morris (chair)
Professor Keith Wheatley
Dr Daniel Abramowicz
Dr Jonathan Emberson (statistician)
Dr Lisa Blackwell (statistician)
University Hospitals Birmingham NHS Foundation Trust: A Sharif, L Fifer, C Waite,
Addenbrooke’s Hospital, Cambridge University Hospitals NHS Trust: C Watson, N
Torpey, A-M O’Sullivan
University Hospital of Wales: A Asderakis, Y Webley
University Hospitals Coventry and Warwickshire NHS Trust: N Krishnan, R Higgins
Royal Infirmary of Edinburgh: M Akyol, J Davidson, J Steven
Western Infirmary, Glasgow: M Clancy, L Buist, B McLaren, L McGregor, D Kelly
Guy’s and St Thomas’ NHS Foundation Trust: P Chowdhury, J Watkins
Hull and East Yorkshire Hospitals NHS Trust: S Bhandari, K James, H Stark, T
King’s College Hospital NHS Foundation Trust: I Macdougall, F Sharples
Leeds Teaching Hospitals NHS Trust: C Newstead, R Baker, E Giddings, R
Wheatley, S Turner, K Tobin
Royal Liverpool and Broadgreen University Hospital Trust: A Hammad, S Heyworth
Central Manchester University Hospitals NHS Foundation Trust: R Pararajasingam, H
Riad, A Pereira, R Flynn, C Griffin
Freeman Hospital, Newcastle-upon-Tyne Hospitals NHS Foundation Trust: N
Sheerin, M Playford, B Boughen
City Hospital, Nottingham University Hospitals NHS Trust: K Rigg, C Byrne, A