Micro-Particle Curcumin for the Treatment of Chronic Kidney Disease
Phase: PHASE3
Conditions: Chronic Kidney Disease
Sponsor: London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's

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Journal canadien de la santé et de la maladie rénale
https://doi.org/10.1177/2054358118813088
Canadian Journal of Kidney Health 
and Disease 
Volume 5: 1 –9
© The Author(s) 2018
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DOI: 10.1177/2054358118813088
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Study Protocol
813088 CJKXXX10.1177/2054358118813088Canadian Journal of Kidney Health and DiseaseWeir et al
research-article20182018
Micro-Particle Curcumin for the 
Treatment of Chronic Kidney Disease-1: 
Study Protocol for a Multicenter  
Clinical Trial
Matthew A. Weir1,2,3, Michael Walsh4,5, Meaghan S. Cuerden2, 
Jessica M. Sontrop2
, Laura C. Chambers2,  
and Amit X. Garg1,2,3
Abstract
Background: The progression to end-stage renal disease (ESRD) is the most important complication of chronic kidney 
disease (CKD). Patients with ESRD require dialysis or transplantation to survive, incur numerous complications, and have 
high mortality rates. Slowing the progression of CKD is an important goal. Unfortunately, even when current treatments are 
appropriately applied, patients with CKD still progress to ESRD. Current treatments do not address the inflammation and 
fibrosis that mediate progression to ESRD, but micro-particle curcumin, a natural health product, has both anti-inflammatory 
and anti-fibrotic properties and may be an effective treatment for patients with CKD.
Objective: Micro-particle curcumin for the treatment of CKD-1 (MPAC-CKD-1) will measure the effect of micro-particle 
curcumin on 2 important markers of CKD progression: albuminuria and estimated glomerular filtration rate (eGFR). Efficacy 
in either of these markers will justify a larger, international trial to investigate micro-particle curcumin’s ability to lower the 
risk of ESRD in patients with CKD.
Design: MPAC-CKD-1 is a multicenter, double-blind prospective randomized controlled trial.
Setting: Four kidney disease clinics in Ontario, Canada (3 in London and 1 in Hamilton).
Patients: We will enroll patients with CKD, defined by an eGFR between 15 and 60 mL/min/1.73 m2 and a daily albumin 
excretion of more than 300 mg (or a random urine sample albumin-to-creatinine ratio more than 30 mg/mmol).
Measurements: We will measure changes in the co-primary outcomes of urinary albumin-to-creatinine ratio and eGFR at 
3 months and 6 months. We will also measure compliance, safety parameters, and changes in health-related quality of life.
Methods: Participants will be randomly assigned to receive micro-particle curcumin 90 mg once daily or matching placebo 
for 6 months. We will enroll at least 500 patients to exclude clinically meaningful 6-month changes in these 2 co-primary 
outcomes (16% difference in albuminuria, and a 2.3 mL/min/1.73 m2 between-group difference in the 6-month change in 
eGFR, at a two-tailed alpha of 0.025, power of 0.80).
Results: Patient enrollment began on October 1, 2015, with 414 participants randomized as of July 2018. We expect to 
report the results in 2020.
Limitations: MPAC-CKD-1 is not powered to assess outcomes such as the need for renal replacement therapy or death.
Conclusions: MPAC-CKD-1 is a multicenter, double-blind prospective randomized controlled trial designed to test whether 
micro-particle curcumin reduces albuminuria and slows eGFR decline in patients with albuminuric CKD. MPAC-CKD-1 will 
also test the feasibility of this intervention and inform the need for a future larger scale trial (MPAC-CKD-2).
Trial registration: MPAC-CKD-1 is registered with U.S. National Institutes of Health at clinicaltrials.gov (NCT02369549). 
Protocol version 2.0, December 6, 2014.
Abrégé 
Contexte: La progression vers l’insuffisance rénale terminale (IRT) est la plus importante complication de l’insuffisance 
rénale chronique (IRC). Les patients atteints d’IRT dépendent de la dialyse ou de la transplantation pour survivre. Ces 
patients subissent de nombreuses complications et font face à des taux de mortalité très élevés. Ralentir la progression de 
la maladie est un objectif majeur. Malheureusement, même lorsque les traitements sont prodigués correctement, certains 
patients atteints de néphropathie chronique progressent vers l’IRT. Les traitements actuels ne parviennent pas à réduire 
l’inflammation et la fibrose qui médient cette progression. Les microparticules de curcumine, un produit de santé naturel qui 

2 
Canadian Journal of Kidney Health and Disease
possède des propriétés anti-inflammatoire et anti-fibrotiques, pourraient s’avérer un traitement efficace pour les patients 
atteints d’IRC.
Objectif: L’étude MPAC-CKD-1 mesurera l’effet des microparticules de curcumine sur deux marqueurs importants de la 
progression de la maladie : l’albuminurie et le débit de filtration glomérulaire estimé (DFGe). L’efficacité des microparticules 
de curcumine sur l’un ou l’autre de ces marqueurs justifiera la conduite d’un essai international à plus grande échelle qui 
étudiera leur capacité à réduire le risque de progression vers l’IRT chez les patients atteints d’IRC.
Type d’étude: L’étude MPAC-CKD-1 est un essai multicentrique prospectif, contrôlé, à répartition aléatoire et à double insu.
Cadre: Quatre cliniques spécialisées en néphropathie de l’Ontario, au Canada (trois à London et une à Hamilton).
Sujets: Seront recrutés les patients atteints d’IRC dont le DFGe se situe entre 15 et 60 ml/min/1,73 m2 et l’excrétion 
d’albumine quotidienne à plus de 300 mg (ou dont un échantillon d’urine présente un rapport albumine/créatinine de plus de 
30 mg/mmol).
Mesures: Les changements dans les deux principaux résultats (DFGe et rapport albumine/créatinine urinaire) seront mesurés 
à trois mois et à six mois. Seront également mesurés la conformité, les paramètres relatifs à l’innocuité et les changements 
dans la qualité de vie du patient en lien avec sa santé.
Méthodologie: Un traitement d’une durée de six mois (dose quotidienne de 90 mg de curcumine ou un placébo) sera 
attribué de façon aléatoire aux participants. Un minimum de 500 patients sera inclus à l’étude afin d’exclure les changements 
cliniquement significatifs survenant au cours des six mois pour les deux principaux résultats étudiés (une différence de 16 % 
de l’albuminurie et une différence de 2,3 ml/min/1,73 m2 du DFGe dans les six mois entre les deux groupes, avec un alpha 
bilatéral de 0,025 à la puissance 0,80).
Résultats: Le recrutement des patients a débuté le 1er octobre 2015 et en date de juillet 2018, 414 participants avaient été 
répartis. La publication des résultats est prévue en 2020.
Limites: L’étude MPAC-CKD-1 n’est pas conçue pour mesurer des résultats tels que le besoin de recourir à une thérapie 
de remplacement rénal ni pour répertorier le taux de mortalité.
Conclusion: L’étude MPAC-CKD-1 est un essai multicentrique prospectif, contrôlé, à répartition aléatoire et à double 
insu, conçu pour mesurer l’effet des microparticules de curcumine chez les patients atteints d’IRC albuminurique. On veut 
pouvoir observer soit une réduction de l’albuminurie, soit un ralentissement du déclin du DFGe. L’étude MPAC-CKD-1 vise 
également à tester la faisabilité de cette intervention et à éclairer le besoin de procéder à un essai futur à plus grande échelle 
(MPAC-CKD-2).
Keywords
CKD (chronic kidney disease), randomized controlled trial, albuminuria
Received August 2, 2018. Accepted for publication September 24, 2018.
1Division of Nephrology, Department of Medicine, Western University, London, ON, Canada
2Kidney Clinical Research Unit, London Health Sciences Centre, University Hospital, London, ON, Canada
3Department of Epidemiology and Biostatistics, Western University, London, ON, Canada
4Division of Nephrology, Department of Medicine, McMaster University, Hamilton, ON, Canada
5Population Health Research Institute, Hamilton Health Sciences, McMaster University, Hamilton, ON, Canada
Corresponding Author:
Matthew A. Weir, Kidney Clinical Research Unit, London Health Sciences Centre, University Hospital, Room A10-213, 339 Windermere Road, London, 
ON, Canada N6A 5A5. 
Email: matthew.weir@lhsc.on.ca
What was known before
Curcumin, a component of the spice turmeric, has anti-
inflammatory and anti-fibrotic properties. Animal models 
and small-scale human studies suggest that curcumin may 
slow the progression of chronic kidney disease.
What this adds
By randomizing at least 500 patients with albuminuric 
chronic kidney disease to 90 mg per day of micro-particle 
curcumin or placebo, we will determine its effects on albu-
minuria and renal function. This trial will also determine the 
need for, and the feasibility of, a large-scale trial to assess 
clinically meaningful end points.
Introduction
Chronic kidney disease (CKD) is defined by an estimated 
glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m2 
or evidence of persistent kidney damage, such as excessive 

Weir et al 
3
albuminuria. CKD is associated with significant morbidity 
and mortality but the most important complication of CKD is 
the progression to kidney failure (end-stage renal disease, 
ESRD). Patients who progress to ESRD require dialysis or 
transpl antation to survive. They experience numerous com-
plications, have high mortality rates,1 and their care is very 
expensive.2 Therefore, preventing or slowing the progression 
from CKD to ESRD is an important clinical and research 
goal. Currently, few treatments have been proven to slow 
progression, and even when these therapies are appropriately 
applied, many patients still progress to ESRD.3 This may be 
explained in part by inflammation and fibrosis, 2 processes 
that play a role in the progression of CKD,4,5 but are not 
addressed by current therapies.
Curcumin, a component of the dietary spice turmeric, 
has proven anti-inflammatory and anti-fibrotic properties 
(Supplement Figure S1) and has been shown to mitigate 
renal damage in multiple animal models of CKD (Supple-
ment Table S1).6-9 The ability of curcumin to reduce albu-
minuria in humans is supported by 2 trials in patients with 
nephrotic-range proteinuria.10-12 However, these trials were 
small and patients were treated with turmeric, of which cur-
cumin is only a small component. Furthermore, curcumin 
in its traditional form has very poor bioavailability.13-15  
To increase patients’ exposure to curcumin, we chose to 
study a micro-particle formulation that is 27 times more 
bioavailable.16
Micro-particle curcumin for the treatment of CKD-1 
(MPAC-CKD-1) is a double-blind, placebo-controlled ran-
domized trial that will measure the effect of micro-particle 
curcumin on 6-month changes in 2 important markers of 
CKD progression: albuminuria and eGFR. Positive effects in 
either of these markers will justify a larger, international trial 
that will determine micro-particle curcumin’s ability to 
decrease the risk of ESRD in patients with CKD.
Methods
This protocol is presented according to the SPIRIT guide-
lines (see supplemental materials).17
Study Setting
We will coordinate this trial through the Lilibeth Caberto 
Kidney Clinical Research Unit at London Health Sciences 
Centre in London, Ontario. The trial steering committee is 
comprised of AX Garg and MA Weir, who will also provide 
outcome and adverse event adjudication. We will identify 
patients through 3 clinics in London, Ontario, Canada, and 1 
clinic in Hamilton, Ontario, Canada. In each clinic, attending 
physicians will introduce the study and interested patients 
will meet with research coordinators to discuss the trial in 
detail. Those who are eligible and willing to participate will 
provide written, informed consent prior to randomization.
Eligibility Criteria
We will recruit patients with advanced CKD but who have 
not yet progressed to an irreparable stage. We will enroll 
patients with an eGFR between 15 and 60 mL/min/1.73 m2 
and overt albuminuria, defined by a 24-hour urine collec-
tion with more than 300 mg of protein or a random urine 
albumin-to-creatinine ratio greater than 30 mg/mmol (265.2 
mg/g). We will exclude patients with conditions that may 
potentially be exacerbated by the use of micro-particle cur-
cumin (active peptic ulcer disease, hepatobiliary disease, 
history of significant bleeding) or who take medications 
that may interact with micro-particle curcumin (Table 1).
Interventions
We will randomly assign patients to receive either micro-
particle curcumin or matching placebo. Micro-particle cur-
cumin will be administered at 90 mg per day (three 30 mg 
capsules once daily) for 6 months. Our rationale for the 
dosage selection is presented in the supplemental materials. 
The dose will remain constant over the study period. 
Randomization to micro-particle curcumin or matching 
placebo will occur in a 1:1 ratio. Balanced block random-
ization will be conducted using a computerized algorithm 
with variable block sizes and treatment allocation will be 
stratified by site (3 sites in London, 1 site in Hamilton) and 
by baseline diabetes mellitus status. After providing written 
informed consent, patients will be allocated randomly by 
means of a 24-hour online computerized system to maintain 
allocation concealment. Participants, investigators, and all 
research staff will remain unaware of the treatment alloca-
tion. Unblinding will occur in the setting of a severe adverse 
reaction in which the treating physician believes the inves-
tigational product may have a role in the patient’s condition 
or treatment.
Concomitant Care
Hypertension and proteinuria will be managed according 
to the Canadian Hypertension Education Program guide-
lines,18 which suggest treatment with an angiotensin-con-
verting-enzyme inhibitor or an angiotensin receptor 
blocker. Patients not taking one of these medications 
require the reason why to be documented in the medical 
record. The doses of these medications may be reduced or 
the drug may be stopped during the course of the study, but 
the medical indication prompting that decision (eg, hyper-
kalemia) must be documented. We will not impose dietary 
restrictions because dietary sources of curcumin provide 
exceedingly small amounts of curcumin19,20; however, we 
will ask patients to refrain from using over-the-counter 
curcumin or turmeric supplements and document any use 
at each study visit.

4 
Canadian Journal of Kidney Health and Disease
Outcomes
Primary outcomes. We will assess the 6-month change in 2 co-
primary outcomes: the change in albuminuria, and the change 
in eGFR. Albuminuria will be measured using albumin-to-
creatinine ratios from first morning urine samples. The eGFR 
will be calculated using the CKD-EPI formula, which includes 
patient age, sex, race (African or non-African), and the serum 
creatinine concentration.21
Secondary outcomes
Glycemic control. We will assess glycemic control using 
the percentage of glycated hemoglobin at baseline, 3 months, 
and 6 months among patients with diabetes mellitus (diabetes 
mellitus was a stratification variable in the randomization). 
Curcumin use has been associated with improved glycemic 
control in animal models,22 and human studies.23
Study agent discontinuation and safety. Because MPAC-
CKD-1 may inform the launch of subsequent larger trial, a bet-
ter understanding of the tolerability of micro-particle curcumin 
in the CKD population is necessary. We will test protocol 
compliance through pill counts and interviews at each follow-
up visit. Side effects will be assessed using standardized case 
report forms at each visit.
Renal failure composite (eGFR loss of ⩾30%, or ESRD, or 
death). We expect less than 10% of participants will experi-
ence these outcomes by 6 months. Although we will not have 
adequate statistical power to detect a meaningful effect of 
curcumin on these outcomes, we will document any trends 
to inform the expected event rate for future studies. We will 
define ESRD as an eGFR <15 mL/min/1.73 m2 or the initia-
tion of renal replacement therapy, which includes dialysis or 
transplantation.
Health-related quality of life. We will compare health-related 
quality of life scores determined by the RAND version of the 
Short Form-36 (SF-36) questionnaire administered at baseline 
and 6 months. We will compare changes in both the physical 
composite score and the mental composite score. Beyond pres-
ervation of kidney function are several other potential mecha-
nisms by which curcumin may benefit quality of life, including 
potential benefits on depression and chronic pain.24,25
Additional outcomes
Serum curcumin levels. The strength of previously identified 
relationships between traditional curcumin exposure and clini-
cal outcomes has been limited by the difficulty in achieving 
measurable serum curcumin levels. To confirm the improved 
bioavailability reported with micro-particle curcumin,16 and to 
strengthen any relationship between micro-particle curcumin 
and any outcomes we identify, we will measure serum trough 
levels of curcumin and its major metabolites in the first 25 
participants randomized.14
Recruitment
To ensure we can achieve this recruitment goal, we have 
assessed the number of provisionally eligible patients man-
aged in the 4 clinics involved in this trial and have gauged the 
success of a recently conducted trial with similar inclusion 
criteria.26,27 In addition, we have worked closely with research 
Table 1. Inclusion and Exclusion Criteria.
Inclusion criteria
18 years of age and older
Chronic kidney disease (eGFR 15 to 60 mL/min/1.73 m2)
Albuminuria (24-hour urine protein ⩾300 mg, or urinary albumin-to-creatinine ratio ⩾30 mg/mmol)
For those with diabetes mellitus, willing to measure and record blood glucose concentrations
Stable dose of ACE inhibitor or ARB
Exclusion criteria
Life expectancy <1 year
Renal replacement therapy in the prior 3 months
Plans for renal transplantation during the study period
Active peptic ulcer disease
Recent hepatobiliary disease
Evidence of recent acute kidney injury (>50% increase in serum creatinine in the preceding 30 days)
Significant bleeding history in the last 6 months
Gastrointestinal bleed or retroperitoneal bleed requiring 
transfusion, or intracranial hemorrhage
Ongoing use of drugs that may interact with 
curcumin
Oral anticoagulants
Chemotherapeutic agents: cyclophosphamide, camptothecin, 
mechlorethamine, or doxorubicin
Anti-psychotic medications: haloperidol, aripiprazole, risperidone, 
ziprasidone, pimozide, quetiapine
Allergy to turmeric or its derivatives (ginger, cumin, cardamom)
Allergy to components of the investigational product
Note. eGFR = estimated glomerular filtration rate; ACE = angiotensin converting enzyme; ARB = angiotensin receptor blocker.

Weir et al 
5
Figure 1. Participant timeline.
Note. eGFR = estimated glomerular filtration rate; SF-36 = Short Form-36; UACR = urinary albumin-to-creatinine ratio.

6 
Canadian Journal of Kidney Health and Disease
coordinators to remove possible barriers to enrollment and 
streamline the data collection process.
Data Collection Methods
We will gather outcome measures 3 months and 6 months after 
randomization. To reduce the variability in the urinary albu-
min-to-creatinine ratio, we will take the mean of first morning 
urine samples collected on 2 consecutive days. In our previous 
work, we determined that the mean of two samples substan-
tially reduced the standard deviation of the log-transformed 
percentage change from 0.59 to 0.49.28 We will calculate the 
eGFR rates using the measured plasma creatinine concentra-
tions. These will be measured at central hospital-based labora-
tories using standardized enzymatic colorimetric methods.
Nonadherence
Patients who miss taking the investigational study medication 
over 7 or more days during any 4-week period will meet with 
an investigator to discuss ways of improving adherence. We 
will catalogue the reasons for nonadherence and the strategies 
used to overcome them. Patients who do not attend study vis-
its will be contacted and encouraged to comply with the pro-
tocol in whatever way they can. Until the study ends or the 
participant withdraws consent, we will attempt to reach them 
3 times within each 4-week period to determine their status. 
In extenuating circumstances, we will contact the patient’s 
family physician to determine the patient’s vital status.
Statistical Methods
Sample size. Most physicians would view a 15% to 25% 
reduction in albuminuria as evidence of a promising treat-
ment effect. Such was the case for ACE inhibitors and angio-
tensin receptor blockers, which showed a reduction in 
albuminuria of 15% to 50% and were later proven to reduce 
the risk of mortality and ESRD.29-32 In our preliminary work 
on urinary albumin-to-creatinine ratio testing, we found 
patients eligible for MPAC-CKD-1 had a mean initial urinary 
albumin-to-creatinine ratio of 128.3 mg/mmol.28 Over 3 
months, we observed a mean increase in the urinary albumin-
to-creatinine ratio of 30.7 mg/mmol and found the standard 
deviation of the change to be 69.2 mg/mmol. Using these 
data, enrolling 250 patients per group will allow an 87% 
power (α= 0.025) to exclude a difference of 21 mg/mmol. To 
allow for loss to follow-up, we expect to recruit up to an addi-
tional 75 patients to reach a minimum of 250 patients per 
arm with complete follow-up data. For changes in eGFR, we 
will have 90% power (α = 0.025) to exclude a difference of 
2.3 mL/min/1.73 m2 between treatment and control groups 
(using a standard deviation of 4 mL/min/1.73 m2). This esti-
mate is based on a reported average decline in eGFR in albu-
minuric CKD patients of 2 to 4 mL/min/1.73 m2/year (with a 
standard deviation of 3-4 mL/min/1.73 m2/year).33,34
Primary outcome. We will conduct all primary analyses 
according to the intention-to-treat principle. Significance 
testing will be conducted with a two-sided alpha level of 
0.05/2 using Hochberg adjustment for 2 simultaneous pri-
mary end points.35 We will use two-sample t tests to compare 
changes in the co-primary outcomes.32,36 Missing data will 
be handled using model-based multiple imputation meth-
ods (and sensitivity analyses will be performed to confirm 
that conclusions are not sensitive to assumptions about the 
missing-data mechanism)37; the albumin-to-creatinine ratio 
data collected at the 3-month visit will be included in the 
imputation model.
Secondary outcomes. We will use a two-sample t test to 
compare changes in hemoglobin A1c between the 6-month 
and baseline values. The risk of the composite outcome of 
loss of ⩾30% of baseline eGFR, ESRD, or death will be 
compared between groups using logistic regression analy-
sis. The proportions of patients discontinuing study capsules 
and experiencing adverse events will be compared between 
groups using the chi-square test.
Baseline characteristics. Randomization reliably removes 
random differences between treatment groups when at least 
1000 participants are included.38 With the size of our sample, 
it is possible that imbalances may arise between the treatment 
groups on important characteristics that may influence out-
comes. We will record baseline characteristics pertinent to the 
progression of CKD and adjust the final point estimates of 
risk for these variables using linear regression analysis. Char-
acteristics that will be included in the multivariable regres-
sion model are the following: age, sex, tobacco use, blood 
pressure, glycemic control, use of angiotensin-converting-
enzyme inhibitors or angiotensin receptor blockers, use of 
aldosterone antagonists. Sodium-glucose co-transporter-2 
(SGLT-2) inhibitors were approved for use in Canada in May 
2014, and gained provincial formulary coverage in 2015. 
Because these medications have been shown to reduce albu-
minuria, we will record these use39,40; however, given their 
minimum eGFR cut off of 45 mL/min/1.73 m2, we anticipate 
that they will not be commonly used in our population.
Other analyses. We will conduct an exploratory per-pro-
tocol analysis consisting of patients with no major protocol 
violations and who were exposed to their randomly assigned 
treatment for a minimum of 3 months. We will also conduct 
a subgroup analysis based on a higher or lower estimated risk 
of kidney failure (using the kidney failure risk equation).41
Results
MPAC-CKD-1 began enrollment on October 1, 2015, and 
has randomized 414 participants as of July 2018. We expect 
to complete enrollment in 2019 and report the results publicly 
in 2020.

Weir et al 
7
Discussion
Micro-particle curcumin holds a great deal of promise as a 
treatment to slow the progression of CKD because of its anti-
inflammatory and anti-fibrotic properties.
In vitro experiments using a variety of cell lines have 
shown that curcumin exposure attenuates the activation of 
nuclear factor-kappa B (NF-κB). Activation of NF-κB is a 
pivotal regulatory step in the inflammatory process that leads 
to the elaboration of interleukin-1 (IL-1), IL-2, IL-6, tumor 
necrosis factor-alpha (TNF-α), and monocyte chemotactic 
protein-1 (MCP-1).42 By blocking its activation, curcumin 
acts as a potent anti-inflammatory agent.43-45 The conversion 
of functional tissue to scar is a hallmark of progressive CKD. 
Transforming growth factor-beta (TGF-β) is one of the most 
important mediators in this process.46,47 In a variety of in 
vitro settings, curcumin has been shown to lessen the effect 
of TGF-β through inhibition of its molecular signaling,48,49 
activation of endogenous inhibitors,50 thereby resulting in 
less scar formation.51,52
Animal models of CKD also support the effectiveness of 
curcumin exposure. Soetikno et al reported that compared 
with placebo, diabetic rats fed with curcumin 100 mg/kg per 
day for 8 weeks had far less scar tissue in their kidneys and 
expressed lower levels of TGF-β.6 In two related studies, 
Ghosh et al showed that rats with 5/6 nephrectomies who 
consumed 75 mg/kg curcumin per day had less proteinuria, 
better kidney function, more normal appearing renal histol-
ogy, and lower levels of NF-κB and TNF-α than those on a 
placebo diet.7 Follow-up study of Ghosh et al showed that 
this benefit was realized even when curcumin treatment was 
delayed until after the appearance of proteinuria (a more 
clinically relevant timing of curcumin exposure).8 Sharma 
et al found similar effects in diabetic rats and demonstrated a 
dose-response.9
Two small trials have tested curcumin supplementation in 
patients with kidney impairment.10,11 In the study most appli-
cable to MPAC-CKD-1, Khajehdehi et al randomized 40 
patients with diabetic CKD to receive placebo or turmeric 
(0.5 g 3 times daily; approximately equivalent to 66 mg of 
curcumin per day) for 2 months. Both groups began the study 
with approximately 4.5 g of daily proteinuria. After only 2 
months of treatment, the turmeric group had a 39% reduction 
in proteinuria while the placebo group’s proteinuria remained 
unchanged.10 The treatment group experienced significant 
reductions in serum levels of TGF-β and TNF-α. In the sec-
ond trial of patients with lupus nephritis, turmeric supplemen-
tation again decreased proteinuria significantly compared 
with placebo.11
MPAC-CKD-1 is the next step in assessing micro-particle 
curcumin’s potential to slow the progression of CKD. If 
meaningful changes in our surrogate outcome measure are 
observed, this will justify a larger, international trial equipped 
to test curcumin’s ability to lower the risk of ESRD.
Acknowledgments
We would like to thank Darek Gozdzik for the development and 
maintenance of the trial database and Virginia Schumann for her 
financial management and assistance in obtaining Health Canada 
approval for this trial.
Availability of Data and Materials
The study investigators will have access to the final trial data set. 
We do not plan to make data sets available to the public.
Data Monitoring
The Data Safety Monitoring Committee (DSMB) will be comprised 
of external content experts with experience in clinical trials. The 
DSMB will review unblinded safety data once 50% of patients have 
completed the study and make recommendations to the trial Steering 
Committee. The unblinded statistician associated with the DSMB 
will make no contribution to the trial design or final analysis of the 
study. No interim analyses are planned. The Lawson Health 
Research Institute will be responsible for conducting periodic audits 
of the conduct of MPAC-CKD-1 (Micro-Particle Curcumin for the 
Treatment of Chronic Kidney Disease-1).
Dissemination Policy
We plan to disseminate the results of MPAC-CKD-1 (Micro-
Particle Curcumin for the Treatment of Chronic Kidney Disease-1) 
through peer-reviewed publication. We will not employ profes-
sional writers and each author on the final article will have fulfilled 
the requirements set out by the International Committee of Medical 
Journal Editors.
Ethics Approval and Consent to Participate
We have obtained approval for the conduct of MPAC-CKD-1 
(Micro-Particle Curcumin for the Treatment of Chronic Kidney 
Disease-1) from both the Western University research ethics 
board and the McMaster University research ethics board. Any 
modifications to the protocol that may impact the conduct of the 
study or affect patient safety, including changes of study objec-
tives, study design, patient population, sample sizes, study proce-
dures, or significant administrative aspects will prompt a formal 
amendment. Revisions will be forwarded to each participating 
site with direction for submission to each respective research eth-
ics board. The protocol and prespecified statistical analysis plan 
were approved by all authors and the data safety and monitoring 
board.
Consent to Participate is not required section for a Protocol publica-
tion type.
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of interest 
with respect to the research, authorship, and/or publication of this 
article: No investigator or research personnel has a financial or 
other competing interest in MPAC-CKD-1. The study design and 
collection, management, analysis, and interpretation of the study 
data have not and will not involve the funders. The trial funders will 
have no role in the reporting of the results.

8 
Canadian Journal of Kidney Health and Disease
Funding
The author(s) disclosed receipt of the following financial support 
for the research, authorship, and/or publication of this article: This 
work was supported by grants from the Kidney Foundation of 
Canada (KFOC130029), and the Canadian Institute of Health 
Research (CIHR365629). Natural Factors Nutritional Products Ltd 
(Coquitlam, BC, Canada) supplied investigational product and 
matching placebo as in-kind support. Michael Walsh holds a New 
Investigator Award from the Canadian Institutes of Health Research. 
Amit X. Garg is supported by a Clinician Investigator Award from 
the Canadian Institutes of Health Research and the Adam Linton 
Chair in Kidney Health Analytics.
ORCID iD
Jessica M. Sontrop 
 https://orcid.org/0000-0001-7784-2028
Supplemental Material
Supplemental material for this article is available online.
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Statistical Analysis Plan (SAP) 
 
Micro-Particle Curcumin for the Treatment of Chronic Kidney Disease-1 (MPAC-CKD-1) 
 
 
 

Signatures: 
Principal Investigator/Author 
Name:   
Matthew A. Weir 
 
 
 
 
 
Signature:  
_____________________________________ 
 
 
 
 
 
Date:   
_____________________________________ 
 
Author/Epidemiologist   
Name:   
 
Jessica Sontrop 
 
 
 
 
 
Signature:  
________________ 
 
 
 
 
 
Date:   
April 29, 2020__________________________ 
 
Author/Statistician 
 
Name:   
Meaghan Cuerden 
 
 
 
 
 
Signature:  
 
 
 
 
 
 
Date:   
April 29, 2020__________________________ 
 
 
 
 
April 29, 2020

List of Abbreviations 
ACE: Angiotensin converting enzyme 
ACR: Albumin-to-creatinine ratio 
ARB: Angiotensin receptor blocker 
CI: Confidence interval 
CKD: Chronic kidney disease 
DSMB: Data safety monitoring board 
eGFR: Estimated glomerular filtration rate 
HR: Hazard ratio 
MAR: Missing at random 
RAAS: Renin-angiotensin-aldosterone  
SD: Standard deviation 
 
Study/trial acronyms 
MPAC-CKD-1: Micro-PArticle Curcumin for the treatment of Chronic Kidney Disease-1 
 
 

Table of Contents 
1. Administrative Information 
2. Introduction 
 
2.1 Background and rationale 
 
2.2 Objectives 
3. Study Methods 
 
3.1 Trial design 
 
3.2 Randomization 
 
3.3 Sample size 
 
3.4 Framework 
 
3.5 Statistical interim analyses and stopping guidance 
 
3.6 Timing of the final analysis 
 
3.7 Timing of outcome assessments 
4. Statistical Principles 
 
4.1 Confidence intervals and P values 
 
4.2 Adherence and protocol deviations 
 
4.3 Analysis populations 
5. Trial Population 
 
5.1 Screening data 
 
5.2 Eligibility 
 
5.3 Recruitment 
 
5.4 Withdrawal/follow-up 
 
5.5 Baseline patient characteristics 
6. Analysis 
 
6.1 Outcome definitions and analysis methods 
 
6.2 Missing data 
 
6.3 Additional analyses 
 
6.4 Harms 
 
6.5 Statistical software 
 
6.6 References 
 

1. Administrative Information 
 
Trial registration number:  
NCT 02369549 
 
SAP version number:   
1.0 dated April 13, 2020 
 
Protocol version:  
 
Protocol Version 2.3 Dated December 22, 2016  
 
Roles and responsibility: 
 
Principal Investigator 
 
Matthew A. Weir, MD, FRCPC, MSc 1,2,3,4 
Co-Investigator  
 
Amit X. Garg, MD, FRCPC, PhD 1,2,3,5 
Epidemiologist  
 
Jessica Sontrop, PhD 3 
Statistician 
 
 
Meaghan Cuerden, PhD 1 
Trial Coordinator 
 
Laura Chambers, BA 4,6 
 
Contributors and Roles  
Matthew A. Weir: Contributed to design of SAP 
 
 
 
 
Jessica Sontrop: Contributed to design of SAP 
 
Meaghan Cuerden: Contributed to design of SAP 
 
Affiliations 
1. London Health Sciences Centre, London, Ontario, Canada 
2. Department of Medicine – Division of Nephrology, Schulich Medicine 
 
& Dentistry, Western University, London, Ontario, Canada 
3. Department of Epidemiology and Biostatistics, Western University, 
 
London, Ontario, Canada 
4. Lawson Health Research Institute, London, Ontario, Canada 
5. Departments of Health Research Methods, Evidence, and Impact 
 
(HEI), McMaster University, Hamilton, Ontario, Canada 
6. Kidney Clinical Research Unit, London, Ontario, Canada 
 
 

2. Introduction 
 
2.1 Background and rationale 
 
Chronic kidney disease (CKD) is defined by an estimated glomerular filtration rate (eGFR) less than 60 
mL/min per 1.73 m2 or evidence of persistent kidney damage, such as excessive albuminuria. CKD is 
associated with significant morbidity and mortality but the most important complication of CKD is the 
progression to kidney failure (end-stage renal disease [ESRD]). Patients who progress to ESRD require 
dialysis or transplantation to survive. They experience numerous complications, have high mortality 
rates,1 and their care is very expensive.2 Therefore, preventing or slowing the progression from CKD to 
ESRD is an important clinical and research goal. Currently, few treatments have been proven to slow 
progression, and even when these therapies are appropriately applied, many patients still progress to 
ESRD.3 This may be explained in part by inflammation and fibrosis, two processes that play a role in the 
progression of CKD,4,5 but are not addressed by current therapies.  
 
Curcumin, a component of the dietary spice turmeric, has proven anti-inflammatory and anti-fibrotic 
properties and has been shown to mitigate renal damage in multiple animal models of CKD.6-9 The ability 
of curcumin to reduce albuminuria in humans is supported by two trials in patients with nephrotic-range 
proteinuria.10-12 However, these trials were small and patients were treated with turmeric, of which 
curcumin is only a small component. Furthermore, curcumin in its traditional form has very poor 
bioavailability.13-15 To increase patients’ exposure to curcumin, we chose to study a micro-particle 
formulation that is 27 times more bioavailable.16 Curcumin use has been associated with improved 
glycemic control in animal models,17 and human studies.18 
 
MPAC-CKD-1 is a double-blind, placebo-controlled randomized trial, where patients are followed for 6-
months after randomization. The primary goal of the trial is to assess the effect of micro-particle 
curcumin (versus placebo) on two important biomarkers of CKD progression: albuminuria and eGFR. 
Positive effects in either of these markers will justify a larger, international trial to determine whether 
micro-particle curcumin versus placebo decreases the risk of ESRD in patients with CKD.  
 
2.2 Objectives 
 
Our primary objective is to assess the between-group difference in two outcomes examined separately: 
urinary albumin-to-creatinine ratio (6-month post-randomization value) and change in eGFR from pre-
randomization to 6-months post-randomization.  
 
Our secondary objective is to assess: i) the between-group difference in health related quality of life (as 
assessed by a 6-month change in the RAND version of the 36-Item Short Form Health Survey [SF-36]), 
ii) the between-group difference in glycemic control (as assessed by a 6-month change in glycated 
hemoglobin among patients with diabetes mellitus; diabetes mellitus was a stratification variable in the 
randomization), iii) the risk of a composite outcome of progressive CKD, ESRD or death with micro-
particle curcumin versus placebo, and iv) the between-group difference in measured serum levels of 
curcumin and its major metabolites (to be done on measurements taken 3-months after randomization in 
the first 30 participants; being done to assess curcumin bioavailability).14,16 
 
We will also conduct a pre-specified exploratory subgroup analysis of the primary outcomes based on a 
higher or lower estimated risk of future kidney failure (based on the kidney failure risk equation19).  

3. Study Methods 
 
3.1 Trial design 
 
MPAC-CKD-1 is a parallel group, double-blind, placebo-controlled randomized trial. Participants were 
randomly assigned to receive either microparticle curcumin or matching placebo in a 1:1 ratio. Micro-
particle curcumin was administered at 90 mg per day (three 30 mg capsules once daily) for 6 months. The 
dose remained constant over the study period.  
 
3.2 Randomization 
 
Balanced block randomization was conducted using a computerized algorithm with variable block sizes; 
treatment allocation was stratified by site (3 sites in London, 1 site in Hamilton) and by the presence or 
absence of baseline diabetes mellitus. After providing written informed consent, patients were allocated 
randomly by means of a 24-hour online computerized system to maintain allocation concealment. 
Participants, investigators, and all research staff are unaware of the treatment allocation. Unblinding could 
have occurred in the setting of a severe adverse reaction in which the treating physician believed the 
investigational product may have had a role in the patient’s condition or treatment. Unblinding events will 
be summarized by group.  
 
3.3 Sample size 
 
Most physicians would view a 15% to 25% reduction in albuminuria as evidence of a promising treatment 
effect. Such was the case for angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor 
blockers (ARBs), which showed a reduction in albuminuria of 15% to 50% and were later proven to 
reduce the risk of mortality and ESRD.20-23 
 
Heerspink et al.24 conducted a meta-analysis of randomized controlled trials with different types of 
interventions, including renin-angiotensin-aldosterone (RAAS) inhibitor versus control, and RAAS 
inhibitor versus calcium-channel blocker. The overall between-group difference in change in log-
transformed urine albumin-to-creatinine ratio after 6-months of follow-up was reported as a geometric 
mean ratio and was estimated using patient-level data. Across all treatment interventions, the estimate of 
the geometric mean ratio was 0.78, 95% confidence interval (CI) 0.74 to 0.82 (i.e. a lowering of urinary 
albumin-to-creatinine ratio across treatment groups). Within the same trials, over a median follow-up time 
of 3.4 years, the active treatment resulted in a lowering of the hazard of the composite progressive CKD 
endpoint defined by ESRD (chronic dialysis or transplant), doubling of serum creatinine or eGFR < 15 
mL/min per 1.73 m2 (hazard ratio [HR] 0.73, 95% CI 0.67 to 0.81). The authors estimated that a 30% 
decrease in geometric mean ratio of 6-month urinary albumin-to-creatinine ratio is associated with an 
average 27% decrease in the hazard for the clinical outcome. Inker et al.25 conducted a similar meta-
analysis of treatment effects in randomized controlled trials to investigate between-group difference in 
change in eGFR over time as a surrogate endpoint for kidney disease progression. The authors found that 
the overall mean treatment effect on the total slope over 3 years was 0.45 mL/min per 1.73 m2, 95% CI 
0.19 to 0.72, comparing treated patients to control arm patients. The active treatment led to a HR of the 
same composite progressive CKD endpoint of 0.76, 95% CI 0.69 to 0.84. The authors estimate that each 
0.75 mL/min per 1.73m2 per year greater treatment effect on the total eGFR slope was associated with an 
average 27% lower hazard for the clinical endpoint.  
 
In our preliminary work on urinary albumin-to-creatinine ratio testing, we found patients eligible for 
MPAC-CKD-1 had a mean initial urinary albumin-to-creatinine ratio of 128.3 mg/mmol.26 Over 3 
months, we observed a mean increase in the urinary albumin-to-creatinine ratio of 30.7 mg/mmol and 
found the standard deviation of the change to be 69.2 mg/mmol. Enrolling a total of 518 patients and 

accounting for 5% loss to follow-up allows for 82% power (α = 0.025) to detect a geometric mean ratio of 
0.75, assuming a standard deviation of the 6-month log-transformed albumin-to-creatinine ratio of 1.0.27 
For the between-group difference in change in eGFR (6-month eGFR minus pre-randomization eGFR), 
we will have 81% power (α = 0.025) to exclude a difference of 1.65 mL/min per 1.73 m2 between 
treatment and control groups (using a standard deviation of the change of 5.8 mL/min per 1.73 m2). In 
general, the average decline in eGFR in albuminuric CKD patients is 2 to 4 mL/min per 1.73 m2 per year 
(with a standard deviation of 3-4 mL/min per 1.73 m2 per year).28,29 The standard deviations used in these 
sample size calculations are based on overall standard deviations observed in the MPAC-CKD-1 study.  
 
3.4 Framework 
 
All comparisons will be presented in a superiority testing framework.  
 
3.5 Statistical interim analyses and stopping guidance 
 
An interim report was created when 50% of patients were randomized and had completed the last 
scheduled visit. An independent statistician, who was blinded to the treatment allocation, created the 
interim report. The statistician reported to an independent Data Safety Monitoring Board (DSMB). The 
DSMB was blinded to all data (stratified groups were denoted as group “A” and group “B”) and discussed 
the results of the interim analysis with the statistician. No between-group tests were conducted for the two 
primary outcomes or for any other endpoints. The DSMB also reviewed safety events. The DSMB 
recommended the trial continue to completion and decided not to unblind itself to the interim data.   
 
3.6 Timing of the final analysis 
 
The final analysis will occur within 6 months of completing data collection; the final analysis is planned 
for mid-2020.  
 
3.7 Timing of outcome assessments 
 
Telephone calls to participants are made at 1 week, 1 month, 2 months, 4 months and 5 months post-
randomization. After a baseline set of measurements, urine samples, blood samples, and SF-36 form 
completion occurs at the 3-month and 6-month visits. The study drug is stopped immediately after the 6-
month follow-up visit; a final telephone call is made to participants 7-months post-randomization.  
 
 

4. Statistical Principles 
 
4.1 Confidence intervals and P values 
 
The overall type I error rate will be fixed at 0.05. The Hochberg procedure will be used to test each of the 
two-sided hypothesis tests for the two primary outcomes. The largest of the two P values will be 
compared to α = 0.05, and if this test is non-significant, the smaller P value will be compared to α/2 = 
0.025. If the largest P value is < 0.05, both hypothesis tests will be rejected.30 If both of the two primary 
outcomes are tested at the 0.05 significance level, 95% CIs will be reported; if either of the primary 
outcomes are tested at the 0.025 significance level, 97.5% CIs will be reported for both tests.  
 
All secondary analyses will be considered exploratory in nature and P values will not be reported; 95% 
CIs will be reported without adjustment for multiple testing.  
 
4.2 Adherence and protocol deviations 
 
Protocol compliance was assessed through pill counts and interviews at each follow-up visit. Protocol 
deviation is defined as missing taking the study medication over 7 or more days during any 4-week 
period. Patients who miss taking the medication over 7 or more days during any 4-week period will meet 
with an investigator to discuss ways of improving adherence. We will report the number and percentage 
of participants who experience at least one protocol deviation, overall and by treatment group. We will 
report the median (25th and 75th percentiles) number of doses missed over the entire study period, overall 
and by group.  
 
Study treatment discontinuation is defined as missing study medication for ≥ 4 weeks consecutively. We 
will report the number and percentage of participants who discontinue the study, overall and by group.  
 
4.3 Analysis populations 
 
We will conduct all primary analyses according to the intention-to-treat (ITT) principle. We will conduct 
an exploratory per-protocol analysis for each of the two primary outcomes consisting of patients who 
were adherent to their randomly assigned treatment, as defined by taking ≥ 80% of pills given during the 
first three months of follow-up (or were adherent until they died or developed ESRD if this occurred 
within the first three months).  
 
 

5. Trial Population 
 
5.1 Screening data 
 
Patient characteristics were not recorded for patients who were assessed for eligibility but were either (i) 
not eligible or (ii) not interested in participating.  
 
5.2 Eligibility 
 
Patients with an eGFR between 15 and 60 mL/min per 1.73 m2 and overt albuminuria, defined by either a 
24-hour urine collection with a minimum of 300 mg of protein or a urinary albumin-to-creatinine ratio 
equivalent to a daily excretion of albumin of at least 300 mg, were recruited. Patients with conditions that 
may potentially be exacerbated by the use of micro-particle curcumin (active peptic ulcer disease, 
hepatobiliary disease, history of significant bleeding) or who take medications that may interact with 
micro-particle curcumin were excluded (Table 1). 
 
5.3 Recruitment 
 
The participant recruitment and randomization flow diagram will follow CONSORT recommendations.31 
We will report the number of participants approached to participate in MPAC-CKD-1, as well as the 
number of participants who: (i) declined to participate, (ii) were approached but were found to be 
ineligible, (iii) were randomized, (iv) received the allocated intervention, (v) were lost to follow-up or 
discontinued the intervention, (vi) were included in the final analysis.  
 
5.4 Withdrawal/follow-up  
 
Participants who stop taking the study drug, but do not withdraw consent to participate in the study, will 
continue with the study’s scheduled telephone visits and may replace remaining in-person visits with 
telephone visits. Participants wishing to withdraw consent will be asked to complete the closing telephone 
visit (scheduled for 4 weeks after study drug completion) 4 weeks after withdrawal of consent. The 
number and percentage of participants who withdraw from the study will be reported overall and by 
group. Reasons for study withdrawal will be presented in a supplementary document.  
 
5.5 Baseline patient characteristics 
 
Table 2 contains a summary of baseline (pre-randomization) characteristics to be summarized by group. 
Continuous baseline characteristics will be summarized as mean (standard deviation [SD]) and categorical 
baseline characteristics will be summarized as number (percent).  
 
 
 

6. Analysis 
 
See Supplemental Table 1 for information on changes made to the analysis section of the MPAC-CKD-1 
study protocol published in The Canadian Journal of Kidney Health and Disease.32 These changes were 
made without knowledge of the trial results.  
 
6.1 Outcome definitions and analysis methods 
 
Two primary outcomes  
We will assess two outcomes: the between-group difference in 6-month urinary albumin-to-creatinine 
ratio (log-transformed, measured in mg/mmol), and the 6-month change in eGFR (6-months post-
randomization minus pre-randomization, measured in mL/min per 1.73m2).  Placebo will serve as the 
referent group in all analyses.  
 
Albuminuria: Albuminuria will be measured using urinary albumin-to-creatinine ratio from first morning 
urine samples. At each visit (pre-randomization, and 3- and 6-months post-randomization), urinary 
albumin-to-creatinine ratio is measured on two consecutive days and the average of the two values will be 
computed. The average of the two values will be log-transformed using the natural logarithm. A summary 
of the pre-treatment, 3-month and 6-month urinary albumin-to-creatinine ratio measurements will be 
provided. The geometric mean ratio of 6-month urinary albumin-to-creatinine ratio will be estimated 
using linear regression, where the outcome is the log-transformed average of two 6-month follow-up visit 
urinary albumin-to-creatinine ratio measurements minus log-transformed average of two pre-treatment 
urinary albumin-to-creatinine ratio measurements, adjusting for a treatment indicator variable and the log-
transformed average of two baseline urinary albumin-to-creatinine ratio measurements. The 95% or 
97.5% CI for the geometric mean ratio will be presented.33 
 
eGFR: eGFR will be calculated using the CKD-EPI formula, which includes patient age, sex, race (black 
vs. other), and the serum creatinine concentration.34 We will summarize the pre-randomization, 3-month 
and 6-month eGFR measurements by group. We will estimate the between-group difference in change in 
eGFR (6-month eGFR minus pre-randomization eGFR), expressed in mL/min per 1.73m2, using linear 
regression. The outcome is the change in eGFR (6-month value minus pre-randomization value) and the 
treatment indicator variable will be included as a covariate. The 95% or 97.5% CI for the between-group 
difference in change in eGFR will be presented.  
 
Secondary outcomes  
 
Health-related quality of life: We will summarize health-related quality of life scores determined by the 
RAND version of the 36-Item Short Form Health Survey (SF-36) administered pre-randomization and at 
3-months and 6-months post-randomization. The physical composite summary (PCS) score and mental 
composite summary (MCS) score of the SF-36 will be examined separately. The between-group 
difference in change in each composite score, 6-month value minus pre-randomization value, will be 
reported with 95% CIs. Beyond preservation of kidney function are several other potential mechanisms 
by which curcumin may benefit quality of life, including potential benefits on depression and chronic 
pain.35,36  
 
Glycemic control: We will summarize the percentage of glycated hemoglobin pre-randomization and at 
3-months and 6-months post-randomization. We will present the between-group difference in change in 
percentage of glycated hemoglobin (6-month value minus pre-randomization value) among patients with 
diabetes mellitus (diabetes mellitus was a stratification variable in the randomization), with the 95% CI.  
 

Progressive CKD, ESRD and death: We will report on the outcome of progressive CKD, ESRD, and 
death, first as a composite outcome, and then as separate components. We will define ESRD as an eGFR 
<15 mL/min/1.73 m2 or the initiation of renal replacement therapy, which includes chronic dialysis or 
transplantation; progressive CKD will be defined as an eGFR loss of ≥ 30% (anytime during follow-up 
from the pre-randomization baseline value) or ESRD. We expect less than 10% of participants will 
experience these outcomes by 6 months. Our focus is to document any trends to inform the expected 
event rate for future studies. Each outcome (progressive CKD, ESRD and death) will be summarized 
separately as number (percentage) of patients with the event by group. The HR of progressive CKD (as its 
own outcome) will be estimated using Cox proportional hazards regression, treating death as a competing 
event. The same approach will be used for the outcome of ESRD. Each estimate will be reported with 
95% CIs.  
 
Serum curcumin levels: To confirm our micro-particle curcumin was bioavailable,16 and to strengthen 
any relationship between micro-particle curcumin and any outcomes we identify, serum levels of 
curcumin and its major metabolites were measured in the first 30 participants 3 months after 
randomization (including patients taking micro-particle curcumin and those taking placebo). Serum 
curcumin and its major metabolites will be summarized in the first 30 participants randomized, by group. 
The between-group difference in average serum curcumin levels measured 3-months post-randomization 
will be reported with the 95% CI.  
 
Pre-specified subgroup analysis 
We will conduct an exploratory subgroup analysis based on a higher or lower estimated risk of kidney 
failure, using the kidney failure risk equation.19 Participants with a 2-year risk of ESRD less than 10% 
will be classified as lower risk, and patients with a risk of 10% or more will be classified as higher risk. 
For both primary outcomes, separate regression models with an interaction term between randomization 
group and the kidney failure risk category indicator variable will be used. The 6-month albumin-to-
creatinine ratio geometric mean ratio will be reported for each kidney failure risk equation group, and the 
difference in change in eGFR will be reported for each kidney failure risk group, along with 95% CIs.  
 
Missing data for reasons other than death will be handled using model-based multiple imputation methods 
(as the primary method to handle missing data in all analyses). Additional analyses will be performed to 
confirm that conclusions are not sensitive to assumptions about the missing-data mechanism.37 In the 
primary analyses, outcomes that are missing due to death will not be imputed (expected in less than 5% of 
patients). In sensitivity analyses, to account for missing values due to death we will (i) use multiple 
imputation to impute missing outcomes; (ii) use single imputation where a missing 6-month albumin-to-
creatinine ratio will be imputed as a doubling of the baseline albumin-to-creatinine ratio value, and 6-
month eGFR will be imputed as half of the pre-randomization eGFR. Pre-randomization data, the 
treatment variable, stratification variables, and data collected at both the 3-month and 6-month visits will 
be included in the multiple imputation models. For patients missing both urinary albumin-to-creatinine 
ratio measurements at a particular visit, one urinary albumin-to-creatinine ratio will be imputed as the 
average value; urinary albumin-to-creatinine ratio will be imputed on the log scale. If a patient is missing 
one of the two urinary albumin-to-creatinine ratio measurements at a particular visit, the single observed 
value will be taken as the average urinary albumin-to-creatinine ratio for that visit and no imputation will 
occur. Estimates from each complete dataset will be combined using standard methods.38 The imputation 
model will allow for an interaction effect between the treatment variable and the kidney failure risk 
equation indicator variable.39  
 
For all primary and secondary outcomes, the pre-randomization, 3-month and 6-month measurements will 
be summarized by group as mean (standard deviation) and median (25th and 75th percentiles) or number 
and percentage, depending on whether the variable is continuous or categorical.  
 

Randomization reliably removes random differences between treatment groups when at least 1000 
participants are included.40 With the size of our sample, it is possible that imbalances may arise between 
the treatment groups on important characteristics that may influence outcomes. In sensitivity analyses, we 
will repeat the two primary analyses while (i) accounting for randomization strata (centre and pre-
randomization diabetes); (ii) accounting for randomization strata and adjusting for variables associated 
with disease progression including age, sex, tobacco use, blood pressure, baseline use of angiotensin-
converting enzyme inhibitors or angiotensin receptor blockers, and baseline use of aldosterone 
antagonists. We do not anticipate that accounting for randomization strata and/or adjustment for pre-
randomization variables will change the results in any meaningful way.  
 
6.2 Missing data 
 
The number and percentage of participants with missing outcome data (all primary and secondary 
outcomes) at the 3-month and 6-month visits will be reported for each group. See Section 6.1 for details 
on multiple imputation for missing values. We will assume that data are missing at random (MAR).  
 
6.3 Additional analyses 
 
No additional analyses are planned. 
 
6.4 Harms 
 
Study medication discontinuation 
We will report the number and percentage of patients who discontinue the study medication by group, as 
study medication discontinuation can suggest that the drug is poorly tolerated.  
 
In addition, we will report the number and percentage of participants who experience the following side 
effects which are assessed using standardized case report forms at the 3-month and 6-month follow-up 
visits. 
 
Minor side-effects 
In rare cases, curcumin has been reported to cause minor nausea, headache, diarrhea, yellow stool, 
temporary giddiness, localized swelling of the skin (contact dermatitis), or hives (urticaria). The number 
and percentage of patients who experience each of these side effects will be reported by treatment group, 
and the number of minor side effects experienced by each patient will be summarized by group. For each 
minor side-effect, a Chi-squared test will be used to test whether the percentage of patients experiencing 
the minor side-effect is equal between groups; P values will be tested at the 0.05 significance level.41 
 
Bleeding 
In the 1990s, two studies described curcumin’s in vitro activity against platelet function.42,43 Further in 
vitro work has since identified curcumin’s ability to inhibit platelet activation, which could increase the 
risk of bleeding.44-48 However, when applied in animal models, curcumin appears to have no effect on 
clinically relevant bleeding,49-53 and in a recent study of oral curcumin loading immediately prior to 
abdominal aortic aneurysm repair, no significant risk of bleeding was identified.54 The number and 
percentage of patients experiencing a bleeding event during the course of the study will be reported by 
treatment group. A Chi-squared test will be used to test whether the percentage of patients experiencing at 
least one bleeding event is equal between groups; P values will be tested at the 0.05 significance level.41 
 
Hypoglycemia 
Curcumin is a potent inhibitor of CYP2C9, which could increase the pharmacologic effects of some anti-
diabetic medications such as sulfonylureas.55 Although curcumin has been studied extensively in the 

setting of diabetes and found to have a low risk of hypoglycemia,56 we will collect data on this potential 
adverse event and report the risk by treatment group. A Chi-squared test will be used to test whether the 
percentage of patients with diabetes pre-randomization experiencing at least one hypoglycemic event in 
follow-up is equal between groups; P values will be tested at the 0.05 significance level.41 
 
6.5 Statistical software 
 
SAS software version 9.4 will be used for all analyses.  
 
 
 

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Table 1. Inclusion and exclusion criteria 
 
Inclusion 
criteria
18 years of age and older 
 
 
eGFR between 15 and 60 mL/min per 1.73 m2 
(calculated on a steady-state serum creatinine level 
using the CKD-EPI formula 34)
 
 
Albuminuria, defined by the most recent measurement 
within the prior 3 months showing either: (a) 24-hour 
urine collection with a minimum of 300 mg of protein, 
or (b) urinary ACR equivalent to a daily excretion of 
albumin of at least 300 mg 
 
 
If receiving an ACE inhibitor or ARB, the dosage must 
be stable for 2 weeks prior to screening. Patients not 
taking an ACE inhibitor or ARB must have a 
documented medical contraindication (e.g. 
hyperkalemia, hypotension)
 
 
For those with diabetes mellitus, willing to measure 
and record blood glucose concentrations
 
 
Willing and able to give written informed consent for 
participation and provide consent for access to medical 
data according to local data protection laws and 
regulations
 
Exclusion 
criteria 
Life expectancy < 1 year 
Operational definition: presence of a terminal illness 
with a poor prognosis resulting in a documented 
expected life span of less than 1 year; advanced chronic 
kidney disease (stage IV or stage V) with a clear plan to 
forgo renal replacement therapy 
 
Known allergy to turmeric or its derivatives (ginger, 
curry, cumin, or cardamom); 
known allergy to ingredients of the study product or 
placebo [microcrystalline cellulose, vegetarian capsule 
(carbohydrate gum [cellulose], purified water), 
vegetable grade magnesium stearate (lubricant), silica] 
 
 
Known allergy to ingredients of the study product or 
placebo [microcrystalline cellulose, vegetarian capsule 
(carbohydrate gum [cellulose], purified water), 
vegetable grade magnesium stearate (lubricant), silica] 
 
 
Pregnant or breastfeeding
 
Women of childbearing potential 
Operational definition: Women of child bearing 
potential are those who are not either surgically sterile 
(bilateral tubal ligation, hysterectomy, bilateral 
salpingo-oophorectomy) or not postmenopausal for at 
least 1 year 
 
Plans for transplantation during the study period  
Operational definition: Patients who have completed a 
transplant recipient work-up or who are active on the 
renal transplant list 
 
Receipt of hemodialysis or peritoneal dialysis in the 
past 3 months 
 
 
Active peptic ulcer disease  
 
Operational definition: Active peptic ulcer disease 
includes patients who are:  
i. Currently receiving H.pylori eradication therapy or 
have received it in the past 30 days (H.pylori 
eradication therapy is combination therapy with a 
proton pump inhibitor [lansoprazole 30 mg twice daily, 
omeprazole 20 mg twice daily,  
pantoprazole 40 mg twice daily, rabeprazole 20 mg 
twice daily, or esomeprazole 40 mg once daily], 
amoxicillin [1 g twice daily], and clarithromycin [500 
mg twice daily] for 7 to 14 days)  
ii. Awaiting upper endoscopy 

(esophagogastroduodenoscopy) for the diagnosis of 
epigastric pain.  
iii. Experiencing ulcer-like dyspepsia (moderate to 
severe epigastric pain that worsens with eating or 
regularly occurs two to five hours after meals) that is 
not otherwise diagnosed. 
 
 
Hepatobiliary disease in the past 4 weeks (biliary 
obstruction, cholecystitis)  
 
Operational definition:  
i. Patients with biliary obstruction includes those with a 
diagnosis of obstruction 
ii. Patients with cholecystitis include those with 
diagnosed cholecystitis and those with suspected 
cholecystitis (right upper quadrant abdominal pain that 
may radiate to the back or right shoulder that lasts four 
to six hours and may be exacerbated by ingestion of 
fatty foods) 
 
Evidence of acute kidney injury (>50% increase in 
serum creatinine in the past 30 days)
 
 
 
History of significant bleeding  
Operational definition: gastrointestinal or 
retroperitoneal bleed requiring transfusion, or any 
intracranial hemorrhage in the last 6 months  
 
Ongoing use of warfarin 
 
Ongoing chemotherapy treatment with 
cyclophosphamide, campatothecin, mechlorethamine 
or doxorubicin 
 
 
Ongoing use of anti-psychotic including haloperidol, 
ariprprazole, risperidone, ziprasidone, pimozide, and 
quetiapine 
 
 
Previous participation in MPAC-CKD-1 
 
Current participation in another investigational 
medication trial 
 
Abbreviations: ACE angiotensin converting enzyme; ACR albumin-to-creatinine ratio; ARB angiotensin receptor blocker; CKD 
chronic kidney disease 
 
 

Table 2. Pre-randomization/pre-treatment participant characteristics 
 
Participant characteristic
Summary measure
Age at recruitment, years
mean (SD)
Male
n (%) 
Height, cm
mean (SD)
Weight, kg
mean (SD)
Body mass index, kg/m2
mean (SD)
Body mass index categories, kg/m2
n (%) 
   < 25 kg/m2 
   25-29 kg/m2
   30-34 kg/m2
   ≥ 35 kg/m2
Systolic blood pressure, mmHg
mean (SD)
Diastolic blood pressure, mmHg
mean (SD)
Serum creatinine, μmol/L
mean (SD)
eGFR, mL/min per 1.73m2 a
mean (SD)
eGFR categories, mL/min per 1.73m2 a
n (%) 
   45-60 
   30-44 
   < 30 
Urinary albumin to creatinine ratio, mg/mmol
mean (SD)
Race/ethnicity
n (%) 
   White/Caucasian
   Black/African American/African Canadian
   Hispanic/Latino 
   Asian (Far East, Southeast Asia, Indian Subcontinent)
   Middle East
   Aboriginal/Native Persons/American Indian
   Other
Diabetes
n (%) 
   HbA1c
mean (SD)
   Insulin use
n (%) 
   Oral hypoglycemic
   Insulin or oral hypoglycemic
History of smoking
n (%) 
   Current
   Remote b
   No
Primary cause of CKD
n (%) 
   Diabetic nephropathy
   Glomerulonephritis
   Hypertensive nephrosclerosis
   Polycystic kidney disease 
   Other
Medication use
n (%) 
   ACE inhibitors
   Angiotensin II receptor blockers (ARBs)
   ACE inhibitors or ARBs
   Diuretics 
   Calcium channel blockers
   Beta blockers
   Aspirin 
   Antiplatelet drugs (not including aspirin)
   Anti-inflammatories (regularly scheduled use)
   Oral glucocorticoids
   Cholesterol lowering medications (niacin, fibrates, statins)
   Opioid analgesic 

   Non-warfarin anticoagulant
a CKD-EPI eGFR equation.34  
b Smoker within the last 10 years, but not currently smoking.  

Micro-Particle Curcumin for the Treatment of Chronic Kidney Disease-1 (MPAC-CKD-1) 
 
Statistical Analysis Plan (SAP) 
 
Supplemental Document 
 
 
 

Supplemental Table 1. Changes to the published MPAC-CKD-1 protocol (Weir MA et al. Can J Kidney 
Health Dis. 2018;5:1-9) 
 
Published protocol
Change in SAP 
Reason for change 
“Using these data, enrolling 250 
patients per group will allow an 
87% power (α=0.025) to exclude a 
difference of 21 mg/mmol. To allow 
for loss to follow-up, we expect to 
recruit up to an additional 75 
patients to reach a minimum of 250 
patients per arm with complete 
follow-up data.” 
“Enrolling a total of 518 patients 
and accounting for 5% loss to 
follow-up allows for 82% power (α 
= 0.025) to detect a geometric mean 
ratio of 0.75, assuming a standard 
deviation of the 6-month log-
transformed albumin-to-creatinine 
ratio of 1.0” 
We will follow the recently published methods 
used by Heerspink et al. (Lancet Diabetes 
Endocrinol. 2019;7:128-39) for between-group 
comparisons involving albumin-to-creatinine data. 
These methods were published after the creation of 
our original protocol. We have updated our sample 
size calculations to reflect this.  
“For changes in eGFR, we will have 
90% power (α = 0.025) to exclude a 
difference of 2.3 mL/min/1.73m2 
between treatment and control 
groups (using a standard deviation 
of 4 mL/min/1.73m2).”  
“For the between-group difference 
in change in eGFR (6-month eGFR 
minus pre-randomization eGFR), we 
will have 81% power (α = 0.025) to 
exclude a difference of 1.65 mL/min 
per 1.73 m2 between treatment and 
control groups (using a standard 
deviation of the change of 5.8 
mL/min per 1.73 m2).”
We have updated our sample size calculations 
using the overall standard deviation of the change 
in eGFR in the MPAC-CKD-1 study (without any 
by-group computations); we have also updated the 
detectable between-group difference to more 
closely align with observed effects in Inker et al. (J 
Am Soc Nephrol. 2019;30:1735-1745). 
“We will use two-sample t tests to 
compare changes in the co-primary 
outcomes.” 
“The geometric mean ratio of 6-
month urinary albumin-to-creatinine 
ratio will be estimated using linear 
regression, where the outcome is the 
log-transformed average of two 6-
month follow-up visit urinary 
albumin-to-creatinine ratio 
measurements minus log-
transformed average of two pre-
treatment urinary albumin-to-
creatinine ratio measurements, 
adjusting for a treatment indicator 
variable and the log-transformed 
average of two baseline urinary 
albumin-to-creatinine ratio 
measurements.”
We will follow the recently published methods 
used by Heerspink et al. (Lancet Diabetes 
Endocrinol. 2019;7:128-39) for between-group 
comparisons involving albumin-to-creatinine data. 
These methods were published after the creation of 
our original protocol.  
 
We have also updated the planned method of 
analysis for the outcome of change in eGFR; linear 
regression will be used instead of a t-test. We 
expect that the estimates and P values will be 
virtually identical in both methods (linear 
regression vs. t-test).  
“We will use a two-sample t test to 
compare changes in hemoglobin 
A1c between the 6-month and 
baseline values. The risk of the 
composite outcome of loss of ⩾30% 
of baseline eGFR, ESRD, or death 
will be compared between groups 
using logistic regression analysis. 
The proportions of patients 
discontinuing study capsules 
and experiencing adverse events 
will be compared between groups 
using the chi-square test.” 
Estimates of between-group 
differences in the secondary 
outcomes will be presented with 
95% confidence intervals, without 
formal hypothesis testing and 
reporting of P values, in order to 
reserve the overall type I error rate 
of 0.05 for the two primary 
outcomes.  
 
Hypothesis tests for between-group 
differences in safety-related 
outcomes will be tested at the 0.05 
significance level. The safety-
related outcomes are: (i) minor side-
effects including minor nausea, 
headache, diarrhea, yellow stool, 
temporary giddiness, localized 
swelling of the skin, or hives; (ii) 
bleeding; (iii) hypoglycemia. 
 
 
These changes are in accordance with new 
guidelines regarding multiple testing and 
adjustment for multiplicity in Harrington et al. (N 
Engl J Med. 2019;381:285-286).  
 
Hypothesis tests for outcomes related to safety will 
be performed according to New England Journal 
of Medicine publication guidelines. 
(https://www.nejm.org/author-center/new-
manuscripts) 

“We will record baseline 
characteristics pertinent to the 
progression of CKD and adjust the 
final point estimates of 
risk for these variables using linear 
regression analysis. Characteristics 
that will be included in the 
multivariable regression 
model are the following: age, sex, 
tobacco use, blood 
pressure, glycemic control, use of 
angiotensin-convertingenzyme 
inhibitors or angiotensin receptor 
blockers, use of 
aldosterone antagonists.”
“In sensitivity analyses, we will 
repeat the two primary analyses 
while (i) accounting for 
randomization strata (centre and 
pre-randomization diabetes); (ii) 
accounting for randomization strata 
and adjusting for variables 
associated with disease progression 
including age, sex, tobacco use, 
blood pressure, baseline use of 
angiotensin-converting enzyme 
inhibitors or angiotensin receptor 
blockers, and baseline use of 
aldosterone antagonists.” 
We have updated the planned sensitivity analyses 
to account for randomization strata, with and 
without adjustment for baseline characteristics. We 
do not anticipate that accounting for randomization 
strata and/or adjustment for pre-randomization 
variables will change results in any meaningful 
way.  
“To confirm the improved 
bioavailability reported with micro-
particle curcumin, and to strengthen 
any relationship between micro-
particle curcumin and any outcomes 
we identify, we will measure serum 
trough levels of curcumin and its 
major metabolites in the first 25 
participants randomized.” 
“To confirm our micro-particle 
curcumin was bioavailable, and to 
strengthen any relationship between 
micro-particle curcumin and any 
outcomes we identify, serum levels 
of curcumin and its major 
metabolites were measured in the 
first 30 participants 3 months after 
randomization (including patients 
taking micro-particle curcumin and 
those taking placebo).”
Serum curcumin and its major metabolites were 
collected in the first 30 patients randomized; the 
measurements were not necessarily taken prior to 
treatment (the values are not necessarily trough 
levels).  
The published protocol contained 
general information on inclusion 
and exclusion criteria. 
The SAP includes detailed 
information on inclusion/exclusion 
criteria.