Micro-Particle Curcumin for the Treatment of Chronic Kidney Disease (MPAC-CKD)

• ClinicalTrials.gov Identifier: NCT02369549
• Recruitment Status: Recruiting
• First Posted: February 24, 2015
• Last Update Posted: July 11, 2018
• Sponsor: Lawson Health Research Institute
• Collaborators: The Kidney Foundation of Canada; Canadian Institutes of Health Research (CIHR)
• Information provided by (Responsible Party): Matthew Weir, Lawson Health Research Institute

Study Description

Brief Summary:

An investigator initiated pilot trial: two arm, double blind, placebo controlled, randomized, parallel group of approximately 750 patients with chronic kidney disease, and who have evidence of overt proteinuria, will be treated with micro-particle curcumin versus placebo over 24 weeks from start of the investigational medication date (approximately 6 months) to test whether curcumin can slow chronic kidney disease progression in patients. Three 30 mg capsules of micro-particle curcumin will be self-administered once daily in the morning to determine the the safety and efficacy of curcumin relative to placebo in reducing albuminuria, reducing urinary interleukin-18 and slowing the loss of eGFR.

Condition or disease	Intervention/treatment	Phase
Chronic Kidney Disease	Drug: Micro-particle Curcumin; Drug: Placebo	Phase 3

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Detailed Description:

Limiting the progression from CKD to end-stage renal disease is one of the most important goals in kidney medicine. The evidence implicating inflammation and fibrosis in that process is strong, and there is abundant mechanistic and animal model data to show that curcumin is a potent inhibitor of both inflammation and fibrosis. Two preliminary randomized trials in human CKD hint at curcumin's enormous therapeutic potential in CKD. The Principal Investigator/Sponsor will rigorously test this potential in a broadly selected sample of up to 750 patients with CKD. Compared to previous studies, this study's results will be generalizable across other etiologies of CKD and with a larger sample size; this study will provide more precise estimates of curcumin's benefits and risks. Also, this study proposes to use a new, micro-particle formulation of curcumin that is highly bioavailable. The Principal Investigator/Sponsor will assess curcumin's effects on three key markers of kidney health that encompass the cardinal functions of the nephron. Positive results from MPAC-CKD will lay solid scientific ground-work for a multi-centre trial capable of testing micro-particle curcumin's effect of the most meaningful outcomes: death and the development of end-stage renal disease.

To ensure that this study will have the necessary adherence and tolerability data, up to 750 patients with proteinuric CKD will be randomly assigned to 90 mg per day of micro-particle curcumin or matching placebo, for a total of 24 weeks (approximately 6 months). In the last few years, new formulations of curcumin have been shown to substantially augment absorption by improving its aqueous solubility. The micro-particle formulation of curcumin is one of these new formulations and is the only curcumin delivery system proven to increase bioavailability. Compared to traditional curcumin, micro-particle curcumin achieves total serum concentrations that are 27 fold higher. In this study, micro-particle curcumin will allow the study team to administer the equivalent of 3000 mg of traditional curcumin (which would require six 500 mg capsules daily), in a single 90 mg capsule. In addition, as opposed to traditional curcumin, there is no requirement to take micro-particle curcumin on a full stomach. The Investigator/Sponsor has selected a dose equivalent to 3 grams per day of curcumin because this is within the range of doses proven safe and effective and it will minimize pill burden by allowing the full daily dose to be achieved by three small 30 mg capsules daily In rare cases, curcumin has been reported to cause minor nausea, headache, diarrhea, yellow stool, and temporary giddiness. All unexpected reactions reported in previous studies were easily managed and happened at higher doses than what will be used in MPAC-CKD.

This study will assess three co-primary outcomes at baseline, 12 weeks (approximately 3 months) and 24 weeks (approximately 6 months) from the date of starting the investigational medication: albuminuria, eGFR, and urinary interleukin-18. Glycemic control will be assessed at baseline, 12 weeks (approximately 3 months) and 24 weeks (approximately 6 months) from the date of starting the investigational medication, among patients with diabetes mellitus.

Medical history, lab values and vitals will be collected and/or updated at each in-person visit. Each participant will be provided with instructions and study schedule. Participants with diabetes mellitus will be given a home glucose log-book.

Protocol compliance will be tested through pill counts and interviews at each follow-up visit. Side effects will be assessed using standardized case report forms at each visit. Participants will be contacted by telephone one week into the trial and then once every 4 weeks (monthly) for 28 weeks (approximately 7 months) for safety monitoring and reporting and to reinforce importance of compliance. In-person visits will occur at 12 and 24 weeks (approximately 3 and 6 months) after randomization and the start of the investigational medication, at which time investigational medication will be counted and supply replenished. First morning at-home urine specimens will be collected at baseline and again arranged at the in-person visits at 12 and 24 weeks (approximately 3 and 6 months). Participants will also be encouraged to report any events they may experience directly to the coordinator(s) and/or PI.

Participants who withdraw consent to continue treatments, will be encouraged to undergo the planned assessments. Withdrawal at the request of investigators or medical personnel may include, but are not limited to:

1. Symptoms are deemed to be potentially related to the sue of the investigational medication;
2. New diagnosis of exclusion criteria;
3. Inter-current illness not related to the use of the investigational Natural Health Product (NHP) medication;
4. Unacceptable side effects;
5. Death;
6. Improved health status.

Estimated time to complete recruitment: Averaging 136 weeks, approximately 34 months.

Long-term outcomes will be tracked using administrative data housed at The Institute for Clinical Evaluative Sciences (ICES), an independent research facility in Toronto, Ontario. ICES works with the Ontario Ministry of Health and Long-Term Care to study the impact of health care and diseases in Ontario.

A panel of external experts and study investigators will comprise the Steering Committee and will ensure the integrity of the study. They will be responsible for reviewing and acting upon the recommendations of the Data Safety Monitoring Board, amendments to the protocol, oversight of publication and dissemination of study results.

Additional analysis:The first 30 consented and randomized participants, will have a 4.5 ml blood sample taken at the 12 week (3 month) visit. This sample will be processed and stored at -80 degrees C. for batch testing for plasma micro-particle curcumin concentrations. Two urine specimens obtained from each day of the home collections at baseline, 12 and 24 weeks (average 3 and 6 months) will be processed and stored at -80 degrees C for batch analysis of IL-18 uncorrected for urinary creatinine concentration (primary outcome #3). Specimens will be stored in the Kidney Clinical Research Unit, London, Ontario and shipped for analysis by Yale University,New Haven, Connecticut, USA.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 500 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Micro-Particle Curcumin for the Treatment of Chronic Kidney Disease
• Actual Study Start Date: September 2015
• Estimated Primary Completion Date: July 2019
• Estimated Study Completion Date: December 2019

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Micro-particle curcumin; Three 30 mg capsules once daily, self-administered for 6 months. Curcumin is a nutraceutical, which are products isolated or purified from foods. The rhizomes of the plant Curcuma longa produces turmeric, a spice commonly used in Indian cuisine. Turmeric is comprised of three curcuminoids, of which curcumin is the most abundant. Curcumin is a polyphenol molecule that has been investigated for anti-inflammatory and anti-neoplastic properties since the 1970s.	Drug: Micro-particle Curcumin; as described in Arm; Other Name: Theracumin-Pro 300
Placebo Comparator: Placebo; Three 30 mg capsules taken once daily, self-administered for 6 months. Placebo capsules are identical to the curcumin capsules in color, taste, smell, size and shape.	Drug: Placebo; Looks, smells, tastes and feels exactly like the Curcumin capsules.

Outcome Measures

Primary Outcome Measures :

1. Percent difference between baseline and 24 week (6 month) albuminuria [ Time Frame: Baseline, 12 weeks (3 months), 24 weeks (6 months) ]
   The percent difference between baseline and 24 week (6 month) albuminuria will be compared between placebo and curcumin groups. Albuminuria will be standardized to the urine creatinine on a first morning urine sample. The loss of selectivity of the filtration barrier in the glomerulus is a factor common to all albuminuric CKD, regardless of etiology. Albuminuria is the cardinal manifestation of a malfunctioning filtration barrier and the spillage of albumin into renal tubules is thought to be toxic to tubular cells, resulting in further kidney damage. Therefore, in the current understanding, albuminuria is both a marker and a mediator of kidney damage. Reduction of albuminuria has repeatedly been associated with improved renal outcomes. Leaders in the field of nephrology recommend that albuminuria be used as a valuable predictor of response to therapy for the prevention of kidney failure.
2. Change in Estimated Glomerular Filtration rate (eGFR) from baseline to 24 weeks (6 months) [ Time Frame: Baseline, 12 weeks (3 months), 24 weeks (6 months) ]
   Change in eGFR from baseline to 24 weeks (6 months) will be compared between the placebo and curcumin groups. by definition, GFR must decline for patients to develop kidney failure. There is no known influence of curcumin on creatinine generation, secretion or extrarenal elimination. eGFR is well suited to assess patients with CKD who experience fast progression to end-stage renal disease.

Secondary Outcome Measures :

1. Glycemic control as assessed by change in the percentage of glycated hemoglobin [ Time Frame: Baseline, 12 week (3 months) and 24 week (6 months) ]
   Monitored among patients with diabetes mellitus. Curcumin use has been associated with improved glycemic control in animal models. Given the large proportion of patients with both CKD and diabetes, this outcome warrants exploration.
2. Study agent discontinuation [ Time Frame: Every 4 weeks (averaging monthly), self-reported ]
   We will test protocol compliance through pill counts and interviews at each follow-up visit. Reasons for discontinuation will be recorded using standardized case report forms.
3. Renal failure composite [ Time Frame: Every 4 weeks (averaging monthly) ]
   eGFR loss of 30% or end-stage renal disease or death. Given our eligibility criteria, it is likely that <10% of participants would experience these outcomes by 24 weeks(approximately 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 future studies.
4. Safety as assessed by adverse events and patient-reported side effects [ Time Frame: Every 4 weeks (averaging monthly), self-reported ]
   Adverse events will be recorded through case report forms and reported to the principal investigator. Side effects will be assessed using standardized case report forms at each 4 week (monthly) visit. Participants are encouraged to contact the coordinator or investigator to report any concerns.

Other Outcome Measures:

1. Long-term incidence of renal replacement therapy [ Time Frame: Assessed 2 years post trial close-out ]
   Long-term outcomes will be tracked using administrative data housed at the Institute for Clinical Evaluative Sciences (ICES), an independent research facility in Toronto, Ontario. ICES works with the Ontario Ministry of Health and Long-Term Care to study the impact of health care and diseases in Ontario. All subjects enrolled in MPAC-CKD will have data on hospital visits, physician services, and vital statistics recorded in health administrative databases housed at ICES.
2. Long-term mortality [ Time Frame: Assessed 2 years post trial close-out ]
   Long-term outcomes will be tracked using administrative data housed at the Institute for Clinical Evaluative Sciences (ICES), an independent research facility in Toronto, Ontario. ICES works with the Ontario Ministry of Health and Long-Term Care to study the impact of health care and diseases in Ontario. All subjects enrolled in MPAC-CKD will have data on hospital visits, physician services, and vital statistics recorded in health administrative databases housed at ICES.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. eGFR between 15 and 60 ml/min/1.73 m2;
2. 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 albumin to creatinine ratio equivalent to a daily excretion of albumin of at least 300 mg;
3. If diabetic, is able and willing to take and record glucose levels at home;
4. If receiving and ACE inhibitor or angiotension II receptor blocker (ARB), the dosage must be stable for 2 weeks prior to screening. Patients not taking and ACE or ARB must have a documented medical contraindication (e.g. hyperkalemia, hypotension);
5. 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:

1. Life expectancy < 1 year;
2. Known allergy to turmeric or its derivatives (ginger, curry, cumin, or cardamom);
3. Known allergy to ingredients of the study product or placebo (microcrystalline cellulose, vegetarian capsule, vegetable grade magnesium stearate, silica;
4. Pregnant or breastfeeding;
5. Women of child-bearing potential who are not either surgically sterile or not postmenopausal for at least 1 year;
6. Plans for transplantation during the study period;
7. Receipt of hemodialysis or peritoneal dialysis in the past 3 months;
8. Active peptic ulcer disease;
9. Hepatobiliary disease in the past 4 weeks;
10. Evidence of acute kidney injury (>50% increase in serum creatinine in the past 30 days);
11. History of significant bleeding (GI or retroperitoneal bleed requiring transfusion, or any intracranial hemorrhage in the past 6 months);
12. Ongoing use of warfarin;
13. Ongoing treatment with cyclophosphamide, camptothecin, mechlorethamine or doxorubicin;
14. Ongoing use of anti-psychotic medication including haloperidol, aripiprazole, risperidone, ziprasidone, pimozide, and quetiapine;
15. Previous participation in MPAC-CKD;
16. Current participation on another investigational medication trial.

Contacts and Locations

Contacts

Contact: Virginia Schumann; 519-685-8500 ext 57394; virginia.schumann@lhsc.on.ca

Locations

Canada, Ontario

Population Health Research Institute; Recruiting

Hamilton, Ontario, Canada, L8L 0A6

Contact: Michael Walsh, MD, PhD 905-521-2100 ext 40334 mike.walsh@phri.ca

Kidney Clinical Care Unit; Recruiting

London, Ontario, Canada, N6A 5A5

Contact: Matthew Weir, Nephrologist 519-663-2998 matthew.weir@lhsc.on.ca

University Hospital; Recruiting

London, Ontario, Canada, N6A 5A5

Contact: Matthew Weir, Nephrologist 519-663-2998 matthew.weir@lhsc.on.ca

Victoria Hospital; Recruiting

London, Ontario, Canada, N6A 5W9

Contact: Amit Garg, Nephrologist 519-685-8502 amit.garg@lhsc.on.ca

Sponsors and Collaborators

Lawson Health Research Institute

The Kidney Foundation of Canada

Canadian Institutes of Health Research (CIHR)

Investigators

• Principal Investigator: Matthew Weir, Nephrologist; LHSC

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Weir MA, Walsh M, Cuerden MS, Sontrop JM, Chambers LC, Garg AX. Micro-Particle Curcumin for the Treatment of Chronic Kidney Disease-1: Study Protocol for a Multicenter Clinical Trial. Can J Kidney Health Dis. 2018 Dec 5;5:2054358118813088. doi: 10.1177/2054358118813088. eCollection 2018.

• Responsible Party: Matthew Weir, Nephrologist, MD, FRCPC, MSc, Lawson Health Research Institute
• ClinicalTrials.gov Identifier: NCT02369549 History of Changes
• Other Study ID Numbers: MPAC-CKD
• First Posted: February 24, 2015
• Last Update Posted: July 11, 2018
• Last Verified: July 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Matthew Weir, Lawson Health Research Institute:

Chronic Kidney Disease (CKD); Micro-particle curcumin; Albuminuria

Additional relevant MeSH terms:

Kidney Diseases; Renal Insufficiency, Chronic; Urologic Diseases; Renal Insufficiency; Curcumin; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action