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

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

Tracking Information
First Submitted Date  ICMJE January 13, 2015
First Posted Date  ICMJE February 24, 2015
Last Update Posted Date July 11, 2018
Actual Study Start Date  ICMJE September 2015
Estimated Primary Completion Date July 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 20, 2017)
  • 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.
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: February 17, 2015)
  • 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.
  • 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.
  • Percent difference between baseline and 24 week (6 month) Interleukin-18 (IL-18) [ Time Frame: Basline, 12 weeks (3 months) and 24 weeks (6 months) ]
    The percent difference between baseline and 24 week (6 month) IL-18 will be compared between the placebo and curcumin groups. A key mechanism by which curcumin may limit progression of CKD is its ability to inhibit inflammation. Urinary IL-18 has been shown to correlate with renal dysfunction in humans. Albuminuria and eGFR largely relate to the health of a component of nephrons call "glomeruli". Damage to other parts of the nephron is better represented by biomarkers such as IL-18. The concentrations of the urinary biomarkers change quickly enough to pick up signals for efficacy or harm before changes in eGFR can be observed. The urine IL-18 assay is reliable with a low coefficient of variation (<5%), concentrations are stable with prolonged storage, and the intra-person variation is low over serial measurements in patients with CKD.
Change History Complete list of historical versions of study NCT02369549 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 17, 2015)
  • 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.
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: February 17, 2015)
  • 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.
  • 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.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Micro-Particle Curcumin for the Treatment of Chronic Kidney Disease
Official Title  ICMJE Micro-Particle Curcumin for the Treatment of Chronic Kidney Disease
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.
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE Chronic Kidney Disease
Intervention  ICMJE
  • Drug: Micro-particle Curcumin
    as described in Arm
    Other Name: Theracumin-Pro 300
  • Drug: Placebo
    Looks, smells, tastes and feels exactly like the Curcumin capsules.
Study Arms  ICMJE
  • 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.

    Intervention: Drug: Micro-particle Curcumin
  • 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.

    Intervention: Drug: Placebo
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 10, 2018)
500
Original Estimated Enrollment  ICMJE
 (submitted: February 17, 2015)
750
Estimated Study Completion Date  ICMJE December 2019
Estimated Primary Completion Date July 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Virginia Schumann 519-685-8500 ext 57394 virginia.schumann@lhsc.on.ca
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02369549
Other Study ID Numbers  ICMJE MPAC-CKD
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Matthew Weir, Lawson Health Research Institute
Study Sponsor  ICMJE Lawson Health Research Institute
Collaborators  ICMJE
  • The Kidney Foundation of Canada
  • Canadian Institutes of Health Research (CIHR)
Investigators  ICMJE
Principal Investigator: Matthew Weir, Nephrologist LHSC
PRS Account Lawson Health Research Institute
Verification Date July 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP