The COMBINE Study: The CKD Optimal Management With BInders and NicotinamidE (COMBINE)

The COMBINE clinical trial is a pilot study evaluating the effects of nicotinamide and lanthanum carbonate on serum phosphate and fibroblast growth factor 23 (FGF23) in patients with Chronic Kidney Disease (CKD) stages 3-4.

Study Overview

• Status: Completed
• Conditions: Chronic Kidney Disease
• Intervention / Treatment: Drug: Lanthanum Carbonate; Drug: Nicotinamide; Drug: Placebo (for Nicotinamide); Drug: Placebo (for lanthanum carbonate)

• Study Type: Interventional
• Enrollment (Actual): 205
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Diego, California, United States, 92161
      • University of California at San Diego
  • Colorado
    • Denver, Colorado, United States, 80230
      • Denver Nephrology Research
  • District of Columbia
    • Washington, District of Columbia, United States, 20037
      • George Washington University
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60201
      • Northshore University Health System
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • University of Utah
    • Salt Lake City, Utah, United States, 84112
      • Utah VA

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients with estimated glomerular filtration rate (eGFR) 20-45 ml/min/1.73m2
2. Age 18-85 years
3. Serum phosphate ≥ 2.8 mg/dL
4. Platelet count ≥ 125,000/mm3
5. Able to provide consent
6. Able to travel to study visits
7. Able to eat at least two meals a day
8. In the opinion of the site investigator, willing and able to follow the study treatment regimen and comply with the site investigator's recommendations.

Exclusion Criteria:

1. History of allergic reaction to nicotinamide, niacin (excluding flushing), multivitamin preparations, or lanthanum carbonate
2. Liver disease, defined as known cirrhosis by imaging or physician diagnosis, documented alcohol use > 14 drinks/week, or aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, or total bilirubin concentrations > 2 times the upper limit of the local laboratory reference range
3. Creatine kinase (CK) concentrations > 2 times the upper limit of the local laboratory reference range
4. Major hemorrhagic event within the past six months requiring in-patient admission
5. Blood or platelet transfusion within the past six months
6. Secondary hyperparathyroidism (PTH > 5 times the upper limit of normal range for the laboratory) or currently taking cinacalcet (Sensipar)
7. Current, clinically significant malabsorption, as determined at the discretion of the site investigator
8. Anemia (screening Hg < 9.0 g/dl)
9. Serum albumin < 2.5 mg/dl
10. Anticipated initiation of dialysis or kidney transplantation within 12 months as assessed by and at the discretion of the site investigator.
11. Use of immunosuppressive medications (stable oral steroids ≤ 10 mg of prednisone/day or inhaled steroids are exempted)
12. In the opinion of the site investigator, active abuse of alcohol or drugs
13. Recent (within the last 14 days) initiation or change in dose of treatment with 1,25 (OH)2 vitamin D or active vitamin D analogues (paricalcitol or hectorol). Patients on stable doses of these agents initiated more than 14 days prior to screening are eligible to participate.
14. Current or recent treatment (within the last 14 days) with phosphate binder or niacin/nicotinamide > 100 mg/day
15. Current participation in another clinical trial or other interventional research
16. Currently taking investigational drugs
17. Institutionalized individuals, including prisoners and nursing home residents

18. Malignancy requiring therapy within 2 years (basal or squamous cell skin carcinoma and localized prostate cancer are exempted)

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Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lanthanum carbonate + nicotinamide; One nicotinamide 750 mg capsule by mouth twice daily (1500 mg) for 12 months. Two lanthanum carbonate 500 mg capsules by mouth with each meal (3000 mg) for 12 months.	Drug: Lanthanum Carbonate; Drug: Nicotinamide
Placebo Comparator: Lanthanum carbonate + nicotinamide placebo; Two lanthanum carbonate 500 mg capsules by mouth with each meal (3000 mg) for 12 months. One Placebo (for nicotinamide) 750 mg capsule by mouth twice daily (1500 mg) for 12 months.	Drug: Lanthanum Carbonate; Drug: Placebo (for Nicotinamide); Sugar pill manufactured to mimic Nicotinamide 750 mg capsule
Active Comparator: Lanthanum carbonate placebo and nicotinamide; One nicotinamide 750 mg capsule by mouth twice daily (1500 mg) for 12 months. Two Placebo (for lanthanum carbonate) 500 mg capsules by mouth with each meal (3000 mg) for 12 months.	Drug: Nicotinamide; Drug: Placebo (for lanthanum carbonate); Sugar pill manufactured to mimic Lanthanum Carbonate 500 mg capsule
Placebo Comparator: Lanthanum carbonate placebo and nicotinamide placebo; One Placebo (for nicotinamide) 750 mg capsule by mouth twice daily (1500 mg) for 12 months. Two Placebo (for lanthanum carbonate) 500 mg capsules by mouth with each meal (3000 mg) for 12 months.	Drug: Placebo (for Nicotinamide); Sugar pill manufactured to mimic Nicotinamide 750 mg capsule; Drug: Placebo (for lanthanum carbonate); Sugar pill manufactured to mimic Lanthanum Carbonate 500 mg capsule

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
FGF23	Change from baseline to 12 months in FGF23 level.	Baseline to 12 months
Serum Phosphate (mg/dl)	Change from Baseline to 12 months in serum phosphate level	Baseline to 12 months

Collaborators and Investigators

• Sponsor: The Cleveland Clinic
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Study Director: Michael F. Flessner, MD, PhD, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Study Director: John W. Kusek, PhD, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Principal Investigator: Jennifer J Gassman, Ph.D., Data Coordinating Center, Cleveland Clinic; Study Chair: Linda F Fried, MD, University of Pittsburgh

Publications and helpful links

General Publications

• Isakova T, Ix JH, Sprague SM, Raphael KL, Fried L, Gassman JJ, Raj D, Cheung AK, Kusek JW, Flessner MF, Wolf M, Block GA. Rationale and Approaches to Phosphate and Fibroblast Growth Factor 23 Reduction in CKD. J Am Soc Nephrol. 2015 Oct;26(10):2328-39. doi: 10.1681/ASN.2015020117. Epub 2015 May 12.
• Ix JH, Isakova T, Larive B, Raphael KL, Raj DS, Cheung AK, Sprague SM, Fried LF, Gassman JJ, Middleton JP, Flessner MF, Block GA, Wolf M. Effects of Nicotinamide and Lanthanum Carbonate on Serum Phosphate and Fibroblast Growth Factor-23 in CKD: The COMBINE Trial. J Am Soc Nephrol. 2019 Jun;30(6):1096-1108. doi: 10.1681/ASN.2018101058. Epub 2019 May 13.
• Srivastava A, Cai X, Lee J, Li W, Larive B, Kendrick C, Gassman JJ, Middleton JP, Carr J, Raphael KL, Cheung AK, Raj DS, Chonchol MB, Fried LF, Block GA, Sprague SM, Wolf M, Ix JH, Prasad PV, Isakova T. Kidney Functional Magnetic Resonance Imaging and Change in eGFR in Individuals with CKD. Clin J Am Soc Nephrol. 2020 Jun 8;15(6):776-783. doi: 10.2215/CJN.13201019. Epub 2020 Apr 28.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2015
• Primary Completion (Actual): November 1, 2018
• Study Completion (Actual): September 1, 2019

Study Registration Dates

• First Submitted: July 28, 2014
• First Submitted That Met QC Criteria: October 2, 2014
• First Posted (Estimate): October 7, 2014

Study Record Updates

• Last Update Posted (Actual): August 2, 2021
• Last Update Submitted That Met QC Criteria: July 29, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urologic Diseases; Renal Insufficiency; Kidney Diseases; Renal Insufficiency, Chronic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Antimetabolites; Micronutrients; Hypolipidemic Agents; Lipid Regulating Agents; Vitamins; Vitamin B Complex; Nicotinic Acids; Niacinamide; Niacin
• Other Study ID Numbers: DK099877-C; U01DK099877 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: The study data will be archived in the NIDDK Data Repository.
• IPD Sharing Time Frame: We anticipate that the data and documentation will be provided to the NIDDK Data Repository in March 2020 and will become available approximately six months later.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR); Analytic Code

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No