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

NCT02258074 | Completed Phase 2 Results DMC

• 2 other identifiers: DK099877-CU01DK099877
• Study Type: interventional
• Target: 205
• Locations: 1 country
• Sites: 7

Brief Summary

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.

Conditions

Chronic Kidney Disease

Outcome Measures

Primary Outcomes (2)

• 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

Study Arms (4)

Lanthanum carbonate + nicotinamide

EXPERIMENTAL

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: Nicotinamide; Drug: Lanthanum Carbonate

Lanthanum carbonate + nicotinamide placebo

PLACEBO COMPARATOR

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)

Lanthanum carbonate placebo and nicotinamide

ACTIVE COMPARATOR

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)

Lanthanum carbonate placebo and nicotinamide placebo

PLACEBO COMPARATOR

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); Drug: Placebo (for lanthanum carbonate)

Interventions

Nicotinamide DRUG

Lanthanum carbonate + nicotinamide; Lanthanum carbonate placebo and nicotinamide

Lanthanum Carbonate DRUG

Lanthanum carbonate + nicotinamide; Lanthanum carbonate + nicotinamide placebo

Placebo (for Nicotinamide) DRUG

Sugar pill manufactured to mimic Nicotinamide 750 mg capsule

Lanthanum carbonate + nicotinamide placebo; Lanthanum carbonate placebo and nicotinamide placebo

Placebo (for lanthanum carbonate) DRUG

Sugar pill manufactured to mimic Lanthanum Carbonate 500 mg capsule

Lanthanum carbonate placebo and nicotinamide; Lanthanum carbonate placebo and nicotinamide placebo

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• History of allergic reaction to nicotinamide, niacin (excluding flushing), multivitamin preparations, or lanthanum carbonate
• 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
• Creatine kinase (CK) concentrations \> 2 times the upper limit of the local laboratory reference range
• Major hemorrhagic event within the past six months requiring in-patient admission
• Blood or platelet transfusion within the past six months
• Secondary hyperparathyroidism (PTH \> 5 times the upper limit of normal range for the laboratory) or currently taking cinacalcet (Sensipar)
• Current, clinically significant malabsorption, as determined at the discretion of the site investigator
• Anemia (screening Hg \< 9.0 g/dl)
• Serum albumin \< 2.5 mg/dl
• Anticipated initiation of dialysis or kidney transplantation within 12 months as assessed by and at the discretion of the site investigator.
• Use of immunosuppressive medications (stable oral steroids ≤ 10 mg of prednisone/day or inhaled steroids are exempted)
• In the opinion of the site investigator, active abuse of alcohol or drugs
• 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.
• Current or recent treatment (within the last 14 days) with phosphate binder or niacin/nicotinamide \> 100 mg/day
• Current participation in another clinical trial or other interventional research

Sponsors & Collaborators

• The Cleveland Clinic: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (7)

University of California at San Diego

San Diego, California, 92161, United States

Location

Denver Nephrology Research

Denver, Colorado, 80230, United States

Location

George Washington University

Washington D.C., District of Columbia, 20037, United States

Location

NorthShore University Health System

Chicago, Illinois, 60201, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

University of Utah

Salt Lake City, Utah, 84112, United States

Location

Utah VA

Salt Lake City, Utah, 84112, United States

Location

Related Publications (5)

• 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.

  PMID: 25967123 BACKGROUND

• 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.

  PMID: 31085679 RESULT

• Natale P, Green SC, Ruospo M, Craig JC, Vecchio M, Elder GJ, Strippoli GF. Phosphate binders for preventing and treating chronic kidney disease-mineral and bone disorder (CKD-MBD). Cochrane Database Syst Rev. 2025 Jun 27;6(6):CD006023. doi: 10.1002/14651858.CD006023.pub4.

  PMID: 40576086 DERIVED

• Trujillo J, Alotaibi M, Seif N, Cai X, Larive B, Gassman J, Raphael KL, Cheung AK, Raj DS, Fried LF, Sprague SM, Block G, Chonchol M, Middleton JP, Wolf M, Ix JH, Prasad P, Isakova T, Srivastava A. Associations of Kidney Functional Magnetic Resonance Imaging Biomarkers with Markers of Inflammation in Individuals with CKD. Kidney360. 2024 May 1;5(5):681-689. doi: 10.34067/KID.0000000000000437. Epub 2024 Apr 4.

  PMID: 38570905 DERIVED

• 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.

  PMID: 32345747 DERIVED

MeSH Terms

Conditions

Renal Insufficiency, Chronic

Interventions

Niacinamide; lanthanum carbonate

Condition Hierarchy (Ancestors)

Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring

Results Point of Contact

• Title: Jennifer J. Gassman, PhD
• Organization: Cleveland Clinic Foundation

gassmaj@ccf.org

216-444-9938

Study Officials

• 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)

  STUDY DIRECTOR

• Jennifer J Gassman, Ph.D.

  Data Coordinating Center, Cleveland Clinic

  PRINCIPAL INVESTIGATOR

• Linda F Fried, MD

  University of Pittsburgh

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator-Data Coordinating Center

Study Record Dates

• First Submitted: July 28, 2014
• First Posted: October 7, 2014
• Study Start: March 1, 2015
• Primary Completion: November 1, 2018
• Study Completion: September 1, 2019
• Last Updated: August 2, 2021
• Results First Posted: July 30, 2021

Record last verified: 2021-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR, ANALYTIC CODE
• 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.

Locations

US (7)