Chronic Kidney Disease
Conditions
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.
Interventions
DRUGNicotinamide
DRUGLanthanum Carbonate
DRUGPlacebo (for Nicotinamide)
Sugar pill manufactured to mimic Nicotinamide 750 mg capsule
DRUGPlacebo (for lanthanum carbonate)
Sugar pill manufactured to mimic Lanthanum Carbonate 500 mg capsule
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
The Cleveland Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
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) \-
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| FGF23 | Baseline to 12 months | Change from baseline to 12 months in FGF23 level. |
| Serum Phosphate (mg/dl) | Baseline to 12 months | Change from Baseline to 12 months in serum phosphate level |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
Nicotinamide
Lanthanum Carbonate | 53 |
| 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.
Lanthanum Carbonate
Placebo (for Nicotinamide): Sugar pill manufactured to mimic Nicotinamide 750 mg capsule | 50 |
| 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.
Nicotinamide
Placebo (for lanthanum carbonate): Sugar pill manufactured to mimic Lanthanum Carbonate 500 mg capsule | 51 |
| 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.
Placebo (for Nicotinamide): Sugar pill manufactured to mimic Nicotinamide 750 mg capsule
Placebo (for lanthanum carbonate): Sugar pill manufactured to mimic Lanthanum Carbonate 500 mg capsule | 51 |
| Total | 205 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Lanthanum Carbonate Placebo and Nicotinamide Placebo | Total | Lanthanum Carbonate + Nicotinamide | Lanthanum Carbonate + Nicotinamide Placebo | Lanthanum Carbonate Placebo and Nicotinamide |
|---|---|---|---|---|---|
| Age, Continuous | 69 years STANDARD_DEVIATION 10 | 69 years STANDARD_DEVIATION 12 | 69 years STANDARD_DEVIATION 12 | 67 years STANDARD_DEVIATION 13 | 70 years STANDARD_DEVIATION 12 |
| Body Mass Index | 31.0 kg / m^2 STANDARD_DEVIATION 6.1 | 31.9 kg / m^2 STANDARD_DEVIATION 7.3 | 33.2 kg / m^2 STANDARD_DEVIATION 8.5 | 30.9 kg / m^2 STANDARD_DEVIATION 6.3 | 32.5 kg / m^2 STANDARD_DEVIATION 8.1 |
| Calcitriol Use | 10 Participants | 41 Participants | 8 Participants | 10 Participants | 13 Participants |
| Diabetes Mellitus | 25 Participants | 112 Participants | 31 Participants | 33 Participants | 23 Participants |
| Diastolic BP | 71.5 mm Hg STANDARD_DEVIATION 12.8 | 71.2 mm Hg STANDARD_DEVIATION 12 | 70.2 mm Hg STANDARD_DEVIATION 11.1 | 71.1 mm Hg STANDARD_DEVIATION 11.7 | 72.0 mm Hg STANDARD_DEVIATION 12.5 |
| eGFR | 32.3 (ml/min/1.73m^2) STANDARD_DEVIATION 7 | 32.4 (ml/min/1.73m^2) STANDARD_DEVIATION 7.3 | 32.2 (ml/min/1.73m^2) STANDARD_DEVIATION 7.2 | 33.0 (ml/min/1.73m^2) STANDARD_DEVIATION 7.9 | 32.1 (ml/min/1.73m^2) STANDARD_DEVIATION 7.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 22 Participants | 5 Participants | 6 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 45 Participants | 183 Participants | 48 Participants | 44 Participants | 46 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Intact PTH | 124.6 pg/ml STANDARD_DEVIATION 94.7 | 121.2 pg/ml STANDARD_DEVIATION 84.8 | 121.4 pg/ml STANDARD_DEVIATION 88.7 | 123.2 pg/ml STANDARD_DEVIATION 75.8 | 115.6 pg/ml STANDARD_DEVIATION 80.4 |
| Phosphorus/Creatinine Ratio | 462.9 mg/g STANDARD_DEVIATION 130.7 | 462.1 mg/g STANDARD_DEVIATION 131.5 | 447.0 mg/g STANDARD_DEVIATION 146.1 | 451.6 mg/g STANDARD_DEVIATION 120.9 | 487.4 mg/g STANDARD_DEVIATION 126.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 3 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 10 Participants | 4 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 16 Participants | 52 Participants | 13 Participants | 14 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 3 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 32 Participants | 136 Participants | 35 Participants | 32 Participants | 37 Participants |
| Region of Enrollment United States | 51 participants | 205 participants | 53 participants | 50 participants | 51 participants |
| Serum Calcium | 9.5 mg/dL STANDARD_DEVIATION 0.5 | 9.5 mg/dL STANDARD_DEVIATION 0.5 | 9.5 mg/dL STANDARD_DEVIATION 0.5 | 9.5 mg/dL STANDARD_DEVIATION 0.5 | 9.5 mg/dL STANDARD_DEVIATION 0.5 |
| Serum FGF-23 | 96.4 pg/ml (range is 10th to 90th pctls) | 98.8 pg/ml (range is 10th to 90th pctls) | 104.0 pg/ml (range is 10th to 90th pctls) | 94.8 pg/ml (range is 10th to 90th pctls) | 103.5 pg/ml (range is 10th to 90th pctls) |
| Serum Phosphate | 3.6 mg/dL STANDARD_DEVIATION 0.5 | 3.7 mg/dL STANDARD_DEVIATION 0.6 | 3.6 mg/dL STANDARD_DEVIATION 0.5 | 3.7 mg/dL STANDARD_DEVIATION 0.6 | 3.8 mg/dL STANDARD_DEVIATION 0.5 |
| Sex: Female, Male Female | 18 Participants | 77 Participants | 20 Participants | 22 Participants | 17 Participants |
| Sex: Female, Male Male | 33 Participants | 128 Participants | 33 Participants | 28 Participants | 34 Participants |
| Systolic BP | 129.3 mm Hg STANDARD_DEVIATION 21.2 | 128.5 mm Hg STANDARD_DEVIATION 17.3 | 126.0 mm Hg STANDARD_DEVIATION 15 | 129.2 mm Hg STANDARD_DEVIATION 17.2 | 129.7 mm Hg STANDARD_DEVIATION 15.3 |
| Urine Albumin Creatinine Ratio | 0.2 (g/g) (range is 10th and 90th pctl) | 0.1 (g/g) (range is 10th and 90th pctl) | 0.1 (g/g) (range is 10th and 90th pctl) | 0.2 (g/g) (range is 10th and 90th pctl) | 0.1 (g/g) (range is 10th and 90th pctl) |
| Urine Phosphorus | 644.4 mg/24 hrs STANDARD_DEVIATION 245.2 | 668.1 mg/24 hrs STANDARD_DEVIATION 252.9 | 657.4 mg/24 hrs STANDARD_DEVIATION 265.2 | 658.5 mg/24 hrs STANDARD_DEVIATION 267.9 | 712.8 mg/24 hrs STANDARD_DEVIATION 235 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 53 | 0 / 50 | 1 / 51 | 1 / 51 |
| other Total, other adverse events | 33 / 53 | 29 / 50 | 30 / 51 | 26 / 51 |
| serious Total, serious adverse events | 18 / 53 | 14 / 50 | 14 / 51 | 14 / 51 |
Outcome results
Primary
FGF23
Change from baseline to 12 months in FGF23 level.
Time frame: Baseline to 12 months
Population: Adults with CKD
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Lanthanum Carbonate + Nicotinamide | FGF23 | .047 pg/ml |
| Lanthanum Carbonate + Nicotinamide Placebo | FGF23 | -.003 pg/ml |
| Lanthanum Carbonate Placebo and Nicotinamide | FGF23 | .193 pg/ml |
| Lanthanum Carbonate Placebo and Nicotinamide Placebo | FGF23 | .138 pg/ml |
Primary
Serum Phosphate (mg/dl)
Change from Baseline to 12 months in serum phosphate level
Time frame: Baseline to 12 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Lanthanum Carbonate + Nicotinamide | Serum Phosphate (mg/dl) | 0.06 mg/dl |
| Lanthanum Carbonate + Nicotinamide Placebo | Serum Phosphate (mg/dl) | 0.06 mg/dl |
| Lanthanum Carbonate Placebo and Nicotinamide | Serum Phosphate (mg/dl) | 0.12 mg/dl |
| Lanthanum Carbonate Placebo and Nicotinamide Placebo | Serum Phosphate (mg/dl) | 0.12 mg/dl |