Bone in CKD Alkali Response (BICARb Pilot Trial) (BICARb)

Bone in CKD Alkali Response Pilot Trial (BICARb)

The goal of this clinical trial is to test whether potassium citrate improves skeletal health in adults and children with chronic kidney disease. The main questions it aims to answer are:

• To evaluate effects of potassium citrate treatment on bone quality and strength.
• To evaluate mechanism(s) underlying the effects of potassium citrate on skeletal health.

Participants will be asked to:

• provide blood, urine and answer questions about health and diet three times during an 8 months period
• undergo advanced bone imaging with high resolution-peripheral quantitative CT scan twice during 8 months
• take study pills for 4-6 weeks at the beginning of the study to ensure safety
• take either potassium citrate or placebo for 6 months during the blinded portion of the study

As part of the study, there will be a run-in period followed by the placebo-controlled randomized clinical trial. Researchers will compare the bone imaging between the potassium citrate and the placebo groups at the end of the study.

Study Overview

• Status: Recruiting
• Conditions: Chronic Kidney Diseases; Bone Loss
• Intervention / Treatment: Drug: Potassium Citrate Extended Release Oral Tablet; Drug: Potassium Citrate and Citric Acid Oral Solution; Other: Placebo

Detailed Description

Chronic kidney disease is associated with bone loss and fractures in both children and adults, but bone protective therapies that are both proven and safe to use across the life-course in CKD are lacking. In this study, the investigators will conduct a pilot, double-blinded, randomized, placebo-controlled trial in 15 children and 88 adults evaluating the skeletal effects of potassium alkali therapy. These data will form the basis for a larger U01 proposal to determine the efficacy of potassium citrate on mitigating the effects of CKD on bone.

• Study Type: Interventional
• Enrollment (Estimated): 103
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Kimberly Reidy, MD; Phone Number: 718-655-1120; Email: kreidy@montefiore.org

Study Locations

• United States
  • New York
    • Bronx, New York, United States, 10461
      • Recruiting
      • Albert Einstein College of Medicine
      • Principal Investigator: Kimberly L Reidy, MD
      • Contact: Jordan Nacimba; Phone Number: 718-430-3301; Email: jordan.nacimba@einsteinmed.edu
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Recruiting
      • University of Pittsburgh Medical Center
      • Contact: Juhi Kumar, MD
      • Principal Investigator: Juhi Kumar, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria (Pediatric Inclusion):

• Children 5-17 years old
• Estimated eGFR >30 and <90 ml/min/1.73m2 by CKiD U25 equations
• Females of child-bearing potential must have had a menstrual period in the last month
• Levels of PTH and alkaline phosphatase within 2x normal range and phosphorus within the normal range for age (per local laboratory reference assay)
• 25-hydroxy Vitamin D ≥ 20 ng/mL
• Females of child-bearing potential must be willing to use one form of effective contraception over the course of the study
• Proficiency in English or Spanish
• For participants < 18 years, the participant and/or parent/guardian capable of providing informed consent and assent (assessed by the provider)

Inclusion Criteria (Adult Inclusion):

• Adults ≥ 18 years old
• Estimated eGFR >30 and <90 ml/min/1.73m2 by the new CKD-Epi without race
• Pre-menopausal women of childbearing age must have had a menstrual period in the last month
• Levels of PTH and alkaline phosphatase within 2x normal range and phosphorus up to 5.0 mg/dL (per local laboratory reference assay)
• Levels of 25-hydroxy Vitamin D ≥ 20 ng/mL
• Women of childbearing potential must be willing to use one form of effective contraception over the course of the study
• Proficiency in English or Spanish

Exclusion Criteria (Pediatric and Adult):

• Baseline potassium ≥ 5.5 mEq/L or prior history of hyperkalemia in the last 6 months (potassium > 5.5 mEq/L) or currently taking a potassium lowering agent
• Alkali therapy within the prior 12 months
• Baseline ECG with abnormalities associated with increased risk of arrythmia, excluding left ventricular hypertrophy
• Baseline serum bicarbonate levels < 17 or ≥ 30 mEq/L
• Serum calcium < 8.6 mg/dL, adjusted for serum albumin
• Significant comorbidity causing acid-base imbalance (e.g., active cancer requiring chemotherapy, chronic liver failure, moderate or severe chronic obstructive lung disease, New York Heart Association class 2 or greater congestive heart failure, obstructive sleep apnea requiring nightly continuous positive airway pressure, active glomerular disease requiring immunosuppressive therapy, intestinal malabsorption or celiac disease)
• Plans to relocate out of the area in the next 3 months
• Urine pH > 8 or history of nephrolithiasis
• Lower extremity amputations or non-ambulatory
• Metabolic bone disease not related to CKD (e.g., Paget's disease, primary hyperparathyroidism)
• Endocrinopathy: untreated hyper or hypothyroidism, Cushing's syndrome
• Medical diseases that can affect therapy (severe myocardial damage, acute dehydration, delayed gastric emptying, esophageal compression, or intestinal obstruction or stricture)
• Use of bisphosphonates, denosumab, teriparatide, abaloparatide, romosozumab, raloxifene, estrogen or testosterone replacement therapy, or an unstable dose of glucocorticoids within the 12-months prior to enrollment
• Previous bilateral wrist and tibia fractures
• Solid or liquid organ transplant
• On dialysis or with rapidly deteriorating kidney function or expectation for transplantation or initiation of dialysis in less than 3 months
• Pregnancy or breastfeeding
• Prisoners or institutionalized individuals
• Unwillingness to provide informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo capsules identical to the active capsules.	Other: Placebo; Placebo capsule identical to active ingredient
Experimental: Potassium Citrate; Potassium Citrate extended-release tablets 30 mEq twice daily. 1 mEq/kg/day divided into two doses for children to a maximum dose of 30 mEq twice daily. OR (for children who cannot take pills): Potassium citrate and citric acid for oral solution 1 mEq/kg/day divided into two doses to a maximum dose of 30 mEq twice daily	Drug: Potassium Citrate Extended Release Oral Tablet; Oral potassium citrate extended-release tablet; Drug: Potassium Citrate and Citric Acid Oral Solution; Oral potassium citrate and citric acid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Total volumetric bone mineral density (BMD) - Distal Radius	Change in total volumetric BMD will be analyzed by high resolution peripheral quantitative computed tomography (HR-pQCT). The 6-month absolute and relative (percent) changes in Z-score in distal radius total volumetric BMD will summarized by study arm and analyzed for between group treatment changes.	Baseline to 6 months
Change in Total volumetric bone mineral density (BMD) - Tibia	Change in total volumetric BMD will be analyzed by high resolution peripheral quantitative computed tomography (HR-pQCT). The 6-month absolute and relative (percent) changes in Z-score in tibia total volumetric BMD will summarized by study arm and analyzed for between group treatment changes.	Baseline to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in 24-hour Urine Net Acid Excretion (NAE)	Change in 24-hour urinary NAE from baseline will be assessed by analyzing samples obtained from 24-hour timed urine collections using laboratory titration methods. Results will be quantified and summarized by study arm using basic descriptive statistics and subsequently analyzed for between group treatment changes. Standard urinary NAE values vary but can range from 250-750 mg/24 hours (1.48 to 4.43 mmol/24 hours).	Baseline to 6 months
Change in Parathyroid Hormone (PTH) levels	Change in circulating PTH concentration from baseline will be assessed by the collection of blood samples via venipuncture and analysis for circulating PTH by an immunoassay. Results will be summarized by study arm using basic descriptive statistics and subsequently statistically analyzed for between group changes. Standard PTH reference ranges can vary but are generally between 10-65 pg/mL in plasma.	Baseline to 6 months
Change in circulating biomarkers of bone resorption	Change in circulating biomarkers of bone resorption from baseline will be assessed following the collection of blood samples via venipuncture and subsequent analysis for circulating C-terminal telopeptides of type I collagen using a cross-linking telopeptide of type I collagen (CTX blood test) assay. C-terminal telopeptides can be used as a biomarker to measure bone resorption and turnover. Elevated levels of C-terminal telopeptide can be indicative of increased bone resorption. While standard reference ranges for C-terminal telopeptide can vary, for premenopausal women ranges are typically 40-465 pg/mL in serum and 19-83 ug/L in plasma.	Baseline to 6 months
Change in circulating biomarkers of bone formation	Change in circulating biomarker of bone formation from baseline will be assessed following the collection of blood samples via venipuncture and subsequent analysis for procollagen type-1 N-terminal propeptide (P1NP). A P1NP assay measures the amount of amino-terminal propeptide of type I procollagen in the serum and can be used as biomarker to measure the rate of bone formation. While reference ranges can vary by age, standard reference ranges in adult premenopausal women are 19-83 ug/L.	Baseline to 6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation of serum bicarbonate and urine NAE	Correlation coefficient will be determined between serum bicarbonate and urine net acid excretion. The correlation coefficient is a number between 0 and 1, with 0 being no correlation and 1 being perfect correlation.	6 months
Correlation of serum bicarbonate and bone quality	Correlation coefficient will be determined between serum bicarbonate and bone quality. The correlation coefficient is a number between 0 and 1, with 0 being no correlation and 1 being perfect correlation.	6 months
Correlation between urine net acid excretion and bone quality	Correlation coefficient will be determined between urine net acid excretion and bone quality. The correlation coefficient is a number between 0 and 1, with 0 being no correlation and 1 being perfect correlation.	6 months
Changes in bone alkaline phosphatase	Changes in bone alkaline phosphatase will be compared between the groups. Bone alkaline phosphatase is measured in IU/L. Higher values are indicative of higher bone turnover.	6 months
Changes in TRAP5b	Changes in TRAP5b compared between the groups. TRAP5b are measured in mIU/mL.	6 months
Changes in bone quality	Bone quality as measured by high resolution peripheral quantitative CT will be compared between groups.	6 months

Collaborators and Investigators

• Sponsor: Albert Einstein College of Medicine
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Columbia University; University of Utah; University of Pittsburgh Medical Center
• Investigators: Principal Investigator: Kimberly Reidy, MD, Albert Einstein College of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): August 15, 2024
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): August 1, 2026

Study Registration Dates

• First Submitted: June 2, 2023
• First Submitted That Met QC Criteria: June 15, 2023
• First Posted (Actual): June 26, 2023

Study Record Updates

• Last Update Posted (Actual): October 15, 2024
• Last Update Submitted That Met QC Criteria: October 11, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: Chronic Kidney Disease; Pediatrics; Fractures; Metabolic acidosis; Bone strength
• Additional Relevant MeSH Terms: Pathologic Processes; Urologic Diseases; Disease Attributes; Renal Insufficiency; Chronic Disease; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Renal Insufficiency, Chronic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Natriuretic Agents; Diuretics; Respiratory System Agents; Anticoagulants; Chelating Agents; Sequestering Agents; Expectorants; Calcium Chelating Agents; Citric Acid; Sodium Citrate; Potassium Citrate
• Other Study ID Numbers: 2023-14826; R01DK131811 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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