Sodium Bicarbonate and Mitochondrial Energetics in Persons With CKD

NCT ID: NCT04984226

Last Updated: 2025-05-14

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 80 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-09-08
• Study Completion Date: 2026-07-30

Brief Summary

Skeletal muscle metabolic health is critical for mobility and an underrecognized target of metabolic acidosis in chronic kidney disease. Impaired muscle mitochondrial metabolism underlies poor physical endurance increasing the risk of mobility disability. The proposed project will use precise in vivo tools to study the pathophysiology of poor physical endurance in a clinical trial treating metabolic acidosis among persons living with chronic kidney disease.

Detailed Description

Chronic kidney disease (CKD) is highly prevalent affecting 14% of the U.S. population leading to substantial morbidity and reduced quality of life. Older adults with CKD identify maintenance of functional independence as their top priority. Skeletal muscle health is critical for mobility and an underrecognized target of metabolic acidosis (MA) and protein energy wasting in CKD. Skeletal muscle endurance provides a window into muscle metabolic health and muscle quality. Muscle mitochondrial metabolism is central to muscle and walking endurance providing energy from carbohydrates and fats to power repeated muscle contraction. Investigators showed metabolic acidosis and muscle adiposity as the major determinants of muscle mitochondrial function.

Metabolic acidosis (MA) is long believed to be the main mechanism leading to skeletal muscle wasting and peripheral insulin resistance in CKD. Skeletal muscle mitochondrial metabolism is considered a principal determinant of peripheral insulin sensitivity and muscle quality, but little is known of the impact of MA on muscle mitochondrial function. Muscle mitochondrial dysfunction leads to defective lipid metabolism augmenting adiposity and lipotoxic intermediates resulting in insulin resistance, low endurance, and muscle atrophy. Using in vivo 31Phosphorus Magnetic Resonance Spectroscopy (31P MRS) investigators showed that the presence and severity of CKD is strongly associated with impaired muscle mitochondrial capacity to generate ATP translating into poor walking endurance. Investigators also showed MA and muscle adiposity are the major determinants of muscle mitochondrial function. Despite the importance of mitochondrial function to muscle health, it is unknown if treatment of MA benefits muscle mitochondrial function, adiposity or endurance in CKD.

The proposed project will use precise, in vivo 31P MRS and gold-standard testing of peripheral insulin sensitivity by hyperinsulinemic euglycemic clamp to probe the pathophysiology of MA and low endurance in a clinical trial of alkali therapy in CKD and MA. We will compare sodium bicarbonate to placebo in a multicenter randomized, cross-over trial design in 80 persons with moderate-severe CKD and MA. First, the efficacy of 4-months of alkali therapy will be tested comparing sodium bicarbonate versus placebo on muscle metabolic health in a randomized crossover trial in MA. Second, we will test the efficacy of 4-months of alkali therapy comparing sodium bicarbonate versus placebo on improving physical endurance in MA. The rationale is that identification of therapeutic targets for low physical endurance will inform the development of pharmacologic interventions. Long term, it is expected that strategies treating MA will improve exercise tolerance enabling effective engagement in lifestyle interventions improving quality of life in CKD.

Conditions

Chronic Kidney Diseases; Metabolic Acidosis; Fatigue; Physical Endurance; Insulin Resistance; Mitochondrial Energetics; Diabetes

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

Sodium bicarbonate 16 weeks

Sodium bicarbonate will be dosed at 0.8meq per kilogram of ideal body weight daily (1meq is approximately 84mg). We will use the Devine formula to determine ideal body weight. Investigational Drug Services at both UC Davis and Vanderbilt will compound the sodium bicarbonate. Sodium bicarbonate 650 mg tablets will be over-encapsulated and matching placebo capsules will be prepared. Participants will be limited to a maximum of 9 capsules daily (maximum dose = 5850mg of sodium bicarbonate). Capsules will be dispensed to patients in two separate 8-week allotments. The dose will be rounded to the nearest whole capsule and depending on participant preference may be divided into portions taken twice or thrice daily. Given the high probability of interruption in sodium bicarbonate supply and availability, we may need to change brands of sodium bicarbonate intermittently.

Group Type: EXPERIMENTAL

Sodium bicarbonate

Intervention Type: DRUG

Sodium bicarbonate will be dosed at 0.8meq per kilogram of ideal body weight daily (1meq is approximately 84mg). We will use the Devine formula to determine ideal body weight. Investigational Drug Services at both UC Davis and Vanderbilt will compound the sodium bicarbonate. Sodium bicarbonate 650 mg tablets will be over-encapsulated and matching placebo capsules will be prepared. Participants will be limited to a maximum of 9 capsules daily (maximum dose = 5850mg of sodium bicarbonate). Capsules will be dispensed to patients in two separate 8-week allotments. The dose will be rounded to the nearest whole capsule and depending on participant preference may be divided into portions taken twice or thrice daily. Given the high probability of interruption in sodium bicarbonate supply and availability, we may need to change brands of sodium bicarbonate intermittently.

placebo 16 weeks

Microcrystalline cellulose

Group Type: PLACEBO_COMPARATOR

placebo

Intervention Type: DRUG

The placebo and filler for for sodium bicarbonate capsules will be comprised of microcrystalline cellulose. Capsule appearance for control and sodium bicarbonate will be the same.

Interventions

Sodium bicarbonate

Sodium bicarbonate will be dosed at 0.8meq per kilogram of ideal body weight daily (1meq is approximately 84mg). We will use the Devine formula to determine ideal body weight. Investigational Drug Services at both UC Davis and Vanderbilt will compound the sodium bicarbonate. Sodium bicarbonate 650 mg tablets will be over-encapsulated and matching placebo capsules will be prepared. Participants will be limited to a maximum of 9 capsules daily (maximum dose = 5850mg of sodium bicarbonate). Capsules will be dispensed to patients in two separate 8-week allotments. The dose will be rounded to the nearest whole capsule and depending on participant preference may be divided into portions taken twice or thrice daily. Given the high probability of interruption in sodium bicarbonate supply and availability, we may need to change brands of sodium bicarbonate intermittently.

Intervention Type: DRUG

placebo

The placebo and filler for for sodium bicarbonate capsules will be comprised of microcrystalline cellulose. Capsule appearance for control and sodium bicarbonate will be the same.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Moderate-severe CKD determined by eGFR <50ml/min per 1.73m2 by CKD EPI equation on at least 2 consecutive occasions.
• Metabolic acidosis defined as bicarbonate level<24 on two consecutive occasions. Bicarbonate level of 24 or less allowed if eGFR<=45ml/min per 1.73m2
• Age 21 to 85 years old

Exclusion Criteria

• Type 1 diabetes
• Poorly controlled diabetes (HgbA1c>10%)
• History of persistent hyperkalemia (K>5.4)
• History of persistent hypokalemia (K<3.3)
• Uncontrolled blood pressure (>170/100)
• Chronic treatment with renal replacement therapy
• History of aortic dissection or severe valvular heart disease
• Exercise induced angina
• Uncontrolled cardiac dysrhythmia
• Oxygen dependent chronic obstructive pulmonary disease (COPD)
• Symptomatic claudication
• End stage liver disease
• Mobility disability defined as inability to walk without human assistance
• Dementia or psychosis
• Patients who cannot consent
• Active use of intraveneous drugs
• Non-english speaking
• History of transplant
• Implants that prohibit MRI measurements or trauma involving metal fragments
• Pacemaker
• Expectation to start dialysis during the course of study.
• Women who are breastfeeding, pregnant, or are wanting to become pregnant
• Any condition which in the judgement of the clinical investigator places the participant at risk from participation in the study.

• Drugs- anticoagulants or antiplatelets:

• Anticoagulants, any 1 (coumadin, rivaroxaban, apixaban, dabigatran, edoxaban)
• Antiplatelets, any 2 (aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticragrelor, ticlopidine, vorapaxar)
• Platelet count <100,000
• International normalized ratio (INR)>1.4

• Minimum Eligible Age: 21 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Vanderbilt University Medical Center

OTHER

Sponsor Role: collaborator

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: collaborator

University of California, Davis

OTHER

Sponsor Role: lead

Responsible Party

Baback Roshanravan

Associate Professor, Nephrology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Baback Roshanravan, MD

Role: PRINCIPAL_INVESTIGATOR

UC Davis

Jorge Gamboa, MD PhD

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University

Locations

University of California Davis Health

Sacramento, California, United States

Site Status: RECRUITING

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Site Status: NOT_YET_RECRUITING

Countries

United States

Central Contacts

Baback Roshanravan, MD

Role: CONTACT

broshanr@ucdavis.edu

530-754-0893

Facility Contacts

Amanda Lopez

Role: primary

aflopez@ucdavis.edu

916-734-0898

Erica Goude

Role: backup

emgoude@ucdavis.edu

(916) 734-0384

Delia Woods, RN

Role: primary

delia.woods@vumc.org

Other Identifiers

5R01DK129793

Identifier Type: NIH

Identifier Source: secondary_id

View Link

1343905

Identifier Type: -

Identifier Source: org_study_id