Veverimer and Mitochondrial Energetics in Persons With CKD (Venergy-CKD)
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|ClinicalTrials.gov Identifier: NCT04984226|
Recruitment Status : Not yet recruiting
First Posted : July 30, 2021
Last Update Posted : May 17, 2022
|Condition or disease||Intervention/treatment||Phase|
|Chronic Kidney Diseases Metabolic Acidosis Fatigue Physical Endurance Insulin Resistance Mitochondrial Energetics Diabetes||Drug: Veverimer Drug: placebo||Phase 2|
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. Recently a non-sodium polymer (veverimer) selectively binding hydrogen chloride in gastrointestinal tract safely improved serum bicarbonate and meaningfully improved physical functioning in a randomized clinical trial. 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 veverimer or low-dose sodium bicarbonate to placebo in a multicenter randomized, cross-over trial design in 102 persons with moderate-severe CKD and MA. First, the efficacy of 4-months of alkali therapy will be tested comparing veverimer versus placebo on muscle metabolic health in a randomized crossover trial in MA. Second, Test the efficacy of 4-months of alkali therapy comparing veverimer 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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||102 participants|
|Intervention Model:||Crossover Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|Official Title:||Randomized Cross-over Trial of Veverimer and Sodium Bicarbonate on Muscle Mitochondrial Energetics and Physical Endurance in Chronic Kidney Disease and Metabolic Acidosis|
|Estimated Study Start Date :||July 15, 2022|
|Estimated Primary Completion Date :||December 31, 2025|
|Estimated Study Completion Date :||July 30, 2026|
Experimental: Veverimer 16 weeks
6 grams daily
Veverimer is an orally administered, non-absorbed polymer selectively binding hydrochloric acid from the gastrointestinal tract safely elevating endogenous serum bicarbonate levels.
Placebo Comparator: placebo 16 weeks
microcrystalline cellulose, National Formulary Grade
- muscle mitochondrial oxidative capacity by 31P MRS [ Time Frame: 16 weeks ]We will use 31P MRS to evaluate the concentration of phospho-creatine (PCr) and other phosphate-energy carrier molecules in limb muscles. After one minute of basal resting measurements, patients will be asked to perform two knee extensions every three seconds against a resistance of 30 to 40% of the maximal voluntary contraction. The exercise protocol will last 90 seconds (a total of 60 knee extensions) followed by four minutes of rest. The exercise/rest cycle will be repeated three times. The intensity of the exercise decreases phosphocreatine (PCr) levels with minimal change in muscle pH. Spectra analysis was performed with AMARES from the jMRUI software package. Spectra are used to calculate the relative concentrations of inorganic phosphate (Pi), PCr, and ATP. The recovery of PCr after the exercise was fit with a monoexponential model that calculated the time constant tau (τ) in unit of seconds, which is the time to restore approximately 63% of the recovery response
- Insulin sensitivity (SI) by insulin clamp [ Time Frame: 16 weeks ]Primary endpoint for the hyperinsulinemic euglycemic clamp testing will be insulin sensitivity defined as (glucose disposal rate - concentration of infused glucose)/(insulin concentration at steady state - fasting insulin concentration). Units are mg/min per microunit per milliliter.
- total work performed on cycle ergometry VO2 [ Time Frame: 16 weeks ]Total work will be obtained by cycle ergometry using standard protocol measuring oxygen uptake starting at 0 watts (W) at 60 rotations per minute (rpm) increasing by 25W every 2 minutes until volitional exhaustion adapting a prior protocol used in CKD patients. The primary measure will be total work completed (Joules).
- muscle work efficiency cycle ergometry [ Time Frame: 16 weeks ]joules/ml Oxygen(VO2 peak)
- Walking endurance by 6-minute walk [ Time Frame: 16 weeks ]Meters
- FACIT-F Fatigue (PRO) [ Time Frame: 16 weeks ]score on FACIT-F questionnaire
- Intermuscular fat by MRI [ Time Frame: 16 weeks ]Percent intermuscular fat.
- 30 second sit to stand test [ Time Frame: 16 weeks ]number of times patient can get up from sitting position over 30 seconds
- PROMIS Fatigue (PRO) [ Time Frame: 16 weeks ]score on NIH PROMIS Fatigue questionnaire
- Muscle mitochondrial respiration from in situ high resolution respirometry of muscle biopsy tissue [ Time Frame: 16 weeks ]We will determine mitochondrial respiration and oxidative stress under different respiratory states including subsaturating and saturating ADP (state 3), using a combination of complex I (glutamate + malate) and complex II (succinate) substrates, state 4 respiration (proton leak in the absence of ADP and the presence of oligomycin), and fully uncoupled respiration using FCCP. The assay for mtH2O2 production is based on the rate of production of the fluorescent molecule, resorufin, when Amplex Red reacts with H2O2 as described. We a priori select mtH2O2 of reverse electron transport (succinate as substrate in the absence of ADP) as our primary endpoint given the evidence that complex I is the predominant source of mtROS during aerobic exercise. Units are pmol/sec.
- Inflammatory cytokines. TNF-alpha and IL-6 [ Time Frame: 16 weeks ]Inflammatory cytokines. Units pg/ml.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04984226
|Contact: Baback Roshanravan, MDfirstname.lastname@example.org|
|United States, California|
|University of California Davis Health|
|Sacramento, California, United States, 95817|
|Principal Investigator: Baback Roshanravan, MD MS|
|United States, Tennessee|
|Vanderbilt University Medical Center|
|Nashville, Tennessee, United States, 37232|
|Contact: Delia Woods, RN email@example.com|
|Principal Investigator: Jorge Gamboa, MD PhD|
|Principal Investigator:||Baback Roshanravan, MD||UC Davis|
|Principal Investigator:||Jorge Gamboa, MD PhD||Vanderbilt University|