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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
Sponsor:
Collaborator:
Vanderbilt University Medical Center
Information provided by (Responsible Party):
Baback Roshanravan, University of California, Davis

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.

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

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. 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 102 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
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


Arm Intervention/treatment
Experimental: Veverimer 16 weeks
6 grams daily
Drug: Veverimer
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
Drug: placebo
microcrystalline cellulose, National Formulary Grade




Primary Outcome Measures :
  1. 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

  2. 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.

  3. 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).

  4. muscle work efficiency cycle ergometry [ Time Frame: 16 weeks ]
    joules/ml Oxygen(VO2 peak)

  5. Walking endurance by 6-minute walk [ Time Frame: 16 weeks ]
    Meters

  6. FACIT-F Fatigue (PRO) [ Time Frame: 16 weeks ]
    score on FACIT-F questionnaire


Secondary Outcome Measures :
  1. Intermuscular fat by MRI [ Time Frame: 16 weeks ]
    Percent intermuscular fat.

  2. 30 second sit to stand test [ Time Frame: 16 weeks ]
    number of times patient can get up from sitting position over 30 seconds

  3. PROMIS Fatigue (PRO) [ Time Frame: 16 weeks ]
    score on NIH PROMIS Fatigue questionnaire


Other Outcome Measures:
  1. 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.

  2. Inflammatory cytokines. TNF-alpha and IL-6 [ Time Frame: 16 weeks ]
    Inflammatory cytokines. Units pg/ml.



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Ages Eligible for Study:   30 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Moderate-severe CKD determined by eGFR <60ml/min per 1.73m2 by CKD EPI equation on at least 2 consecutive occasions.
  • Metabolic acidosis defined as bicarbonate level<23 on two consecutive occasions.
  • Age 21 to 85 years old

Exclusion Criteria:

  • Type 2 diabetes managed with insulin treatment
  • Poorly controlled diabetes (HgbA1c>10%)
  • History of persistent hyperkalemia (K>5.4)
  • Chronic treatment with renal replacement therapy
  • History of aortic dissection or severe valvular heart disease
  • Exercise induced angina
  • Uncontrolled cardiac dysrhythmia
  • Oxygen dependent 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 IV 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.
  • Any condition which in the judgement of the clinical investigator places the participant at risk from participation in the study.

Information from the National Library of Medicine

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


Contacts
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Contact: Baback Roshanravan, MD 530-754-0893 broshanr@ucdavis.edu

Locations
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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       delia.woods@vumc.org   
Principal Investigator: Jorge Gamboa, MD PhD         
Sponsors and Collaborators
University of California, Davis
Vanderbilt University Medical Center
Investigators
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Principal Investigator: Baback Roshanravan, MD UC Davis
Principal Investigator: Jorge Gamboa, MD PhD Vanderbilt University
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Responsible Party: Baback Roshanravan, Associate Professor, Nephrology, University of California, Davis
ClinicalTrials.gov Identifier: NCT04984226    
Other Study ID Numbers: 1343905
First Posted: July 30, 2021    Key Record Dates
Last Update Posted: May 17, 2022
Last Verified: May 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual participant data will be available to other investigators on request. The requests will include a proposal outlining the research question, specific exposures, outcomes of interest and analytic plan. All requests will be reviewed by the study principal investigators and coinvestigators prior to release of data. All data will be de-identified.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Time Frame: within 18 months after the conclusion of the study. This data will be available indefinitely

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Baback Roshanravan, University of California, Davis:
Metabolic acidosis
Chronic kidney disease
Insulin resistance
Additional relevant MeSH terms:
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Kidney Diseases
Renal Insufficiency, Chronic
Insulin Resistance
Acidosis
Urologic Diseases
Renal Insufficiency
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Acid-Base Imbalance