Atorvastatin and Alkali Therapy in Patients With Autosomal Dominant Polycystic Kidney Disease

NCT05870007 | Enrolling By Invitation Phase 2

• 1 other identifier: TMU-JIRB N202208049
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 3

Brief Summary

Polycystic Kidney Disease (PKD) is the most common genetic disease leading to End Stage Kidney Disease (ESKD), affecting between 1 in 500-1000 individuals from every ethnic group. The autosomal dominant (ADPKD) form arises from a two-hit downregulation of proteins encoded by either PKD1 or PKD2. Although many potential therapies have been studied to slow progression of ADPKD, none to date have been proven to be both safe and effective in slowing disease progression. Cholesterol-lowering agents called statins have shown promise in the treatment of younger ADPKD patients, reducing inflammation and progression as assessed by kidney growth, but their utility appears to be limited in older populations and those with more advanced chronic kidney disease (CKD). Recent evidence suggests that acidosis, as often seen in patients with worsening CKD and which may enhance CKD progression, limits the effectiveness of statins and enhances their potential toxicity. The investigators thus hypothesize that correction of acidosis along with statin treatment will be a safe and effective therapeutic regimen to slow CKD progression in the adult ADPKD population and improve overall quality of life in these patients. To test this hypothesis, the investigators will conduct a pilot open-label randomized clinical trial in ADPKD patients with estimated GFR \>45 min (Stage 1-3a CKD) comparing three treatment groups: control, atorvastatin (20 mg po qd), and atorvastatin plus sodium bicarbonate tablets (upto 1800mg po total daily dose) over one year. At the beginning of the study, the investigators will determine the genotype of the trial participants. During the study period, through study visits along with serial blood draws and urinary measurements, the investigators will evaluate safety and tolerability of these treatment regimens, follow renal function and investigate the role of these treatments on acidosis, inflammatory and metabolic biomarkers in patients enrolled at an outpatient facility. Serial follow-up imaging study will also be done in selected patients. This study will establish the framework for larger clinical trials in ADPKD. Moreover, if the results of this study suggest safety/tolerability or potential benefits of statins and alkali therapy in this ADPKD population, the investigators will seek extramural funding for a larger clinical trial to test this therapeutic strategy in ADPKD.

Conditions

Autosomal Dominant Polycystic Kidney Disease; Chronic Kidney Diseases

Outcome Measures

Primary Outcomes (11)

• Changes in kidney function in patients enrolled in different arms of the study

  The investigators will estimate the effect of Atorvastatin and NaHCO3 on kidney function in patients with ADPKD compared to Atorvastatin alone or Standard therapy: serum creatinine-derived estimated glomerular filtration rate (eGFR) calculated by CKD-EPI equation, to evaluate kidney function.

  12 months

• Changes in kidney function in patients enrolled in different arms of the study

  The investigators will estimate the effect of Atorvastatin and NaHCO3 on kidney function in patients with ADPKD compared to Atorvastatin alone or Standard therapy: serum blood urea nitrogen (BUN), to evaluate kidney function.

  12 months

• Changes in kidney function in patients enrolled in different arms of the study

  The investigators will estimate the effect of Atorvastatin and NaHCO3 on kidney function in patients with ADPKD compared to Atorvastatin alone or Standard therapy: serum sodium level (Na), to evaluate kidney function.

  12 months

• Changes in kidney function in patients enrolled in different arms of the study

  The investigators will estimate the effect of Atorvastatin and NaHCO3 on kidney function in patients with ADPKD compared to Atorvastatin alone or Standard therapy: serum potassium level (K), to evaluate kidney function.

  12 months

• Changes in liver function in patients enrolled in different arms of the study

  The investigators will test liver function test panels in patients with ADPKD compared to Atorvastatin alone or Standard therapy. The liver function panel should be within normal limits for enrollment and continuation in the study. Liver function test with ALT will be evaluated at the end of the trial.

  12 months

• Changes in liver function in patients enrolled in different arms of the study

  The investigators will test liver function test panels in patients with ADPKD compared to Atorvastatin alone or Standard therapy. The liver function panel should be within normal limits for enrollment and continuation in the study. Liver function test with AST will be evaluated at the end of the trial.

  12 months

• Changes in liver function in patients enrolled in different arms of the study

  The investigators will test liver function test panels in patients with ADPKD compared to Atorvastatin alone or Standard therapy. The liver function panel should be within normal limits for enrollment and continuation in the study. Liver function test with total bilirubin will be evaluated at the end of the trial.

  12 months

• Changes in liver function in patients enrolled in different arms of the study

  The investigators will test liver function test panels in patients with ADPKD compared to Atorvastatin alone or Standard therapy. The liver function panel should be within normal limits for enrollment and continuation in the study. Liver function test with increase in prothrombin time will be evaluated at the end of the trial.

  12 months

• Changes in muscle injury marker function in patients enrolled in different arms of the study

  The investigators will estimate the effect of Atorvastatin and NaHCO3 on creatine phospho kinase (CPK) in patients with ADPKD compared to Atorvastatin alone or Standard therapy.

  12 months

• Changes in muscle tenderness in patients enrolled in the study

  The investigators will estimate the effect of Atorvastatin and NaHCO3 on muscle tenderness in patients with ADPKD compared to Atorvastatin alone or Standard therapy. The physical exam will evaluate tenderness to palpation in major muscle groups such as leg, arm and back muscles. It will be graded as presence or absence. The patients will only be enrolled if there is absence of tenderness in muscles upon palpation on physical exam. If there is tenderness on exam or the patient reports tenderness that is then confirmed by exam the patient will be removed from the study.

  12 months

• Changes in blood pressure in patients enrolled in different arms of the study

  The investigators will estimate the effect of Atorvastatin and NaHCO3 on blood pressure (systolic and diastolic) in patients with ADPKD compared to Atorvastatin alone or Standard therapy

  12 months

Secondary Outcomes (3)

• Urinary alkalinization changes

  12 months

• Inflammatory markers in blood and urine

  12 months

• AMPK pathway activation

  12 months

Study Arms (3)

Control group

NO INTERVENTION

Standard treatment alone

Atorvastatin

ACTIVE COMPARATOR

Standard treatment + Atorvastatin 20mg QD

Drug: Atorvastatin 20 Mg Oral Tablet

Atorvastatin AND Alkali

ACTIVE COMPARATOR

Standard treatment + Atorvastatin 20mg QD + Sodium Bicarbonate therapy up to 1800mg per day

Drug: Atorvastatin 20 Mg Oral Tablet; Drug: Sodium Bicarbonate 600 Mg Oral Tablet

Interventions

Atorvastatin 20 Mg Oral Tablet DRUG

Atorvastatin 20mg

Atorvastatin; Atorvastatin AND Alkali

Sodium Bicarbonate 600 Mg Oral Tablet DRUG

Sodium bicarbonate would be titrated up to 1800mg per day according to metabolic acidosis severity during clinical follow-up

Atorvastatin AND Alkali

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient voluntarily gives informed consent to participate in the study and signed study's IC and HIPAA.
• Patient is age 18 or older at the time of consent.
• If applicable, female of reproductive potential (Females who are successfully sterilized (surgical sterilization methods include hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are postmenopausal (defined as amenorrhea for at least 12 consecutive months) are not considered to be of reproductive potential) must be non-pregnant (as confirmed by a urine pregnancy test at screening) and non-lactating, and agree:
• Either abstain from intercourse (when it is in line with their preferred and usual lifestyle), or
• Use 2 medically acceptable, highly-effective forms of contraception for the duration of study, and at least 30 days after discontinuing study drug (highly-effective forms of contraception can include approved hormonal contraceptives (oral, injectable, and implantable), and barrier methods (such as a condom or diaphragm) when used with a spermicide.))
• The following ultrasonographic criteria for the diagnosis of ADPKD are for at-risk patients from families of where the genotype is not known:
• If the patient is between 18 and 39 years of age, at least three unilateral or bilateral kidney cysts. The specificity and positive predictive value at this age-range is 100 percent. (sensitivity of 82 and 96 percent for individuals between 15 and 29 years and between 30 to 39 years of age, respectively).
• If the patient is 40 to 59 years of age, at least two cysts in each kidney (sensitivity, specificity, and positive predictive value of 90, 100, and 100 percent, respectively).
• Among individuals 60 years or older, at least four cysts in each kidney. (100 percent sensitivity and specificity).
• The above patients with estimated GFR ≥30 ml/min i.e. with stage 1-3b CKD
• Plasma bicarbonate ≤ 25 mMol/L
• Metabolic acidosis
• The patient agrees to immediately inform Investigator and research coordinator of any changes or planned changes in concomitant medication

You may not qualify if:

• Patients with known allergy or sensitive to Atorvastatin or NaHCO3
• Acute coronary disease, liver disease, muscle disease, or a history of pulmonary edema
• Creatine Phospho Kinase (CPK) \> 2ULN (2.5 ULN in African Americans). Elevated creatine phosphokinase could be a marker of rhabdomyolysis, which is a potential side effect of pravastatin. In general, patients with African American ancestry can have higher normal level of CPK
• Patients with systemic disease that impacting kidney per Investigator's decision
• Patients with known unstable cerebral aneurysm per Investigator's decision
• Pregnancy or lactation, or patients who refuse to use recommended contraception methods
• Proteinuria \> 1000 mg/day
• History of non-compliance of medication per Investigator's decision
• Patients with uncontrolled hypertension, edema, or development of severe MA as per Investigator's decision
• History of cancer
• History of liver disease: hepatic failure/shock, cirrhosis
• Current or planned use of any of prohibited concomitant medication
• Patients with history of nephrolithiasis
• Following medications prohibited at the time of enrollment and during the study and if the patient is started on these medications then the patient will be excluded from the study:
• rapamycin or its analogues tolvaptan spironolactone cimetidine and ketoconazole erythromycin cyclosporine gemfibrozil colchicine niacin (\>1 g/day) other lipid lowering medications in the class of statins

Sponsors & Collaborators

• Taipei Medical University Shuang Ho Hospital: lead
• University of Southern California: collaborator

Study Sites (3)

Shuang Ho Hospital

New Taipei City, 235, Taiwan

Location

Taipei Medical University Hospital

Taipei, Taiwan

Location

Wan Fang Hospital

Taipei, Taiwan

Location

Related Publications (1)

• St Pierre K, Cashmore BA, Bolignano D, Zoccali C, Ruospo M, Craig JC, Strippoli GF, Mallett AJ, Green SC, Tunnicliffe DJ. Interventions for preventing the progression of autosomal dominant polycystic kidney disease. Cochrane Database Syst Rev. 2024 Oct 2;10(10):CD010294. doi: 10.1002/14651858.CD010294.pub3.

  PMID: 39356039 DERIVED

MeSH Terms

Conditions

Polycystic Kidney, Autosomal Dominant; Renal Insufficiency, Chronic

Interventions

Atorvastatin; Tablets; Sodium Bicarbonate

Condition Hierarchy (Ancestors)

Polycystic Kidney Diseases; Kidney Diseases, Cystic; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Ciliopathies; Genetic Diseases, Inborn; Renal Insufficiency; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heptanoic Acids; Fatty Acids; Lipids; Dosage Forms; Pharmaceutical Preparations; Bicarbonates; Carbonates; Carbonic Acid; Carbon Compounds, Inorganic; Inorganic Chemicals; Sodium Compounds

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 12, 2023
• First Posted: May 23, 2023
• Study Start: May 1, 2023
• Primary Completion: December 1, 2025
• Study Completion (Estimated): December 1, 2026
• Last Updated: May 23, 2023

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will not share

Locations

TW (3)