Probenecid (PB) to Treat Hereditary Nephrogenic Diabetes Insipidus (NDI), ADPKD Treated With Tolvaptan, and Severely Polyuric Patients With Previous Lithium Administration

NCT05190744 | Completed Phase 2 DMC FDA Drug

• 1 other identifier: 21-005437
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this research is to study the effectiveness and safety of the medication PB in slowing the frequent urination related to tolvaptan as long-term treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD), or frequent urination related to inherited nephrogenic diabetes insipidus as an inherited condition or as an acquired condition from prior treatment with lithium.

Conditions

Autosomal Dominant Polycystic Kidney Disease; Nephrogenic Diabetes Insipidus; Acquired Nephrogenic Diabetes Insipidus; Congenital Nephrogenic Diabetes Insipidus

Keywords

Tolvaptan; ADPKD; Polycystic Kidney Disease; Nephrogenic Diabetes Insipidus (NDI); Nephrogenic diabetes insipidus; Inherited nephrogenic diabetes insipidus; Diabetes Insipidus; Lithium; Lithium-induced nephrogenic diabetes insipidus; Vasopressin receptor antagonist; Tolvaptan-induced aquaresis

Outcome Measures

Primary Outcomes (1)

• Change in urine osmolality

  Measured in milliosmoles per kilogram of water (mOsm/kg) from a urine specimen and is a measure of the concentration of osmotically active particles, principally sodium, chloride, potassium, and urea

  Baseline, 30 days

Secondary Outcomes (1)

• Change in urine output

  From Baseline 2 to Post Treatment Follow Up at the end of 5 weeks

Study Arms (3)

Polyuric subjects with Hereditary Nephrogenic Diabetes Insipidus

EXPERIMENTAL

Polyuric subjects with hereditary nephrogenic diabetes insipidus with loss of function of arginine vasopressin receptor 2 (AVPR2) or aquaporin 2 (AQP2) will be treated with PB

Drug: PB

Polyuric subjects with Autosomal Dominant Polycystic Kidney Disease treated with Tolvaptan

EXPERIMENTAL

Polyuric subjects with autosomal dominant polycystic kidney disease on chronic tolvaptan treatment will be treated with PB

Drug: PB

Polyuric subject secondary to lithium administration

EXPERIMENTAL

Polyuric subject post lithium administration will receive PB

Drug: PB

Interventions

PB DRUG

1000mg twice daily (BID). The dose of PB inducing the maximal increase in urine osmolality will be continued for up to four weeks providing that no side effects are observed including clinical and laboratory surveillance.

Polyuric subject secondary to lithium administration; Polyuric subjects with Autosomal Dominant Polycystic Kidney Disease treated with Tolvaptan; Polyuric subjects with Hereditary Nephrogenic Diabetes Insipidus

Eligibility Criteria

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

You may qualify if:

• Male or female, ≥ 18 years of age (inclusive) at time of screening
• Diagnosis of one of the following:
• ADPKD(as delineated in cohort 1)
• Congenital NDI (as delineated in cohort 1)
• Lithium-induced NDI (as delineated in cohort 1)
• Glomerular filtration rate (GFR) ≥ 25 ml/min/1.73 m2 at time of screening visit calculated as in cohort
• hours urine volume in baseline 1 visit ≥ 5000 ml/ day
• If hypertensive, blood pressure controlled on antihypertensives (\<130/80 mm Hg) at least 30 days before day 1. Antihypertensives may be adjusted at time of baseline 2 per PI discretion.
• Have read, understood, and provided written informed consent after the nature of the study has been fully explained and must be willing to comply with protocol requirements and study-related procedures.
• Negative urinary pregnancy test (if applicable) at baseline 2
• Capable of providing urine samples as dictated by the protocol

You may not qualify if:

• Advanced diabetes (e.g., glycosylated hemoglobin \[HgbA1c\] \>7.5%, and/or glycosuria by dipstick, significant proteinuria \[\>300 mcg albumin/mg creatinine\]), other significant kidney disease, kidney cancer, transplanted kidney, single kidney, kidney surgery within the past 6 months (including cyst drainage or fenestration) or acute kidney injury within 6 months prior to screening.
• Clinically significant incontinence, overactive bladder, or urinary retention (e.g., benign prostatic hyperplasia).
• Other significant chronic medical disease (heart failure, diabetes mellitus, liver disease, transient or persistent elevated transaminases)
• History of acute gout attack in the past 30 days
• History of clinically significant drug or alcohol abuse in the 2 years prior to screening visit.
• Uncontrolled hyperuricemia or active gout
• History of hepatotoxicity related to tolvaptan; or clinically significant liver disease or impairment; or alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin values \>1.2 x Upper Limit of Normal (ULN) during screening.
• Medical history or findings that preclude safe participation in the trial or participants who are likely to be non-compliant with trial procedures in the opinion of the investigator or medical monitor.
• Requirement for ongoing diuretic use.
• Participants who are currently taking, or are expected to be taking, strong or moderate CYP3A4 or CYP2C8 inhibitors or inducers including regular use of grapefruit juice, Seville oranges, or St. John's wort. If applicable, there should be a 14-day washout of these treatments prior to Day 1.
• Prior use of a sodium-glucose cotransporter 2 inhibitor (SGLT2i) (e.g., canagliflozin, dapagliflozin, empagliflozin, etc.) within the 2 months prior to screening visit or expected need for initiation of treatment with a SGLT2i inhibitor during the study. Current use of SGLT2i will be reviewed by PI and allow enrollment if patient has been on stable dose for at least 2 months.
• Prior use of a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor within the 2 months prior to screening visit or expected need for initiation of treatment with a HIF-PH inhibitor during the study;
• Participants who have taken any investigational drug or used an investigational device within 30 days, or 5 half-lives, whichever is longer, prior to screening visit 1a or plan to participate in an interventional trial during the study.
• Allergy to probenecid
• History of persistent hyponatremia

Sponsors & Collaborators

• Mayo Clinic: lead
• Otsuka America Pharmaceutical: collaborator

Study Sites (1)

Mayo Clinic

Jacksonville, Florida, 32224, United States

Location

Related Links

• Mayo Clinic Clinical Trials

MeSH Terms

Conditions

Polycystic Kidney, Autosomal Dominant; Diabetes Insipidus, Nephrogenic; Polycystic Kidney Diseases; Diabetes Insipidus

Condition Hierarchy (Ancestors)

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; Pituitary Diseases; Endocrine System Diseases

Study Officials

• Fouad Chebib, MD

  Mayo Clinic

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: SUPPORTIVE CARE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: December 29, 2021
• First Posted: January 13, 2022
• Study Start: September 1, 2022
• Primary Completion: December 8, 2025
• Study Completion: December 8, 2025
• Last Updated: January 27, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)