Effect of Increasing Doses of Cystine Binding Thiol Drugs on Cystine Capacity in Patients With Cystinuria

The purpose of this study is to evaluate the effect of escalating doses of cystine biding thiol drugs, including tiopronin and d-penicillamine, on the urinary cystine capacity, which is a measure of the amount of cystine in the urine, in patients with cystinuria. The overall goal will be to help guide therapy and ultimately minimize unnecessary side effects caused by larger doses.

Study Overview

• Status: Completed
• Conditions: Cystinuria
• Intervention / Treatment: Drug: Tiopronin 1g per day; Drug: Tiopronin 2g per day; Drug: Tiopronin 3g per day

Detailed Description

Cystinuria is a rare genetic cause of kidney stones that leads to significant morbidity due to the recurrent nature of the disease. As a result, a significant part of treatment is focused on prevention of stone formation. Current methods of prevention include increasing fluid intake, dietary modifications, alkali therapy, and cystine binding thiol drugs (CBTDs), which help increase the solubility of cystine in the urine. At present, the dosing of CBTDs is empiric, and not titrated to a specific measured effect. Our primary objective will be to measure the effect of increasing doses of CBTDs on cystine capacity. The investigators predict that higher dosages of these medications will lead to a more positive urinary cystine capacity, or the ability of urine to take up more cystine (and therefore decreased risk of stone formation). However, the dose at which increasing dosages of the medications cease to provide additional benefit is unknown. The investigators will directly measure the cystine capacity in the urine in response to increasing doses of medications to determine if there is a dose at which the maximum benefit of the drug exists.

This is a cross-over trial of escalating doses. There will be four parts to the study. In the first part, subjects will stop taking CBTDs for 7 days, and perform a 24-hour urine collection on day 7. In part 2, they will take their usual CBTD (either tiopronin or d-penicillamine) 1 gram per day for 7 days. They will perform another 24-hour urine collection on day 7 of this study period. In part 3, they will take their usual CBTD at 2 grams per day for 7 days and in part 4 they will take their CBTD at 3 grams per day for 7 days. Again, they will perform 24-hour urine collections on day 7 of each period. The order in which the parts of the study are performed will be randomized for each subject. The mean cystine capacities in each part of the study will be compared to determine the effect of drug dosage on urinary cystine capacity.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10016
      • NYU Langone Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Be a patient with a confirmed diagnosis of cystinuria.
• Be already taking a CBTD (either D-penicillamine (Cuprimine®) or tiopronin (Thiola®) as part of your medication regimen.
• Be between 18 and 80 years of age
• Be enrolled in the Cystinuria Registry.

Exclusion Criteria:

• You are not a patient with cystinuria
• You are not already taking a cystine binding thiol drug
• You have renal colic (if you are passing a stone)
• You are scheduled to undergo a urologic procedure
• You are unwilling or unable to provide informed consent in order to be able to participate.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: CBTD Patients; Part 1: patients will stop taking CBTDs for seven days and perform a 24-hour urine collection on day 7 Part 2: patients will take their usual CBTD, either tiopronin or d-penicillamine, 1g per day for 7 days, taken as 500 mg twice a day Part 3: patients will take a total of 2g of tiopronin or D-penicillamine daily for 7 days Part 4: patients will take a total of 3g/d of tiopronin or D-penicillamine, also for a 7 day period

Drug: Tiopronin 1g per day; 500mg PO BID x 7 days; Other Names: Thiola or tiopronin; d-penicillamine; Drug: Tiopronin 2g per day; 1g PO BID x 7 days; Other Names: Thiola or tiopronin; d-penicillamine; Drug: Tiopronin 3g per day; 1.5g PO BID x 7 days; Other Names: Thiola or tiopronin; d-penicillamine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cystine Capacity	We will test for a negative correlation between progressive increases in doses of thiol drugs and cystine capacity	4 weeks on assigned therapy

Collaborators and Investigators

• Sponsor: NYU Langone Health
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: David S Goldfarb, MD, NYU Langone Medical Center

Study record dates

Study Major Dates

• Study Start: June 1, 2012
• Primary Completion (Actual): December 1, 2017
• Study Completion (Actual): December 1, 2017

Study Registration Dates

• First Submitted: April 24, 2014
• First Submitted That Met QC Criteria: April 25, 2014
• First Posted (Estimate): April 29, 2014

Study Record Updates

• Last Update Posted (Actual): August 23, 2021
• Last Update Submitted That Met QC Criteria: July 28, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: cystinuria; D-penicillamine (Cuprimine®); tiopronin (Thiola®)
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Genetic Diseases, Inborn; Renal Tubular Transport, Inborn Errors; Renal Aminoacidurias; Cystinuria; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Protective Agents; Antidotes; Chelating Agents; Sequestering Agents; Penicillamine
• Other Study ID Numbers: 16-00108; 1U54DK083908 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No