Citrate Salts for Stone-free Result After Flexible Ureterorenoscopy for Inferior Calyx Calculi (CiRUS)

Citrate Salts for Stone-free Result After Flexible Ureterorenoscopy for Inferior Calyx Calculi: a Randomized Placebo Controlled Trial

The prevalence of urolithiasis is around 10 % in the French population. It is thus a major public health issue. When the stone is not spontaneously removed, interventions such as extracorporeal lithotripsy or flexible ureteroscopy (F-URS) are performed. F-URS is usually preferred in renal stones > 7 mm in comparison with lithotripsy, with better results. Efficacy of ureteroscopy is based on the "stone-free rate" (SFR) at 3 months. A SFR index is assessed according to the existence of residual fragments and their size. SFR score 1 (fragment ≤ 1mm) has been poorly studied, and is supposed to occur in 60% of cases. These residual fragments account for the high frequency of recurrence, probably favored by crystals aggregation and growth of these fragments under supersaturated urines.

Indeed, calcium stones risk factors are urine supersaturation and crystal growth inhibitors deficiency. Citrate is the major crystal growth inhibitor in human urine. A hypocitraturia is reported in half of the lithiasic population.

Consequently, citrate salts appear as an interesting therapeutic option, in order to slow crystal growth but also to chelate calcium, and consequently to solubilize stones in situ. However, to date, there is no available controlled study after surgical intervention such as flexible ureteroscopy.

The aim of the investigator's study is to evaluate the efficacy of a 3-month potassium and magnesium citrate treatment following ureteroscopy on the elimination of residual fragments (SFR score 1).

Study Overview

• Status: Recruiting
• Conditions: Urolithiasis; Calyx; Calculus
• Intervention / Treatment: Dietary supplement: Potassium and magnesium citrate; Dietary supplement: Placebo

Detailed Description

The screening visit takes place 3 months to 3 days before the baseline visit. Patient will be informed of the study protocol by the surgeon who will perform the flexible ureteroscopy. As usual in clinical practice, a CT scan will be routinely performed. CT-scan interpretation will be centralized and performed blindly.

At the ureteroscopy day (baseline visit: Some sites, according to their usual practice, may admit their patients to hospital the day before the surgery (D-1)), inclusion and exclusion criteria will be checked by the surgeon. A second information on the study protocol will be given and the protocol consent will be signed.

The day of hospital admission, blood and urine will be collected by a nurse in order to define stone risk factors and other comorbidities after informed consent of the patients. Then patients will undergo ureteroscopy.

Stone fragments will be sent for analysis to the stone centre Laboratory (Tenon Hospital, Paris) with images of the stones during surgery (morphoconstitutional analysis).

Patients will be randomized for treatment within 7 days following F-URS, and after verification of randomization criteria. If the randomisation criteria are not completed, the patient will end its participation to the study.

Else, the patient is randomized and treatment for 3 months (placebo or citrate salts, blinded) will be delivered by the investigational site and administration will begin the day following surgery, thus discharge. A 33 cl glass will be provided for the administration of the treatment. Furthermore 24-hour urine collection will be explained and patients will be given the vessel in order to collect urine at M3 visit.

The end of study visit will take place at 3 months +/- 10 days after ureteroscopy visit.

Medical check-up by the urologist in charge, including a CT-scan and blood and urine biological tests under randomized treatment.

Randomized treatment will be stopped the day of this M3 visit. Adverse events (including drug tolerance, urinary symptoms) and date of stent removal if any will be collected. Compliance will be assessed, using a log book.

• Study Type: Interventional
• Enrollment (Anticipated): 262
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Nathalie TABIBZADEH, MD; Phone Number: + 33 1 56 01 83 29; Email: nathalie.tabibzadeh@aphp.fr
• Study Contact Backup: Name: Jean-Philippe HAYMANN; Phone Number: +33 1 56 01 67 74; Email: jean-philippe.haymann@aphp.fr

Study Locations

• France
  • Paris, France, 75020
    • Recruiting
    • Department : Exploration fonctionnelles rénales, Centre de la lithiase Hôpital TENON
    • Contact: Nathalie TABIBZADEH, MD; Phone Number: + 33 1 56 01 83 29; Email: nathalie.tabibzadeh@aphp.fr
    • Contact: Jean-Philippe HAYMANN, PU-PH; Phone Number: + 33 1 56 01 67 74; Email: jean-philippe.haymann@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age ≥ 18 years old
• Efficient contraceptive method in women of childbearing age
• At least one renal urolithiasis 10 ≤ size ≤ 20 mm
• No recent ureterorenoscopy (< 6 months)
• Planned flexible ureterorenoscopy procedure with holmium-laser dusting
• CT-scan performed within 3 months before surgery
• Affiliation to a social security regime
• Informed consent

Exclusion Criteria:

• Stone density < 700 UH on pre-operative CT-scan
• History of infectious renal stones or monogenic lithiasic disease (cystinuria, primary hyperoxaluria)
• Obstructive urinary tract malformation Cacchi-Ricci disease, Horseshoe kidney
• Chronic renal failure (eGFR<30 ml/min/1.73m²)
• Ongoing renal colic (within 7 days)
• Untreated urinary tract infection (within 7 days)
• Contraindications to ureterorenoscopy: coagulation disorders, high anesthetic risk
• Contraindications to potassium and magnesium citrate: known hyperkalemia, known hypermagnesemia, uncontrolled diabetes, acute dehydration
• Pregnant or breastfeeding women
• Patient deprived of liberty or under legal protection measure (tutorship or curatorship);
• Participation in another therapeutic trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Potassium and magnesium citrate; Patients are treated with potassium and magnesium citrate	Dietary supplement: Potassium and magnesium citrate; Patients are treated with potassium and magnesium citrate 5.2 grams daily during 3 months, following flexible ureterorenoscopy for inferior calyx urolithiasis.; Other Names: Lithos
PLACEBO_COMPARATOR: Placebo; Patients are treated with placebo	Dietary supplement: Placebo; Patient are treated with placebo 5.2 grams daily during 3 months, following flexible ureterorenoscopy for inferior calyx urolithiasis.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stone-free result	Percentage of stone-free patients (SFR score 0 and 1) between the 2 groups at 3 months after ureteroscopy assessed by non-injected, low irradiation, thin slice CT-scan.	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SFR score 2, 3 and 4	Percentage of SFR score 2, 3 and 4 in the 2 groups at 3 months assessed by non-injected, low irradiation, thin slice CT-scan	3 months
Urine supersaturation index	Urine supersaturation index calculation based on the combination of urine pH, calciuria, phosphaturia, uricosuria, oxaluria) at 3 months in the two groups	3 months
To evaluate the Safety of potassium and magnesium citrate: Percentage of patients with at least one adverse event throughout the study	Percentage of patients with at least one adverse event throughout the study and collected at 3 months: epigastralgia, nausea, vomiting, bloating, constipation, diarrhea and urinary tract infection. Mean USSQ (ureteral stone symptom questionnaire) score in each group.	3 months
To evaluate the compliance of potassium and magnesium citrate as assessed by citraturia	24-hour and fasting citraturia (mmol/L) at 3 months.	3 months
To evaluate the compliance of potassium and magnesium citrate as assessed by urinary pH	24-hour and fasting pH at 3 months.	3 months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Nathalie TABIBZADEH, MD, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 25, 2020
• Primary Completion (ANTICIPATED): March 1, 2022
• Study Completion (ANTICIPATED): June 1, 2022

Study Registration Dates

• First Submitted: May 24, 2019
• First Submitted That Met QC Criteria: July 15, 2019
• First Posted (ACTUAL): July 16, 2019

Study Record Updates

• Last Update Posted (ACTUAL): October 20, 2021
• Last Update Submitted That Met QC Criteria: October 15, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Urolithiasis; Ureteroscopy; Citrate; Urinary Calculi; Residual fragments; Morphoconstitutional analysis
• Additional Relevant MeSH Terms: Urologic Diseases; Pathological Conditions, Anatomical; Urinary Calculi; Urolithiasis; Calculi; Gastrointestinal Agents; Cathartics; Magnesium citrate
• Other Study ID Numbers: P170933J; 2018-A03500-55 (OTHER: ANSM)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No