Early Oxybutinin Treatment for Boys With Posterior Urethral Valves (PRETIPUV)

Prospective Randomized Clinical Trial of Early Oxybutinin Treatment for Boys With Posterior Urethral Valves

Boys with posterior urethral valves have bladder dysfunction of varying severity. Early treatment of these children with anticholinergics is recommended by some teams, although there have never been any clear studies on the subject. To our knowledge, no comparative study of the evolution of valve bladders with or without treatment has been carried out to date.

Anticholinergic treatment, although it may be beneficial in patients with abnormal bladder function, such as the neurologic bladders ( in Spina Bifida) for example, may have side effects and may not be of benefit for this valve population. The evolution of the valves could be spontaneously favorable.

This study would be the first randomized clinical trial of early therapeutic drug intervention in the posterior urethral valve population.

Study Overview

• Status: Not yet recruiting
• Conditions: Male Urogenital Diseases
• Intervention / Treatment: Drug: Oxybutynin 1 mg/ml Syrup

Detailed Description

Posterior urethral valves (VUPs) are the leading cause of subvesical obstruction in children with an incidence between 1 / 3,000 to 1 / 8,000 births. 25-45% of patients will have chronic renal failure and 10-20% will require a transplant. The association between long-term prognosis and bladder dysfunction is well known, leading many teams to suggest early initiation of treatment with anticholinergics.

However, this treatment has never been properly evaluated. In fact, a single study carried out in boys with valves taking oxybutynin from the age of 3 months to 2 years without a control group concluded that "the early use of anticholinergics in boys with VUP presenting high voiding pressures and low bladder capacity has a beneficial effect on bladder function. It is true that in children with neurologic bladders as in Spina Bifida, early treatment with anticholinergics seems to provide a benefit, but VUPs are not strictly speaking neurologic bladders. In addition, treatment with anticholinergics can have side effects and could even be harmful to the bladder, leading to myogenic bankruptcy. The only way to properly assess oxybutynin in this population is to conduct a prospective randomized study.

The proposed study includes a group treated with oxybutynin and a group without. Boys who have had valve resection for VUP within the first three months of life and who present an abnormal urodynamic assessment 3 months after valve resection will be included. Oxybutynin will be given at a dose of 0.1 mg / kg 2x / day, as syrup, in the treatment group. The control group will not have any treatment affecting bladder function. The pharmacokinetics of oxybutynin will be studied. Several urodynamic parameters including capacity or volume, voiding pressure and compliance will be studied. The objective is to perform a composite analysis that can reflect the complex functioning of the bladder. The children included will have urodynamics at the end of the study, after 9 months of treatment. The performance of urodynamic examinations will be standardized and there will be an external centralized analysis to validate the urodynamic results.

• Study Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Luke L HARPER, MD; Phone Number: 05 56 79 56 17; Email: luke.harper@chu-bordeaux.fr
• Study Contact Backup: Name: Aurore A CAPELLI, PhD; Phone Number: 05 57 82 08 77; Email: aurore.capelli@chu-bordeaux.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 10 months (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Boys
• Aged 3 to 6 months
• Diagnosed with posterior urethral valves, and having undergone valve resection within the first 3 months of life
• Children who have had their valve resection at least 3 months before inclusion
• Having undergone urodynamic studies between 10 weeks and 6 months of age andshowing abnormal urodynamics, notably: high voiding pressure (>60cm H2O)/ small capacity bladder (<70% expected bladder volume)and for those without pop-off mechanisms, poor compliance (<10ml/cmH2O)/
• Holders of parental authority affiliated to French national health insurance
• With informed consent signed by holders of parental authority

Exclusion Criteria:

• Boys with posterior urethral valves and normal urodynamics or no urodynamic assessment
• Boys in whom urodynamic assessment is not possible for medical or anatomical reasons
• Boys requiring dialysis before the age of 3 months
• Contra-indication to oxybutynin such as hypersensitivity to oxybutynin or any of the excipients, digestive obstruction, occlusive or sub-occlusive syndrome, megacolon, digestive stasis, intestinal atony, paralytic ileus, ulcerative colitis, Hemorrhagic rectocolitis, Crohn's disease, Inflammatory bowel disease, Inflammatory organic colopathy, myasthenia, congenital glaucoma

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Oxybutynin during 9 months.; 0.1mg / kg 2x / day from inclusion and for 9 months.	Drug: Oxybutynin 1 mg/ml Syrup; The Investigational Medicinal Product of this study is Oxybutynin 1 mg/ml Syrup (see Annex 1 for the Monograph of PMS-Oxybutynin provided by ANSM under the ATU.). It will be administered at the dose of 0.1 mg/kg/twice a day to patients randomized to the study treatment group. The dose will be adapted to the child's weight to the nearest kilogram. The recommended dosage for older children with neurologic bladder is 0.3 to 0.4mg/kg/day, whilst the dosage we will be using is effectively 0.2mg/kg/day. This is because we are taking into account the absence or pharmacological studies of oxybutynin use in children <1 year of age, as well as their specific liver metabolism. Furthermore, the dose of 0.1mg/kg twice daily is the dose used in children within the same age group in the study by Casey et al, 2012
No Intervention: No oxybutynin; No treatment affecting bladder function

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
success of treatment defined by the association of the three events	composite endpoints where the success of treatment at 9 months after inclusion is defined by the association of the three following events: Voiding pressure <60 cmH2O AND; Bladder Volume ≥70% of theoretical value AND; for those without pop-off mechanisms, Bladder compliance >10mL/cmH2O A failure of treatment will be defined as the absence of at least one of these events. In presence of a pressure pop-off mechanism, only voiding pressure and bladder volume will be analyzed.	9 months after inclusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of adverse events in each group		through study completion, an average of 9 months
Type of adverse events in each group	adverse event or serious adverse event	through study completion, an average of 9 months
Incidence of urinary tract infections in each group		through study completion, an average of 9 months
Compliance with treatment	Compliance with treatment will be evaluated through the proportion of oxybutynin treatment interruption	9 months after inclusion
Sonographic changes	Sonographic changes will be expressed as a degree of hydronephrosis at 12-15 months of life (9 months after inclusion)	9 months after inclusion
Area under the plasma concentration versus time curve (AUC) of oxybutynin in treated boys over treatment	Area under the plasma concentration versus time curve (AUC) of oxybutinin in treated boys over treatment. Pharmacokinetic samples (6 points from Cmin to H+3h) at 2 weeks, 3 and 9 months after inclusion will be used to study and determine the pharmacokinetic parameters. In order to avoid having to take blood sample from the child several times, it is proposed to use a small venous catheter during the time of the pharmacokinetic samples	through study completion, an average of 9 months
Peak Plasma Concentration (Cmax) of oxybutynin in treated boys over treatment	Peak Plasma Concentration (Cmax) of oxybutynin in treated boys over treatment. Pharmacokinetic samples (6 points from Cmin to H+3h) at 2 weeks, 3 and 9 months after inclusion will be used to study and determine the pharmacokinetic parameters. In order to avoid having to take blood sample from the child several times, it is proposed to use a small venous catheter during the time of the pharmacokinetic samples	through study completion, an average of 9 months
Minimum plasma concentration (Cmin) of oxybutynin in treated boys over treatment	Minimum plasma concentration (Cmin) of oxybutynin in treated boys over treatment. Pharmacokinetic samples (6 points from Cmin to H+3h) at 2 weeks, 3 and 9 months after inclusion will be used to study and determine the pharmacokinetic parameters. In order to avoid having to take blood sample from the child several times, it is proposed to use a small venous catheter during the time of the pharmacokinetic samples	through study completion, an average of 9 months
Half-life of oxybutynin in treated boys over treatment	Half-life of oxybutynin in treated boys over treatment. Pharmacokinetic samples (6 points from Cmin to H+3h) at 2 weeks, 3 and 9 months after inclusion will be used to study and determine the pharmacokinetic parameters. In order to avoid having to take blood sample from the child several times, it is proposed to use a small venous catheter during the time of the pharmacokinetic samples	through study completion, an average of 9 months
Area under the plasma concentration versus time curve (AUC) of desethyloxybutynin (metabolite) in treated boys over treatment	Area under the plasma concentration versus time curve (AUC) of desethyloxybutynin (active metabolite) in treated boys over treatment. Pharmacokinetic samples (6 points from Cmin to H+3h) at 2 weeks, 3 and 9 months after inclusion will be used to study and determine the pharmacokinetic parameters. In order to avoid having to take blood sample from the child several times, it is proposed to use a small venous catheter during the time of the pharmacokinetic samples	through study completion, an average of 9 months
Peak Plasma Concentration (Cmax) of desethyloxybutynin (metabolite) in treated boys over treatment	Peak Plasma Concentration (Cmax) of desethyloxybutynin (active metabolite) in treated boys over treatment. Pharmacokinetic samples (6 points from Cmin to H+3h) at 2 weeks, 3 and 9 months after inclusion will be used to study and determine the pharmacokinetic parameters. In order to avoid having to take blood sample from the child several times, it is proposed to use a small venous catheter during the time of the pharmacokinetic samples	through study completion, an average of 9 months
Minimum plasma concentration (Cmin) of desethyloxybutynin (metabolite) in treated boys over treatment	Minimum plasma concentration (Cmin) of desethyloxybutynin (active metabolite) in treated boys over treatment. Pharmacokinetic samples (6 points from Cmin to H+3h) at 2 weeks, 3 and 9 months after inclusion will be used to study and determine the pharmacokinetic parameters. In order to avoid having to take blood sample from the child several times, it is proposed to use a small venous catheter during the time of the pharmacokinetic samples	through study completion, an average of 9 months
Half-life of desethyloxybutynin (metabolite) in treated boys over treatment	Half-life of desethyloxybutynin (active metabolite) in treated boys over treatment. Pharmacokinetic samples (6 points from Cmin to H+3h) at 2 weeks, 3 and 9 months after inclusion will be used to study and determine the pharmacokinetic parameters. In order to avoid having to take blood sample from the child several times, it is proposed to use a small venous catheter during the time of the pharmacokinetic samples	through study completion, an average of 9 months
creatinine clearance in each group		through study completion, an average of 9 months

Collaborators and Investigators

• Sponsor: University Hospital, Bordeaux
• Investigators: Principal Investigator: Laurent L FOURCADE, MD, University Hospital, Limoges; Principal Investigator: Alice A FAURE, MD, APHM - Hôpital Timone Enfants; Principal Investigator: Thomas BLANC, MD, APHP - Hôpital Necker Enfants Malades; Principal Investigator: Alaa A EL GHONEIMI, MD, APHP- Hôpital Robert Debré; Principal Investigator: Alexis A ARNAUD, MD, Rennes University Hospital; Principal Investigator: Ourdia O BOUALI, MD, University Hospital, Toulouse; Principal Investigator: Jean-Baptiste JB MARRET, MD, University Hospital, Caen

Publications and helpful links

General Publications

• Casey JT, Hagerty JA, Maizels M, Chaviano AH, Yerkes E, Lindgren BW, Kaplan WE, Meyer T, Cheng EY. Early administration of oxybutynin improves bladder function and clinical outcomes in newborns with posterior urethral valves. J Urol. 2012 Oct;188(4 Suppl):1516-20. doi: 10.1016/j.juro.2012.03.068. Epub 2012 Aug 19.

Study record dates

Study Major Dates

• Study Start (Anticipated): September 10, 2020
• Primary Completion (Anticipated): September 10, 2023
• Study Completion (Anticipated): September 10, 2023

Study Registration Dates

• First Submitted: July 29, 2020
• First Submitted That Met QC Criteria: August 24, 2020
• First Posted (Actual): August 25, 2020

Study Record Updates

• Last Update Posted (Actual): August 25, 2020
• Last Update Submitted That Met QC Criteria: August 24, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: anticholinergic; posterior urethral valves; urodynamic
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Urological Agents; Oxybutynin
• Other Study ID Numbers: CHUBX 2018/65

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