Prospective comparative study between Deflux® and Vantris® for endoscopic treatment of vesico-ureteral reflux in children.

Vesico-ureteral reflux (VUR) usually is a congenital defect of the
vesico-ureteral junction which closes off insufficiently when the bladder fills
up. As a result, urine may flow back to the kidney during bladder filling
and/or during micturition. This is in itself not harmful. However, in case of
existing VUR bacteria that are in the bladder may easier emerge to the kidney,
resulting in a pyelonephritis. Such pyelonephritis may be harmful as it may
cause scars to the kidney resulting in a loss of kidney tissue. Antibiotic
prophylaxis might decrease the infection rate in boys under one year of age and
in girls.
Vesico-ureteral reflux may disappear spontaneously (maturation). Bladder
dysfunction and recurrent urinary tract infections are associated with
persistent VUR. It is, therefore, important that these are managed before
considering a possible further (operative) treatment.
The conservative policy is continued until the child is toilet-trained. For
boys the antibiotic prophylaxis is stopped than, and the boy is monitored for
further urinary-tract infections. If these do not occur no further treatment
will be performed and the boy is further followed yearly until after puberty
for kidney growth and hypertension. Girls, who are more prone to urinary-tract
infections due to the shorter urethra, are in principle always treated for VUR
in case of a VUR graded higher than 2 that does not spontaneously disappear.
However, there are very few studies on which treatment recommendations rely. A
recent Swedish study proved that after 2 years of follow-up, antibiotic
prophylaxis and endoscopic treatment decreased the infection rate and new
kidney damage significantly compared to no treatment. In view of the increasing
resistance to antibiotics it is however difficult to defend to prolong
antibiotic treatment instead of operative treating the VUR if resolution rate
is predicted to be low.
An operative correction of VUR is carried out if despite antibiotic prophylaxis
children continue to have febrile urinary tract infections (pyelonephritis), or
if the chance of maturation of the VUR is low. The parents* preference also
plays a role: despite adequate counselling, some parents prefer an operative
correction of the VUR to administering a small daily dose of antibiotics.
There are two techniques for surgical correction of VUR: endoscopically,
usually applied for lower grades of VUR, or an ureteral reimplantation (an open
surgical procedure). This study deals with the endoscopic procedure, which we
will therefore describe in more detail.

Endoscopic treatment of VUR by means of a subosteal injection of a bulk-forming
substance (usually called STNG procedure) was described for the first time in
19816 and has gained considerable popularity ever since. The technique can be
applied for all grades of VUR. The operation*s success is not so much
determined by the product used as by the correct position of the implants
towards the ureteral orifice and the grade of VUR. Failing in the long term is
usually attributed to reabsorption or otherwise disappearance of product.
When one endoscopic procedure does not resolve the VUR, a second procedure can
be carried out. In case this treatment fails again and VUR is still
demonstrated in a new micturition cystogram (possibly after suffering a new
pyelonephritis), an open operative correction is considered the next step. A
third subosteal injection of a substance is generally not deemed useful in view
of the low success rate of a third attempt.
In The Netherlands most centres use Deflux® as the bulk-forming substance. As a
result of its success and effective marketing, this product has virtually
obtained a monopoly position on the Dutch market. Internationally and in only a
few centres in The Netherlands Macroplastique® is also used. As the latter
product causes a more significant tissue reaction it is not very popular.
The control of the successfulness of a STING procedure is traditionally
performed by means of a micturition cystogram. This is an invasive X-ray
examination involving the insertion of a bladder catheter to fill the bladder
with contrast medium to establish whether there is reflux or not.
In children with low grade reflux antibiotic prophylaxis is stopped 2 to 6
weeks after the endoscopic procedure and a MCUG not routinely performed if no
UTIs occur.
Most children with persisting or relapsing VUR will present with a febrile
urinary tract infection. In these cases following treatment of the UTI a MCUG
will need to be performed. In higher grades of VUR (grade 4-5) a MCUG will be
routinely performed following endoscopic treatment.
The ideal bulk-forming product should meet a number of requirements:
• It must be easily injectable
• It must be inert
• It must be sustainable (it should not disappear)
• It should not calcify or transmute in any way
• It must be cost-effective
• The chance to successfully treat VUR with this product should approximate an
operative correction (> 95%) of VUR.
Vantris® is a new bulk-forming substance introduced in the market for the
treatment of VUR. The results reported in the literature are promising but
scarce. The success rate after one single injection for VUR grade III-V with
this product is reported to be higher (84,4%) than after injection of other
existing products (71% with Deflux® in the Swedish reflux trial).
Animal-experimental research proved that the product is sustainable and does
not cause a tissue reaction. Moreover, the product is pro vial less expensive
than the other substances on the Dutch market for this treatment.
So far, there is no comparative study between Vantris® and other existing
products. This study*s objective is to make a comparison between Deflux® and
Vantris ® regarding short term (6 months) and long term (1, 2.5, 5 and 10 yrs)
efficacy (VUR disappearance and non-occurrence of infections). The Dutch
paediatric urologists do not want to cross over to another product without
proving its effectiveness and comparing it to the established treatment, even
if this is allowed by the Dutch government without further testing (wet
medische hulpmiddelen en Europese regelgeving).

Primary Objective: The treatment result expressed as the proportion of
successful treatments per treatment arm (successful = VUR <= grade 1 and/or no
urinary-tract infections 6 months after the operation) does at least not show a
significant difference between endoscopic procedures performed with Deflux®
compared to those performed with Vantris®. In case there is a difference, this
is in favour of successful treatment with Vantris®.

Secondary Objective(s):
• The treatment with Vantris® is cost-effective compared to treatment with
Deflux®
• There is no significant difference in the number of urinary-tract infections
within 6 months after the treatment in both treatment arms, neither after 1,
2.5, 5 and 10 years. In case there is a significant difference, treatment with
Vantris® is followed by less infections than treatment with Deflux®.
• There is no significant difference between both treatment arms in the number
of proven recurrences of VUR in the long term (1, 2.5, 5 and 10 years). In case
there is a significant difference, treatment with Vantris® shows less
recurrences of VUR than treatment with Deflux®.

Multi-centre single blind randomized study with children affected with VUR for
whom an operative endoscopic correction is the advised procedure.

Duration of the study: 12.5 years in total
• Primary completion point: 6 months after randomisation of the last patient
• Secondary completion point: 10 years after randomisation of the last patient

In conformity with the current standards the following examinations have to be
performed preoperatively:
• Micturition cystogram to establish the grade of VUR
• DMSA scan to investigate presence of preoperative scarring of the kidney
• Creatinin for checking the kidney function
• Ultrasound of the kidneys to register kidney size + eventual dilation of the
kidney
• Urine analysis to exclude a UTI at the time of surgery

The operative procedure will be carried out as the paediatric urologist usually
does. To prevent bias, each centre describes per participating paediatric
urologist which technique he or she does apply and in which circumstances
he/she will opt for a particular technique (traditional STING procedure, single
or double hit procedure). The paediatric urologist will disclose not to change
anything in this technique or follow-up unless after consultation with the
study coordinator. This disclosure is part of the protocol and will be attached
as enclosure 4 to this protocol.

Postoperative follow-up procedures will be carried out as the paediatric
urologist usually does. Each participating paediatric urologist will describe
this follow-up procedure before the beginning of the study (enclosure 4) and
he/she will state no deviation from this procedure will be performed without
prior consultation. This means that some paediatric urologists will examine the
disappearance of VUR by means of a MCUG; others will refrain from this but
instead monitor the child by monitoring for a possible urinary tract infection.
In the existing literature there is no unequivocal idea about the procedure to
be followed postoperatively5. Performing an MCUG gives certainty to parents and
physician but it burdens the child. Not performing an MCUG is less of a burden
to the child but may lead to unnecessary contacts with the physician due to the
parents* uncertainty. As VUR in itself is not harmful but urinary-tract
infections may well be, it would, in cases of a lower infection risk (lower
grades of VUR, earlier history of fewer infections and little damage to the
kidneys with an acceptable urination pattern) in itself be safe to wait until
the parents contact the physician the moment urinary-tract infections occur.
UTI*s following endoscopic treatment need to be documented by a dip stick or
microscopic examination and urine culture (a clean catch midstream for a child
with fever with one single micro-organism being cultured, or a catheterized
urine sample in the other cases).

The long-term follow-up will take place by telephone interview by the treating
paediatric urologist. If deemed necessary clinically, additional examinations
can be reported in between.
DMSA is a nuclear examination and is, after endoscopic treatment of VUR, only
indicated in case of recurrent febrile urinary tract infections
(pyelonephritis). If no urinary-tract infections occurred, the risk of newly
formed scars is negligible; this makes a DMSA scan unnecessary.

Urine microscopy and culture are not necessary and uselessly burdensome if
there are no signs indicating an active UTI.
In all cases of suspicion of UTI and /or fever a urine microscopy and urine
culture should be performed in order to rule out a concomitant urinary tract
infection, .

Nature, extent of the burden and risks associated with participation are
minimal as we compare an established treatment although with 2 different
products. Both products have a CE-validation and both products will be used for
the intervention they are intended for. The reason we perform this study is,
that both products have not been compared to each other and that the Dutch
pediatric urologists do not want to replace a product by another one
(especially in children) only because it is said to be better while it is
cheaper.
In case the Dutch pediatric urologists would not perform this study, they would
have been imposed by the hospital purchasing divisions to use the new and
cheaper product without any registration of possible effects. This would have
been more of a risk as no registration of side-effects, treatment failures and
so on would have taken place.