A non-inferiority/superiority trial was designed for the treatment of uncomplicated cystitis in the Dutch community, in which we compare a 1-day and 3-day regimen of FT to a 5-day regimen of nitrofurantoin to investigate the effect on time to…
ID
Source
Brief title
Condition
- Bacterial infectious disorders
- Urinary tract signs and symptoms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
* Duration of cystitis symptoms defined as *the number of days with full
resolution of relevant cystitis symptoms within the period of 28 days in the
absence of aggravation to pyelonephritis or urosepsis (see definition for the
secondary endpoint below)*. Relevant symptoms of cystitis include:
o Dysuria
o Urgency
o Frequency of miction
o suprapubic tenderness
Secondary outcome
* Rate of clinical failure, defined as new or persisting cystitis symptoms or
aggravation to pyelonephritis or urosepsis for which a new antibiotic treatment
was prescribed within 28 days
* Rate of microbiological failure at day 28 (26 to 30) defined as persistence
of the initial infecting organism (* 103 colony forming units (cfu) /ml)
* Rate of pyelonephritis or urosepsis, defined as the occurrence of signs or
symptoms of pyelonephritis or urosepsis (fever, flank pain, or other matching
symptoms) for which antibiotic treatment was prescribed*
* Rate of relapses at day 28, defined as clinical failure caused by the initial
infecting organism (> 103 cfu /ml)
* Rate of reinfections at day 28, defined as clinical failure caused by another
organism than the initial infecting organism
* Rate of mortality (all-cause)
* Rate of hospital admission (all-cause)
* Duration of adverse events symptoms (including diarrhea, nausea, abdominal
cramps, increased vaginal discharge or other).
* Incidence and nature of severe adverse events, see chapter 9 for definitions
* Rate of complete self-reported therapy adherence after 7 days
* Satisfaction with the treatment received after 28 days on a scale of 5
* The rate of emergence of antibiotic resistance to fosfomycin and
nitrofurantoin
* Correlation between in vivo and in vitro activity for the different
antibiotic arms
* The number of days of absenteeism:
o education
o (voluntary) work
Background summary
Cystitis is the most common problem in primary care in the Netherlands for
women (3.7% of all consultations in women). Women are disproportionally
affected with about 70/1000 new lower urinary tract infections (UTIs) per
year, compared to 10/1000 new UTIs per year for men. In the Netherlands this
implies more than 600,000 women suffer from a UTI every year.
Empiric treatment of lower urinary tract infection (UTI) targets
Enterobacterales and in particular E.coli, the most prevalent causative
pathogen. In the Netherlands, the current first choice treatment for
uncomplicated cystitis is nitrofurantoin for 5 days (four times daily 50mg or
twice daily 100mg in slow release form, mainly depending on availability at the
pharmacy), the second choice is fosfomycin-trometamol (FT) in a single dose and
the third choice is trimethoprim for 3 days.FT is increasingly prescribed,
probably because it is easy to administer, well tolerated and patient friendly
due to its shorter treatment duration. In a large database of prescribed drugs
in primary care (Utrecht region) there is a clear increase in FT use since (in
2013). FT became 2nd choice for the treatment of uncomplicated cystitis, at the
expense of nitrofurantoin (NIT) (now 1st choice) and trimethoprim (now 3rd
choice). FT as a second choice is much more frequently used than trimethoprim
as a second choice in 2013.
In two randomized controlled trials, performed more than 20 years ago, efficacy
(based on participant reported symptoms) between a single gift of FT compared
to nitrofurantoin four times 50mg or twice daily 100mg for 7 days did not
differ statistically significant. Yet, one of these studies did not meet the
necessary number of inclusions and was thus underpowered and the other was
performed in a population in which causative pathogens had higher levels of
resistance to nitrofurantoin than is usual in the Netherlands.
A recent open-label randomized controlled trial suggests that a single gift of
FT is less effective compared to thrice daily 100mg nitrofurantoin for 5 days
for uncomplicated cystitis in non-pregnant women. Compared to the Dutch
recommendation they applied a higher dose of nitrofurantoin, reported
nitrofurantoin adherence was very high, and the study also included
hospitalized patients (7,4% of study population) whereas in the Netherlands
nitrofurantoin for uncomplicated cystitis is almost exclusively prescribed to
outpatients. This implies that the findings of this study may not be fully
generalizable to the Dutch situation, and call for a reevaluation and possible
optimization of fosfomycin treatment for UTI.
Although usually prescribed in a single dose, the optimal dose of FT for
cystitis is still unknown. The pharmacodynamic parameter most strongly linked
to effectiveness is the area under the curve / minimal inhibitory concentration
(AUC/MIC) ratio. High inter-individual variability in urinary FT concentrations
in healthy female volunteers were observed after a single-gift FT with
fosfomycin concentrations in urine below the EUCAST breakpoint in two-thirds of
the volunteers after 72 hours. Moreover, in vitro bladder models have shown
that a single dose of oral FT 3000mg is insufficient to kill E.coli strains
with a minimal inhibitory concentration (MIC)>4mg/L in urine. Consequently, a
single dose FT may be insufficient and it is suspected that extended dosing of
FT improves outcomes.
Besides, in vitro activity of a single dose of FT for cystitis correlates badly
to in vivo bacteriological efficacy, even when using agar dilution, a reference
standard for susceptibility testing.3,9 For that reason, dose-finding studies
in clinical patients such as in our trial are indispensable for cystitis.
In summary, the current recommendation for Dutch GPs is to treat uncomplicated
cystitis with a 5-day course of nitrofurantoin (2x100mg or 4x50mg daily). It is
unknown whether a single dosage might be equally effective and if the efficacy
of FT could be improved by an additional dosage on day 3. Efficacy reflects the
rapidity in which complaints disappear and the likelihood of not developing a
relapse or recurrence cystitis or pyelonephritis within 28 days.
We, therefore, designed a non-inferiority/superiority trial for the treatment
of uncomplicated cystitis in the Dutch community, in which we compare a 1-day
and 3-day regimen of FT to a 5-day regimen of nitrofurantoin to investigate the
effect on time to resolution of symptoms and the occurrence of
recurrence/relapse within 28 days.
Study objective
A non-inferiority/superiority trial was designed for the treatment of
uncomplicated cystitis in the Dutch community, in which we compare a 1-day and
3-day regimen of FT to a 5-day regimen of nitrofurantoin to investigate the
effect on time to resolution of symptoms and the occurrence of
recurrence/relapse within 28 days.
We will test the following hypotheses related to the primary objective:
1) FT in a single dose is non-inferior to nitrofurantoin,
2) FTin two dosages on day 1 and 3 is non-inferior to nitrofurantoin
3) FT in two dosages on day 1 and 3 is superior to fosfomycin in a single dose.
Study design
An open-label non-inferiority/superiority randomized clinical trial. Patients
will be randomized in a 1:1:1 ratio to either of:
A) FT in a single dose on day one (FT1)
B) Extended use of FT during three days with a dose given on day one and three
(FT1+3);
C) Nitrofurantoin for 5 consecutive days (2 times daily 100mg in slow release
form (Furabid®) (NIT1-5)*
Intervention
I. Fosfomycin-trometamol (FT)
o Single dose scheme: 3000mg taken orally once (arm A)
o Extended dosing scheme: 3000mg taken orally on day 1 and day 3 (arm B)
II. Nitrofurantoin
o 100mg b.i.d. in slow release form (Furabid) taken orally for 5 days (arm C).
Only in case the slow-release formulation is not available, participants
receive 4 times 50mg normal release nitrofurantoin as an alternative
(Furadantine®).
Study burden and risks
All study arms have particular benefits and possible disadvantages.
FT1: Based on PK/PD studies a single dose FT may be insufficient. The
pharmacodynamic parameter most strongly linked to effectiveness is the area
under the curve / minimal inhibitory concentration (AUC/MIC) ratio. For this
reason it is possible that extended or higher dosing of FT improves outcomes.
Additionally, high inter-individual variability in urinary FT concentrations in
healthy female volunteers were observed after a single-gift FT with fosfomycin
concentrations in urine below the EUCAST breakpoint in two-thirds of the
volunteers after 72 hours. It is however a very patient friendly due to its
simple dosing and limited side-effects which might explain why FT is
increasingly used for treatment of uncomplicated UTI.
FT1+3: An extended dose of fosfomycin could have a higher efficacy than a
single dose of FT for above mentioned reason, but also have a higher chance of
side-effects.
NIT1-5: Is the 1st choice and possibly has the highest efficacy, but it is also
the longest treatment with most pills.
Resistance rates for fosfomycin and nitrofurantoin are similar and low (1% and
2% resistance rate in primary care in 2018) and does not favour fosfomycin nor
nitrofurantoin.
In summary, the current recommendation for Dutch GPs is to treat uncomplicated
cystitis with a 5-day course of nitrofurantoin (at least 10 pills), and it is
unknown whether a single dosage or 2 dosages of FT in 3 days might be equally
effective.
Heidelberglaan 100
Utrecht 3584 CX
NL
Heidelberglaan 100
Utrecht 3584 CX
NL
Listed location countries
Age
Inclusion criteria
-Adult women (><=18 years of age) with a diagnosis of uncomplicated cystitis in
primary care
- Cystitis diagnosis is according to the flow diagram in the Dutch
NHG-guideline. In line with the NHG guideline 2020, recognition of symptoms
should always be accompanied with either a positive nitrite test or leucocyte
and dipslide test
Exclusion criteria
-Pregnancy or nursing
-Diabetes Mellitus
-Immunocompromised state
o Untreated infection with human immunodeficiency virus (hiv)
o Use of high-dose systemic corticosteroids
o Use of other immunosuppressive medication (specified in protocol)
-Presence of an indwelling urinary catheter
-History of abnormalities in urinary tract or kidneys
-Neurogenic bladder dysfunction
-UTI in past 28 days before inclusion
-Antibiotic prophylaxis in past 28 days with nitrofurantoin or fosfomycin
-Known GFR <30mL/min
-Contra-indication for nitrofurantoin or fosfomycin use (e.g. allergic
reactions, lung or liver reaction or peripheral neuropathy after previous use
in clinical history, acute porphyria, G6PD deficiency)
-Current use of an antibiotic for any reason
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-005337-33-NL |
| CCMO | NL75841.041.20 |
| OMON | NL-OMON25501 |