The primary objective is to evaluate the potential efficacy of personalized adjunctive antibiotic therapy in maintaining clinical remission in pediatric subjects undergoing SOC induction therapy for mild to moderate Crohn*s disease who have a…
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Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Outcome variable: Sustained remission defined as no need of
re-induction for clinical flare (new course of nutritional therapy, need to
start steroids), steroid dependence, biologic (anti-TNF) use, and/or intestinal
surgery by 12 months.
Secondary outcome
Secondary Outcome variables: Longitudinal (clustered and with respect to
baseline) changes in disease activity indices (PCDAI: 0-100) components and
inflammatory markers in stool and blood at each study visit up to 12 months.
Longitudinal (clustered and with respect to baseline) changes in
patient-reported outcomes (PRO) by 12 months.
Exploratory Outcome variable: Longitudinal (clustered and with respect to
baseline) changes in fecal microbiome taxonomic composition or in total gene
(metagenome) content. The changes will be analyzed for association with
changes in disease activity (e.g. relapse or sustained remission) over time up
to 12 months.
Background summary
Crohn*s disease (CD) is a major phenotype of inflammatory bowel disease (IBD)
characterized by transmural (often granulomatous and patchy) inflammation
throughout the gastrointestinal (GI) tract, most often involving the ileum and
colon. Chronic inflammation within the GI tract can cause progressive tissue
damage leading to serious complications requiring surgery, including
intra-abdominal abscesses, fistulas, and intestinal strictures. CD is highly
heterogeneous with respect to age of onset, disease location (i.e. anatomical
extent) and behavior (i.e. inflammatory or stricturing/penetrating disease).
Disease course is also highly variable among patients with some experiencing
chronically active severe disease while other have intermittent periods of
clinical remission and disease exacerbation (i.e. *flares*). Patient responses
to therapy are also highly variable, but the reasons for this are not fully
understood.
Current treatments for CD aim to not only control symptoms but to maintain
clinical remission and mucosal healing (deep remission). Recently, the Crohn*s
Disease Exclusion diet was shown to be associated with comparable efficacy but
superior tolerance and maintenance of remission than exclusive enteral
nutrition in a randomized controlled trial.Corticosteroids, enteral nutrition,
thiopurines, methotrexate and biologics (such as monoclonal antibodies against
tumour necrosis factor-α: *anti-TNF*) are effective to modulate inflammatory
activity, but surgery is still frequently required.
The exact cause of CD is unclear, but current thinking holds that disease
results from a defective or inappropriate activation of the mucosal immune
system response to commensal gut microbiota, collectively termed the gut
microbiome. Certain bacteria can adhere to and invade epithelial cells of the
inflamed mucosa and granulomas to replicate inside macrophage phagolysosomes.
Numerous CD susceptibility genes are involved in pathways that govern innate
immunity, recognition of bacterial pathogens, and handling of intracellular
bacteria. Diversion of the fecal stream can lead to clinical improvement in
medically refractory Crohn*s colitis.
The field of microbiome research has grown exponentially over the past several
years. Studies using next-generation sequencing and new bioinformatics
approaches have begun to characterize fundamental differences in the gut
microbiome in children (and adults) with CD versus healthy controls. The ileum
and colon is densely populated with a variety of metabolically active bacteria
that interact with the host immune system. The collective genomic content of
the microbiome*the metagenome*has been estimated to contain at least 100-times
more genes than the human genome. The influence of the microbiome on disease
pathogenesis and progression in CD is a significant area of research interest,
since a breakdown in the balance between protective and harmful bacteria
(termed *dysbiosis*) is the current prevailing hypothesis for the development
of CD. Animal studies have shown that bacterial load and the composition of
bacterial communities can influence both the site and degree of inflammation in
the GI tract. Several studies applying microbial profiling and in-depth
sequencing techniques to the collective DNA content of gut microbiota (i.e.
microbiome) of CD patients have shown distinct microbiome profiles associated
with different clinical outcomes or responses to treatment.
The probable role for bacteria in triggering disease activity implies that
antibiotics could have a role in CD therapy. However, while several
meta-analyses support the use of antibiotics in controlling luminal
inflammation, results of individual trials are heterogeneous. Recently, a
combination of azithromycin/metronidazole has been found to be superior to
metronidazole alone for induction of remission and improvement in fecal
calprotectin. However, individual responses to this antibiotic treatment were
variable, showing the percentage of clinical response to equal that of
remission. This *all or nothing* phenomenon suggests that the effect of
antibiotics may depend on the type of microbiota involved and their
susceptibility to antibiotics.
The purpose for the proposed pilot trial is to determine whether personalized,
microbiome-informed administration of an azithromycin/metronidazole antibiotic
can improve clinical response to nutritional induction therapy and prolong
remission compared to induction therapy alone.
Study objective
The primary objective is to evaluate the potential efficacy of personalized
adjunctive antibiotic therapy in maintaining clinical remission in pediatric
subjects undergoing SOC induction therapy for mild to moderate Crohn*s disease
who have a relapse-associated microbiome profile
The secondary objectives are to evaluate the potential efficacy of personalized
adjunctive antibiotic therapy in improving PRO, components of established
disease activity measures in remission, as well as *biochemical* remission in
pediatric subjects undergoing SOC induction therapy for mild to moderate
Crohn*s disease who have a relapse-associated microbiome profile.
The exploratory objective is to investigate relationship between changes in
subject microbiome composition and changes in disease activity over time.
Study design
This is a multi-center, randomized, controlled open-label add-on design trial
pilot study to evaluate the efficacy of personalized adjunctive antibiotic
(azithromycin + metronidazole) therapy in pediatric subjects with mild to
moderate Crohn*s disease (CD) who have a relapse-associated microbiome
profile. The study hypothesis is that adjunctive antibiotic therapy will
improve clinical response to standard of care (SOC) induction therapy in a
subgroup of CD patients with a relapse-associated microbiome profile. This is
an add-on design trial for subjects already receiving SOC induction therapy;
there will be no placebos.
Prior to starting SOC induction therapy at week 0, subjects will provide a
baseline stool sample that will be screened for microbiome profiles associated
with risk of relapse according to an established statistical model.
At week 4, subjects with a relapse-associated microbiome will be randomized
into either a control arm that will continue to receive SOC induction therapy
for an additional 8 weeks, or a treatment arm that will receive adjunctive
antibiotic therapy in addition to continuing to receive SOC induction therapy
for an additional 8 weeks. Subjects who do not have a relapse-associated
microbiome will enter a separate control arm that will continue to receive SOC
induction therapy and will have data collected for exploratory objectives.
Subjects who are not in clinical remission by week 4 will receive antibiotic
therapy regardless of microbiome signature at baseline. Subjects will be
monitored for an additional 40 weeks after the treatment period (52 weeks
total).
Intervention
Antibiotics will be administered orally for an 8-week period. Azithromycin
will be administered at a dose of 7.5mg/kg to a maximum of 500mg/day for 5
consecutive days per week for the first 4 weeks and then 3 consecutive
days/week for 4 weeks. Metronidazole will be administered 10mg/kg twice daily
to a maximum of 1000mg/day for 8 weeks.
Study burden and risks
The available information suggests that the present clinical study has an
acceptable risk-benefit ratio.
Approximately 50% of pediatric patients with CD will relapse within a year of
starting induction therapy and require repeated courses of induction therapy
and/or treatment escalation.41,42 Subjects in the antibiotic treatment arm of
this trial will continue to receive standard therapy and are at comparable risk
of relapse as subjects in the control arms. In group C of subjects not
achieving remission with nutritional induction therapy alone, there will be no
randomization and antibiotics will be given as additional induction treatment.
The risk of rare, but serious, heart-related side effects from the antibiotic
drug azithromycin are minimized by screening patients for heart rhythm
irregularities prior to administering antibiotics. Metronidazole presents
minimal risk to the subjects and is routinely used in this pediatric
population. The safety monitoring practices employed by this protocol are
adequate to protect the subjects* safety and detect all anticipated adverse
events.
Subjects in the antibiotic intervention arm may experience direct health
benefit through the study treatment by reducing their risk of disease flare
thus avoiding additional intestinal damage as well as additional immune
suppression or surgery. There will be no additional direct benefit for
subjects in the reference arms because they will be receiving standard care.
The knowledge gained from this trial could lead to improved treatment
approaches for a subgroup of patients who have a relapse-associated microbiome
profile.
Meibergdreef 9
Amsterdam 1105 AZ
NL
Meibergdreef 9
Amsterdam 1105 AZ
NL
Listed location countries
Age
Inclusion criteria
1. Provision of signed and dated informed consent form (and assent form, as
applicable)
2. Stated willingness to comply with all study procedures and availability for
the duration of the study
3. Male or female, aged 3 to 17 years
4. Diagnosed with CD according to standard clinical and histological criteria,
within 36 months of week 0
5. Exhibiting mild to moderate symptoms of active disease, as determined by a
PCDAI score >10 (or >7.5 excluding the height item) and <=37.5
6. Evidence of active inflammation based on either: fecal calprotectin level
>=250 microgram/g (local laboratory or pre-arranged sponsor testing) within 30
days prior to week 0 visit; or according to accepted endoscopic and histologic
evidence obtained during an endoscopy procedure completed within 30 days prior
to Week 0 Visit.
Exclusion criteria
1.Current or previous use of anti-TNF or other biologic therapy
2.Presence of stricturing, penetrating (intestinal or perianal) and/or
fistulizing CD.
3.Pregnancy or lactation
4.Have undergone intestinal resection
5.Laboratory diagnosis of Clostridium Difficile Infection (CDI), if performed
for clinical indication
6.Treatment with another investigational drug or other intervention within 30
days before week 0
7.Risk factors for arrhythmia including history of prolonged QTc, hypokalemia
or hypomagnesemia, resting bradycardia, or concurrent treatment with other
drugs with potential for QT prolongation.
8.History of Cockayne syndrome
9.Prior diagnosis of any hematologic condition/blood dyscrasia which may result
in leukopenia (even if leukocyte count is normal at screening)
10.Known allergy or intolerance to azithromycin or metronidazole
11.Subjects who received IV anti-infective within 35 days prior to week 0 visit
or oral anti-infectives within 14 days prior to the week 0 visit.
12.Subject on oral aminosalicylates who has not been on stable doses for
greater than, or discontinued within, at least 14 days prior to week 0.
13.Subject on cyclosporine, tacrolimus or mycophenolate mofetil. Stable doses
(no change within 14 days prior to week 0) of Azathioprine, 6-mercaptopurine or
MTX are not a reason for exclusion.
14.Subject who received fecal microbial transplantation within 35 days prior to
week 0 visit.
15.Screening laboratory and other analyses show any of the following abnormal
results:
o AST, ALT > 2 X upper limit of the reference range (as determined locally at
each site)
o Urea, Creatinine > 1.5X upper limit of the reference range (as determined
locally at each site)
o White blood cell (WBC) count < 3.0 X 109/L
o Total bilirubin >= 20 micromol/liter (1.17mg/dl); except for subjects with
isolated elevation of indirect bilirubin relating to Gilbert syndrome
o Hemoglobin < 80 gram/liter
o Platelets < 100,000/µL
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
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-004219-29-NL |
| CCMO | NL71847.018.19 |