Primary objective:To demonstrate the efficacy of Rifaximin -EIR 400 mg Tablet (800mg /BID, total daily dose 1600 mg) versus placebo in the prevention of endoscopic Crohn*s disease recurrence following ileocolonic resection
ID
Source
Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint of this trial will be the proportion of patients with
endoscopic recurrence at 26 weeks after randomization, defined as Rutgeerts
score >=i2 (with central blinded reading of video ileocolonoscopies).
Secondary outcome
The following secondary endpoints will be assessed:
Patients with endoscopic Rutgeerts score
anastomosis or maximum of 5 aphthous lesions in the neo-terminal ileum with
normal mucosa between the lesions) at 26 weeks after randomization.
*
Clinical recurrence according to CDAI score (defined as an increase higher than
70 points in CDAI score from baseline and CDAI>220 points; CDAI will be
assessed at each visit).
Proportion of patients with clinical symptom remission according to PRO defined
by (1) the total number of liquid/very soft stools for the 7 days prior to each
visit being <= 10 (from CDAI Item 1); AND (2) an abdominal pain rating of <=
1(from CDAI Item 2) on each day for the 7 days prior to each visit.
Development of a new/re-draining fistula or abscess by week 26
Time to clinical recurrence
Change from baseline in CRP (C reactive protein) and faecal calprotectin at
each visit during the Treatment Period.
Change from baseline in indices of health outcomes (SF-36®) at Week 26.
Background summary
Crohn*s disease (CD) is a chronic, relapsing, remitting, systemic disease,
which may result in transmural inflammation of the gastrointestinal tract. The
precise aetiology is unknown: it is a lifelong disease arising from an
interaction between genetic and environmental factors, but predominantly
observed in developed countries of the world. CD can affect the entire
digestive tract from the mouth to the anus (Spinelli A, 2011), but the most
commonly affected sites are the ileum and the ascending colon (Cho SM, 2009).
The clinical course of CD is characterized by exacerbations and remissions.
Therefore, recurrent inflammation can cause bowel strictures, fistulae (often
perianal) or abscesses. Moreover, Crohn*s disease (CD) often requires
intestinal resection, despite treatment with immunosuppressive and biologic
therapies (Cosnes J, 2005; Lazarev M, 2010).
Surgery in CD is not curative, and post-operative recurrence (POR) is a
frequent event. Historically, up to 70% of patients who undergo CD-related
resection develop postoperative endoscopic recurrence at or proximal to the
surgical anastomosis within 1 year (Rutgeerts P, 1990; Pascua M, 2008) and
approximately one-third of patients with CD, who have a first resection,
require a second within 10 years. The majority of these second intestinal
resections (about 20%) occur within 5 years of the first.
Potential risk factors, which predict early post- operative recurrence (Frolkis
AD, 2014) in CD are: cigarette smoking (Caprilli R, 2003) penetrating disease
behaviour (Rutgeerts P, 1995.), perianal localization (Chermesh I, 2007.) and
previous intestinal surgery (including appendectomy) (Ewe K, 1999).
Endoscopic lesions usually precede and correlate with future clinical
recurrence (about 20-25% per year), and predict the development of Crohn*s
disease- related complications and the need for re-intervention.
Therefore, endoscopic follow-up 6-12 months after surgery is recommended
(Terdiman JP, 2008).
Ileocolonoscopy is considered the gold standard for the diagnosis of the
recurrence and allow the definition of the presence and severity of morphologic
recurrence by the Rutgeerts score (Rutgeerts P, 1990).
Several drugs have shown efficacy in preventing POR, but the optimal medical
strategy has yet to be defined.
Prophylactic treatments include 5-aminosalycilates (Van Assche G, 2010),
imidazole antibiotics (Rutgeerts P, 1995), thiopurines (Peyrin-Biroulet L,
2009;) and the anti-TNF drugs infliximab and adalimumab (Carla-Moreau A, 2015).
However, the effect of mesalazine is low; the imidazole antibiotics are
associated to adverse events that preclude their use in the long-term;
thiopurines are often withdrawn because of side effects, and their efficacy is
moderate and anti-TNF drugs are expensive and concern exists about long-term
safety (Vicent Hernández-Ramírez, 2015).
Only patients with very low risk of recurrence may not require a prophylactic
treatment, whilst nitroimidazole antibiotics and immunomodulators may provide
benefit for those patients with low-to-moderate risk of postoperative
recurrence. Prevention of postoperative disease recurrence in high-risk
patients may require anti-TNF drugs (Kofi C., 2009 Aug).
Recurrence of CD postoperatively starts with aphthous ulcerations in the
neoterminal ileum and at the anastomosis, with progression to larger ulcers and
eventually stricture and fistula formation. This recurrence is thought to be
triggered by the presence of intestinal contents and bacteria in the lumen,
that lead to mucosal invasion by inflammatory cells and lymphocyte activation.
An interesting observation into the pathogenesis of post-operative CD is that
the faecal stream is needed for recurrence (Rutgeerts P, 1991) and contact with
intestinal fluid for only eight days was sufficient to trigger early histologic
changes in a previously normal neo-terminal ileum and anastomosis (D'Haens GR,
1998).
The degree of inflammation is related to the severity of mucosal lesions and
also correlates with clinical recurrence down the line. Within three months
after ileo-colectomy, the neoterminal ileum has been shown to have an increase
in colonization with colonic flora, specifically Escherichia coli (E. coli),
Enterococci, Bacteroides and Fusobacteria spp. (Neut C, 2002)
Given the association between enteric bacteria and postoperative CD recurrence
as noted above, antibacterial agents directed against anaerobic bacteria
(ornidazole and metronidazole) were shown to be effective in reducing the
severity of endoscopic recurrence, but prolonged administration (more than 3
months) of these antibiotics causes significant toxicity, mainly neuropathy and
gastrointestinal intolerance (Duffy LF, 1985.).
Rutgeerts et al. (Rutgeerts P, 1995) performed a controlled trial with
metronidazole 20 mg/kg per day or placebo started within a week after the
resection for 12 weeks. At week 12, severe endoscopic recurrence was observed
in 13% of metronidazole treated patients and in 43% of placebo-treated patients
(P <0.02).
The usefulness of antibiotics was also confirmed in a trial where all patients
received metronidazole for 3 months and either azathioprine or placebo for one
year. Metronidazole in combination with azathioprine resulted in less frequent
and less severe endoscopic recurrence (D'Haens GR, 2008)
Moreover, while the efficacy of nitroimidazole antibiotics supports the
hypothesis that colonic flora contribute to the etiology of CD, the duration of
the therapy remains a challenge particularly due to the potential side effects.
In fact, unfortunately, both metronidazole and ornidazole are potent broad
spectrum antibiotics with significant side effect profiles and high systemic
exposures,
The efficacy of *systemic antibiotics* and the experimental evidence of the
central role of luminal flora as an essential factor in the development of post
chirurgic CD recurrence provide the rationale for evaluating a locally acting
antibiotic like Rifaximin in this condition.
Rifaximin is a semi-synthetic derivative of Rifamycin with a large
antimicrobial spectrum covering gram-positive and gram-negative bacteria,
including aerobes and anaerobes, such as Clostridium and Bacteroides. It has
low systemic bioavailability which gives it an excellent safety profile: the
majority of the drug is excreted unchanged in the faeces, less than 1% is
excreted in urine and bioavailability is not modified by the presence of
inflamed mucosa.
Rifaximin inhibits bacterial RNA and therefore protein synthesis by blocking
the enzymatic activity of bacterial DNA-dependent RNA polymerase by
irreversible binding with the beta-subunit of this enzyme. Rifaximin activity
is very selective since the DNA-dependent RNA polymerase of bacteria is
different from that of human cells. Furthermore, its activity is bactericidal
owing to the irreversibility of the binding with the enzyme.
Several studies indicate that intestinal inflammation in CD results from
aggressive cellular immune responses to bacteria normally present in the
intestinal lumen; thus, acute flares may be prevented by decreasing the levels
of luminal bacteria. Previous clinical experiences also support the role of
antibiotic treatment in the prevention of post-operative Crohn*s disease
recurrence, mainly due to the reduction of luminal bacterial flora.
The use of Rifaximin in the prevention of post-operative recurrence of CD is
supported by recent microbiological and pharmacodynamic evidence which suggest
both antibacterial and anti-inflammatory mechanisms of action. The
antibacterial effect of Rifaximin on intestinal microflora and the host effects
are thought to play important roles in the mechanism of action, as summarized
in the scheme below:
Antibacterial effect and impact on intestinal microbiota:
• Rifaximin is active against the bacteria that have been investigated as
possible pa
Study objective
Primary objective:
To demonstrate the efficacy of Rifaximin -EIR 400 mg Tablet (800mg /BID, total
daily dose 1600 mg) versus placebo in the prevention of endoscopic Crohn*s
disease recurrence following ileocolonic resection
Study design
Phase II, Multicentre, Double-blind, Randomized, Placebo-Controlled Study
Duration of treatment:
The patient's participation period is approximately 30 weeks and consists of
the following phases:
• Screening phase: Within 2 weeks prior to randomization, including visit 1
(B1).
• Treatment phase: 26 weeks of treatment, starting with the randomization visit
(B2) and including visits after 4 (B3), 8 (B4), 16 (B5) and 26 weeks after the
randomization (B6: end of treatment). A deviation of ± 3 days relative to the
randomization visit (B2) is allowed for visit 3 (B3) to 5 (B5), while a
deviation of ± 7 days is allowed for visit 6 (B6).
• Post-control phase: at week 28, ie at least 2 weeks after the end of
treatment; Visit at the end of the study (B7). A deviation of +3 days is
allowed for visit 7 (B7).
The duration of the entire study can be calculated as approximately 20 months,
taking into account a 12-month registration period.
Intervention
Patients are randomized to 1: 1 in the following treatment groups and treated
for 26 weeks by oral administration:
• GROUP A: Rifaximin-EIR 400 mg, 2 film-coated tablets b.i.d. (1600 mg / day)
• GROUP B: Placebo 400 mg, 2 film-coated tablets b.i.d. (1600 mg / day)
Study burden and risks
The patients will have to visit during 20 weeks the hospital, for a study
visit 7 times (visit lasts approximately 1 hour)..
The patients will undergo the following tests:
- Physical examination and control of vital functions (blood pressure, heart
rate, body temperature, body weight and length, electrocardiogram
- Detailed survey on medical history
- Patients will be queried about their previous and current medication and
possible side effects
- A blood sample (7x in total 140ml)) and a urine sample (3x) will be taken for
some laboratory values, among others. Hematocrit value and to determine the
severity of the disease (the Crohn's Disease Activity Index Score, CDAI score).
Women of child bearing potential will have to perform a urine pregnancy test.
- Completion/fill in a patient diary for 7 days prior to the next visit from
visit 1 to visit 6, patients are asked to keep track of their condition (number
of times they have stools, stomach aches and fever, how the patient feels and
The drugs used).
- The patient receives a stool collector box with the request to collect a
stool sample for determination of calprotectin content.
- 1x ileocolonoscopy (video registration of the study is sent to another
hospital for an independent blind assessment required to determine whether the
therapy is effective). Patient receives an intestinal preparation prescribed
for this study.
-
There are no special risks associated with the administration of this research
agent. Adverse reactions reported very frequently after administration of
rifaximine include dizziness, headache, gastrointestinal disorders such as
abdominal pain, abdominal distension, constipation, diarrhea, nausea, vomiting,
flatulence, painful, cramped urge for rectal tearing Feces and finally fever
(elevated temperature). Rarely reported rash (red skin).
Blood sample collection, some known risks are pain, bleeding, burning
sensation, unpleasant feeling, or a bleeding or infection at the site where the
needle is inserted.
Ileocolonoscopy:
Endoscopic examination of the last part of the gastrointestinal tract,
including the rectum (colon), the colon (large intestine) and the ileum (last
part of the small intestine). Known risks are possible perforation (bowel bowel
piercing) and bleeding.
Blood pressure measurement; The cuff that is pumped may cause some unpleasant
feeling to the intestine.
Electrocardiogram (ECG): The adhesion and removal of the ECG patch (small
sticky pads) can cause a transient skin reaction such as a red skin or itch.
Local skin discomfort and / or hair loss may also occur by applying the
electrodes.
Intake of study medication for 26 weeks 4 tablets per day
Via Ragazzi del' 99
Bologna 40133
IT
Via Ragazzi del' 99
Bologna 40133
IT
Listed location countries
Age
Inclusion criteria
Patients of both sexes aged between 18 and 75 years old, inclusively.
Patients with diagnosis of CD, who had undergone curative ileocolonic resection, with ileocolonic anastomosis and for whom a randomization within 45 days from surgical intervention is feasible.
If the patients had an end or loop ileostomy within 1 year prior to randomization, they can be included but stoma closure should occur within 45 days prior to randomization.
Patients have had faecal stream restoration at least 14 days prior to randomization.
Patients must have at least one of the following risk factors for the development of early/severe post-operative endoscopic recurrence of their CD:
1) qualifying surgery that was their second intestinal resection within 10 years
2) third or more intestinal resections,
3) surgery for a penetrating CD complication (e.g., abscess or fistula), or
4) smoking 10 or more cigarettes per day for the past year.;Patients treated with glucocorticosteroids (systemic or topical) must discontinue treatment within 6 weeks after surgery.
Patients are capable of and willing to adhere to the study protocol requirements.
Patients have provided signed and dated written informed consent.
Female patients must be:
Post-menopausal (at least 2 years without spontaneous menses), or
* surgically sterile (bilateral tubal ligation, or hysterectomy, or ablation of both ovaries),
* or have a negative urine pregnancy test result at screening and at randomization and agree to
use an acceptable method of contraception throughout their participation in the study.
Acceptable methods of contraception include: condom and spermicide; intrauterine device
(IUD), diaphragm with spermicide; hormonal methods (oral contraceptives, patches, implants,
injectable or ring) with a documented failure rate of less than 1% per year.
* Or commit to absolute and continuous sexual abstinence
Exclusion criteria
Presence of macroscopic evidence for CD proximally or distally to the site of resection (presence of frank erythema, oedema, aphthae, ulcers or wall thickening > 3 mm, or creeping fat) according to the surgeon or previous imaging
Patients who had strictureplasties at index surgery
Patients with an ileorectal anastomosis.
Patients with active perianal Crohn*s disease
Patients treated with (treatment which was not discontinued at the time of surgery):
* Aminosalicylates
* Any biologicals (e.g., TNF-α inhibitor, natalizumab, or similar drugs)
* Azathioprine, 6-mercaptopurine
* Methotrexate,
* Cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil, or similar drugs
* antibiotics specific for CD such as metronidazole or ciprofloxacin
Patients with active infectious, ischemic, or immunological diseases with GI involvement
Patients with symptoms attributed to Short Bowel Syndrome (more than cm 100 in total of small bowel resected);
Patients with sepsis or other post-operative complications necessitating use of antibiotics for more than 14 days after surgery.
Patients with colorectal stenosis precluding ileocolonoscopy.
Patients who had qualifying ileocolonic resection for dysplasia or cancer without ongoing inflammation
Hepatic Impairment defined as severe (Child-Pugh C) hepatic impairment or patients with MELD (Model for End-Stage Liver Disease) score > 25.
Patients with an alanine transaminase (ALT) or aspartate transaminase (AST) > 2.5 upper limit of normal (ULN) at randomization.
Patients with severe cardiac insufficiency (NYHA, New York Heart Association classes 3 - 4).
Patient has a history of sensitivity to rifaximin, rifampin, rifamycin antimicrobial agents, or any of the components of Rifaximin -EIR or placebo (see list in the protocol at section 10.2.1)
Patients with kidney failure at randomization.
Any condition or circumstance that would prevent completion of the study or interfere with analysis of study results, including a history of drug or alcohol abuse, mental illness or non-compliance with treatments or visits, with immunological (including HIV infection), haematological, or neoplastic disease.
Pregnant or nursing woman
Patients who have donated 250 ml or more of blood in the last 3 months.
Patients who have used any investigational drug (except biological therapies) within 3 months prior to screening.
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 | EUCTR2017-002258-36-NL |
| CCMO | NL62876.018.17 |