Crohn's DiseasePhase 4NCT00114465
VSL#3 Versus Placebo in Maintenance of Remission in Crohn's Disease
A Phase 4 study testing VSL#3 in people with Crohn's Disease, run by Orphan Australia at 1 site in Australia.
Trial summary
The primary objective of the study is to compare the efficacy of the probiotic VSL#3 versus placebo, in addition to standard maintenance drugs, in maintaining remission in Crohn's disease (CD). The secondary objectives are: To determine the time till flare of CD patients on VSL#3 compared to placebo. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Crohn's Disease
- What is being tested?
- VSL#3
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 38 participants
- Where
- 1 siteAustralia
- Study dates
- Jun 2005to Dec 2008
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Subjects should have a definitive diagnosis of colonic CD or small bowel and colonic CD based on clinical, radiological, endoscopic and pathological findings.
- Subjects should have a CDAI score <150 at week 0
- Patients receiving the following treatment are eligible:
- 5 aminosalicylates, if the dose remained constant for 4 weeks before the screening visit and had been used continuously for 8 weeks before screening and the patient has previously flared whilst on the medication; Azathioprine/6MP, if the dose remained constant for 8 weeks prior to the screening visit and had been used continuously for 12 weeks before screening and the patient has previously flared whilst on the medication. Proprietary probiotic preparations must be stopped at least two weeks prior to starting the trial preparation.
- Concomitant use of any other immunosuppressant eg. Methotrexate, tacrolimus, cyclosporine, mycophenolate mofetil, must be at a stable dose of 8 weeks continuous use for 12 weeks prior to screening and the patient has previously flared whilst on the medication.
- Subjects must demonstrate their willingness to participate in the study and comply with the proceedings by signing a written informed consent.
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- Men and women ≥18 to < 75 years of age of any race and gender
- Subjects must be free of any clinically significant disease, other than Crohn's disease, that would interfere with the study's evaluations.
- Subjects should understand and be able to adhere to the dosing and visit schedules; and agree to record symptom severity scores, medication times, concomitant medications and adverse events accurately and consistently in a daily diary.
Who cannot join
- Patients should not be enrolled into the study if they meet any of the following criteria:
- Patients with Ulcerative colitis
- Patients with fistulising CD or isolated small bowel CD
- Patients with a CDAI ≥150 at week 0
- Patients on prednisone, budesonide or any form of corticosteroids for the treatment of CD.
- Patients who are incapacitated, largely or wholly bed-ridden or confined to wheelchair, and who have little or no capacity for self-care
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- Symptomatic stenosis or ileal strictures.
- Short bowel syndrome
- Serious infections, such as hepatitis, pneumonia, pyelonephritis in the previous 3 months. Less serious infections in the previous 3 months, such as acute upper respiratory tract infection (colds) or uncomplicated urinary tract infection need not be considered exclusions at the discretion of the investigator.
- Documented HIV infection.
- Current signs or symptoms of severe, progressive or uncontrolled renal, hepatic, haematological, endocrine, pulmonary, cardiac, neurological or cerebral disease.
- Any currently known malignancy or pre-malignant lesions or any history of malignancy within the past 5 years.
- Patients with alcoholism, alcoholic liver disease, or other chronic liver disease
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Randomized, Double-Blind, Placebo-Controlled Study of VSL#3 Versus Placebo in the Maintenance of Remission in Crohn's Disease
The primary objective of the study is to compare the efficacy of the probiotic VSL#3 versus placebo, in addition to standard maintenance drugs, in maintaining remission in Crohn's disease (CD).
The secondary objectives are:
- To determine the time till flare of CD patients on VSL#3 compared to placebo.
- To assess whether concurrent therapy with VSL#3 leads to an improvement in the quality of life (QOL).
- To assess whether concurrent therapy with VSL#3 reduces the severity of a flare if it occurs.
Read the detailed description
Advancing knowledge regarding the biology of Crohn's Disease (CD) has identified that the host's innate immunity may impact on the development of intestinal inflammation. Pattern recognition receptors and the Toll-like receptors are able to detect both gram positive and gram negative bacteria, yeasts and flagellin and respond by activation of the innate immune system. By identification of the unmethylated CpG dinucleotide sequences found in bacteria, lymphocytes are stimulated, proinflammatory cytokines like interleukin (IL)-12 and the interferons are induced, and both the mucosal and host defences against the invading pathogens are increased.
A body of evidence from clinical and experimental observations indicates a role for endogenous digestive microflora in the pathogenesis of inflammatory bowel disease (IBD). The distal ileum and the colon are the areas with highest luminal bacterial concentrations and represent the sites of inflammation in IBD. Probiotics have been shown to reduce intestinal inflammation in animal studies. In the human, probiotics may also reduce inflammation particularly in Crohn's disease (CD) and ulcerative colitis (UC). Probiotics are effective in the treatment of acute pouchitis and its prevention. Their use also appears to have some effect in the management of active intestinal inflammation in UC and preliminary results suggest a role in the maintenance of remission.
NOD-2/CARD-15 is a gene that identifies colonic bacteria and can activate the NF-kb pathway in order to destroy the invading bacteria. The identification that mutation of the NOD-2/CARD-15 gene increases a person's susceptibility to developing CD suggests that a defect in the innate immunity may impact on the development of the chronic intestinal inflammation. CD patients are also more likely to have an increase in the mucosal permeability, thus allowing colonic bacteria to cross into the mucosal layer. A central role for the colonic bacteria would thus appear to be possible in the development and maintenance of intestinal inflammation and thus the potential effects and benefits of probiotics in the management of CD requires further investigation.
It appears that treatment with high-potency probiotic preparations for oral bacteriotherapy may enhance the concentrations of protective bacteria of the endogenous digestive microflora and therefore may provide a therapeutic benefit in patients with CD.
This is a phase IV multicentre, randomised, double-blind, placebo-controlled trial of VSL#3 versus placebo in the maintenance of remission in patients with CD. The patients will be randomised to a treatment group receiving one sachet of VSL#3 twice a day, and a group receiving the placebo drug in one sachet twice a day. The patients are assessed at baseline and every 12 weeks until the completion of the study at 52 weeks. At every visit the patient will have routine blood tests for CD, a physical examination and questionnaire will be applied.
- Conditions
- Crohn's Disease
- Being tested
- VSL#3, Placebo
- Keywords
- Randomized, Double-Blind, Probiotic, Remission, Crohn's Disease
- Medical subject headings
- Crohn Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
VSL#3Drug
VSL#3 1 sachet twice a day
PlaceboOther
Also called Blacebo
Placebo 1 sachel twice a day
| Study group | Role | What they receive |
|---|---|---|
| VSL#3 | Experimental | Probiotic Receives: Drug: VSL#3 |
| Placebo | Placebo comparator | Placebo Receives: Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
The primary objective of the study is to compare the efficacy of the probiotic VSL#3 versus placebo, in addition to standard maintenance drugs, in maintaining remission in Crohn's disease (CD)
Measured: 2 years
Secondary outcomes (3)
Time till flare of CD
Measured: within 1 year of commencing therapy
To assess whether concurrent therapy with VSL#3 leads to an improvement in the quality of life
Measured: within 1 year of commencing therapy
To assess whether concurrent therapy with VSL#3 reduces the severity of a flare if it occurs
Measured: within 1 year of commencing therapy
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Jun 2005 (estimated)
- Study startJun 2005
- Primary completionDec 2008
- Study completionDec 2008
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Crohn's DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 38 participants (actual)
Sponsor and investigators
- Lead sponsor
- Orphan Australia
- Sponsor type
- University, hospital or other
- Investigators
- Ian C Lawrance, MD PhD, Principal investigator, School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00114465
- Sponsor's protocol ID
- VSL#3Freo
- Status last verified
- Sep 2009
- First submitted
- 14 Jun 2005
- Last updated
- 18 Sep 2009
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Rachmilewitz D, Katakura K, Karmeli F, Hayashi T, Reinus C, Rudensky B, Akira S, Takeda K, Lee J, Takabayashi K, Raz E. Toll-like receptor 9 signaling mediates the anti-inflammatory effects of probiotics in murine experimental colitis. Gastroenterology. 2004 Feb;126(2):520-8. doi: 10.1053/j.gastro.2003.11.019.
PubMed 14762789Gionchetti P, Rizzello F, Helwig U, Venturi A, Lammers KM, Brigidi P, Vitali B, Poggioli G, Miglioli M, Campieri M. Prophylaxis of pouchitis onset with probiotic therapy: a double-blind, placebo-controlled trial. Gastroenterology. 2003 May;124(5):1202-9. doi: 10.1016/s0016-5085(03)00171-9.
PubMed 12730861Gionchetti P, Amadini C, Rizzello F, Venturi A, Poggioli G, Campieri M. Diagnosis and treatment of pouchitis. Best Pract Res Clin Gastroenterol. 2003 Feb;17(1):75-87. doi: 10.1053/bega.2002.0348.
PubMed 12617884Gionchetti P, Amadini C, Rizzello F, Venturi A, Campieri M. Review article: treatment of mild to moderate ulcerative colitis and pouchitis. Aliment Pharmacol Ther. 2002 Jul;16 Suppl 4:13-9. doi: 10.1046/j.1365-2036.16.s4.3.x.
PubMed 12047254Secondulfo M, de Magistris L, Fiandra R, Caserta L, Belletta M, Tartaglione MT, Riegler G, Biagi F, Corazza GR, Carratu R. Intestinal permeability in Crohn's disease patients and their first degree relatives. Dig Liver Dis. 2001 Nov;33(8):680-5. doi: 10.1016/s1590-8658(01)80045-1.
PubMed 11785714
Study at a glance
From the registry record, last updated by the sponsor on 18 Sep 2009. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Randomized, Double-Blind, Placebo-Controlled Study of VSL#3 Versus Placebo in the Maintenance of Remission in Crohn's Disease
- ClinicalTrials.gov ID
- NCT00114465
- Acronym / sponsor ID
- VSL#3Freo
- Conditions
- Crohn's Disease
- Keywords
- Randomized, Double-Blind, Probiotic, Remission, Crohn's Disease
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 38 participants (actual)
- Lead sponsor
- Orphan AustraliaUniversity, hospital or other
- Study start
- Jun 2005
- Primary completion
- Dec 2008 (actual)
- Study completion
- Dec 2008 (actual)
- First posted
- 15 Jun 2005 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The primary objective of the study is to compare the efficacy of the probiotic VSL#3 versus placebo, in addition to standard maintenance drugs, in maintaining remission in Crohn's disease (CD).
The secondary objectives are:
- To determine the time till flare of CD patients on VSL#3 compared to placebo.
- To assess whether concurrent therapy with VSL#3 leads to an improvement in the quality of life (QOL).
- To assess whether concurrent therapy with VSL#3 reduces the severity of a flare if it occurs.
Detailed description
Advancing knowledge regarding the biology of Crohn's Disease (CD) has identified that the host's innate immunity may impact on the development of intestinal inflammation. Pattern recognition receptors and the Toll-like receptors are able to detect both gram positive and gram negative bacteria, yeasts and flagellin and respond by activation of the innate immune system. By identification of the unmethylated CpG dinucleotide sequences found in bacteria, lymphocytes are stimulated, proinflammatory cytokines like interleukin (IL)-12 and the interferons are induced, and both the mucosal and host defences against the invading pathogens are increased.
A body of evidence from clinical and experimental observations indicates a role for endogenous digestive microflora in the pathogenesis of inflammatory bowel disease (IBD). The distal ileum and the colon are the areas with highest luminal bacterial concentrations and represent the sites of inflammation in IBD. Probiotics have been shown to reduce intestinal inflammation in animal studies. In the human, probiotics may also reduce inflammation particularly in Crohn's disease (CD) and ulcerative colitis (UC). Probiotics are effective in the treatment of acute pouchitis and its prevention. Their use also appears to have some effect in the management of active intestinal inflammation in UC and preliminary results suggest a role in the maintenance of remission.
NOD-2/CARD-15 is a gene that identifies colonic bacteria and can activate the NF-kb pathway in order to destroy the invading bacteria. The identification that mutation of the NOD-2/CARD-15 gene increases a person's susceptibility to developing CD suggests that a defect in the innate immunity may impact on the development of the chronic intestinal inflammation. CD patients are also more likely to have an increase in the mucosal permeability, thus allowing colonic bacteria to cross into the mucosal layer. A central role for the colonic bacteria would thus appear to be possible in the development and maintenance of intestinal inflammation and thus the potential effects and benefits of probiotics in the management of CD requires further investigation.
It appears that treatment with high-potency probiotic preparations for oral bacteriotherapy may enhance the concentrations of protective bacteria of the endogenous digestive microflora and therefore may provide a therapeutic benefit in patients with CD.
This is a phase IV multicentre, randomised, double-blind, placebo-controlled trial of VSL#3 versus placebo in the maintenance of remission in patients with CD. The patients will be randomised to a treatment group receiving one sachet of VSL#3 twice a day, and a group receiving the placebo drug in one sachet twice a day. The patients are assessed at baseline and every 12 weeks until the completion of the study at 52 weeks. At every visit the patient will have routine blood tests for CD, a physical examination and questionnaire will be applied.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| VSL#3 | Experimental | Drug: VSL#3Probiotic |
| Placebo | Placebo comparator | Other: PlaceboPlacebo |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- Subjects should have a definitive diagnosis of colonic CD or small bowel and colonic CD based on clinical, radiological, endoscopic and pathological findings.
- Subjects should have a CDAI score <150 at week 0
- Patients receiving the following treatment are eligible:
- 5 aminosalicylates, if the dose remained constant for 4 weeks before the screening visit and had been used continuously for 8 weeks before screening and the patient has previously flared whilst on the medication; Azathioprine/6MP, if the dose remained constant for 8 weeks prior to the screening visit and had been used continuously for 12 weeks before screening and the patient has previously flared whilst on the medication. Proprietary probiotic preparations must be stopped at least two weeks prior to starting the trial preparation.
- Concomitant use of any other immunosuppressant eg. Methotrexate, tacrolimus, cyclosporine, mycophenolate mofetil, must be at a stable dose of 8 weeks continuous use for 12 weeks prior to screening and the patient has previously flared whilst on the medication.
Key exclusion criteria (13 listed)
- Patients should not be enrolled into the study if they meet any of the following criteria:
- Patients with Ulcerative colitis
- Patients with fistulising CD or isolated small bowel CD
- Patients with a CDAI ≥150 at week 0
- Patients on prednisone, budesonide or any form of corticosteroids for the treatment of CD.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| VSL#3VSL#3 1 sachet twice a day | Drug | VSL#3 |
| PlaceboAlso: BlaceboPlacebo 1 sachel twice a day | Other | Placebo |
Primary outcome
The primary objective of the study is to compare the efficacy of the probiotic VSL#3 versus placebo, in addition to standard maintenance drugs, in maintaining remission in Crohn's disease (CD)
Time frame: 2 years
3 secondary outcomes
Time till flare of CD
Time frame: within 1 year of commencing therapy
To assess whether concurrent therapy with VSL#3 leads to an improvement in the quality of life
Time frame: within 1 year of commencing therapy
To assess whether concurrent therapy with VSL#3 reduces the severity of a flare if it occurs
Time frame: within 1 year of commencing therapy
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Sep 2009.
- Background: PubMed 14762789Rachmilewitz D, Katakura K, Karmeli F, Hayashi T, Reinus C, Rudensky B, Akira S, Takeda K, Lee J, Takabayashi K, Raz E. Toll-like receptor 9 signaling mediates the anti-inflammatory effects of probiotics in murine experimental colitis. Gastroenterology. 2004 Feb;126(2):520-8. doi: 10.1053/j.gastro.2003.11.019.
- Background: PubMed 12730861Gionchetti P, Rizzello F, Helwig U, Venturi A, Lammers KM, Brigidi P, Vitali B, Poggioli G, Miglioli M, Campieri M. Prophylaxis of pouchitis onset with probiotic therapy: a double-blind, placebo-controlled trial. Gastroenterology. 2003 May;124(5):1202-9. doi: 10.1016/s0016-5085(03)00171-9.
- Background: PubMed 12617884Gionchetti P, Amadini C, Rizzello F, Venturi A, Poggioli G, Campieri M. Diagnosis and treatment of pouchitis. Best Pract Res Clin Gastroenterol. 2003 Feb;17(1):75-87. doi: 10.1053/bega.2002.0348.
- Background: PubMed 12047254Gionchetti P, Amadini C, Rizzello F, Venturi A, Campieri M. Review article: treatment of mild to moderate ulcerative colitis and pouchitis. Aliment Pharmacol Ther. 2002 Jul;16 Suppl 4:13-9. doi: 10.1046/j.1365-2036.16.s4.3.x.
- Background: PubMed 11785714Secondulfo M, de Magistris L, Fiandra R, Caserta L, Belletta M, Tartaglione MT, Riegler G, Biagi F, Corazza GR, Carratu R. Intestinal permeability in Crohn's disease patients and their first degree relatives. Dig Liver Dis. 2001 Nov;33(8):680-5. doi: 10.1016/s1590-8658(01)80045-1.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ian C Lawrance, MD PhD principal investigator
School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing VSL#3 in people with Crohn's Disease, run by Orphan Australia at 1 site in Australia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Sep 2009. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The primary objective of the study is to compare the efficacy of the probiotic VSL#3 versus placebo, in addition to standard maintenance drugs, in maintaining remission in Crohn's disease (CD) (time frame: 2 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00114465, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Sep 2009.