Edited by: Yeong Yeh Lee, University of Science, Malaysia
Reviewed by: Nazri Mustaffa, University of Science, Malaysia; Angel Lanas, University of Zaragoza, Spain
This article was submitted to Gastroenterology, a section of the journal Frontiers in Medicine
†Passed away on November 8th, 2018
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal (GI) tract with a relapsing and remitting course. Chronic uncontrolled inflammation can lead to progressive bowel damage and complications such as stenosis and fistula, often leading to surgery (
Accumulating clinical and genetic evidence suggests that a defective innate immune response may be fundamental to the pathogenesis of CD (
This was a Phase 1/2 randomized, double-blind, placebo-controlled study (NCT01809275; Health Canada approval 27-02-2013) for the treatment of moderate-to-severe CD. All study subjects provided written informed consent and the trial was conducted in compliance with the Declaration of Helsinki and Good Clinical Practice guidelines. The study protocol was approved by the institutional research ethics boards at the four study sites.
Eligible subjects were randomized 1:1 to receive self-administered subcutaneous injections of blinded placebo or blinded QBECO every second day for 8 weeks. At the time the study was conducted, the Crohn's Disease Activity Index (CDAI) was the instrument of choice to assess disease severity (
Subjects ≥ 18 years with a diagnosis of CD of >6 months duration established by clinical, endoscopic or radiological, and histopathological assessment were enrolled following informed consent. All subjects had moderate-to-severe disease, defined by CDAI > 220 but <450 points, AND either a CRP (C-reactive protein) level > 2.87 mg/L or a fecal calprotectin (FCP) level > 250 μg/g, or an ileocolonoscopy or radiographic tests showing active CD within the last 6 months. CRP, FCP, and standard laboratory measures were taken at each study visit. Continued stable doses of the following medications were allowed: oral 5-ASA compounds, oral corticosteroid prednisone equivalent dose <30 mg/day or budesonide <9 mg/day if there was dose stability >2 weeks before trial screening visit; probiotics, anti-diarrheal medications, azathioprine or 6-mercaptopurine, or methotrexate provided the dose had been stable for 8 weeks preceding first study dose; and antibiotics providing dose stability was present for 2 weeks prior to first study dose. Male and pre-menopausal female subjects were required to agree to practice effective birth control.
QBECO is an investigational immune modulator consisting of all major macromolecules of an inactivated pathogenic strain of
Following three in-clinic supervised doses, subjects self-administered QBECO at home, recording the date of the injection, dose (volume) injected, location of the injection site, local skin response diameter (if present) on the day following administration, and any other relevant observations. Compliance was evaluated by diary review and clinic visit assessment.
Safety variables included adverse events, concomitant therapies, physical exams, and laboratory tests to assess hematologic, hepatic, and renal function at scheduled time points. Adverse events were graded according to National Cancer Institute Common Terminology Criteria, Version 4.0 (
Primary endpoints were safety (adverse events, clinical laboratory findings, concomitant therapies) and clinical improvement defined as a decrease in CDAI from baseline of ≥100 points or a CDAI score of ≤ 150 points at Week 8. Secondary endpoints were clinical remission at Week 8 (CDAI ≤ 150 points); clinical response at Week 8 (decrease in CDAI score from baseline ≥ 70 points); and CDAI score change from baseline to Week 8. Treatment failure was defined by the need for rescue medications, major surgical intervention for the treatment of CD, or QBECO-related adverse events leading to discontinuation of QBECO.
Exploratory end-points included the relationship between QBECO response and baseline demographic and disease characteristics, concomitant therapies, serum immune biomarkers, and CD-associated genotypes.
Serum immune cytokines and chemokines were analyzed by multiplex technology (assay performed by Eve Technologies, Calgary, AB, Canada) using the Human Cytokine/Chemokine Array 42-Plex with IL-18 (HD42; Millipore).
Genetic analysis with respect to QBECO response/non-response was performed on 30 CD subjects treated with QBECO, including 27 subjects from this trial and 3 subjects treated in a compassionate use program (
Genotyping was performed using the InfiniumOmni2-5-8 v1.3 array (Illumina, San Diego, CA). Preprocessing and quality control were completed in Genome Studio v2011.1 (Illumina). Only single-nucleotide polymorphisms (SNPs) with GenCall scores >0.2 in 90% of samples, call rates > 95%, minor allele frequency >5%, and Hardy–Weinberg equilibrium
An initial sample size of 60 subjects was chosen to achieve 80% power with a two-sided 0.05-level chi-square test assuming a 42% (33 vs. 75%) difference in clinical improvement rate between QBECO and placebo at Week 8. An interim sample-size re-estimation was performed based on aggregate, blinded, clinical improvement rates, and the sample size was increased to 68 subjects.
Week 8 and 16 clinical response, improvement and remission rates were compared between placebo and QBECO groups using a 2-sided Fisher's Exact test. Change in CDAI from baseline was compared using a 2-sided, 2-sample paired
The intention to treat (ITT) analysis evaluated all 68 subjects by randomized group. Subjects considered as treatment failures or who did not provide Week 8 CDAI scores were considered non-responders in the ITT analysis. The Week 8 per protocol (PP) analysis excludes 10 subjects who did not complete 8 weeks of treatment (
Patient flow by treatment assignment. Subjects with moderate-to-severe Crohn's disease were randomized 1:1 to QBECO or Placebo for 8 weeks. Those responding to allocated blinded treatment continued blinded treatment for another 8 weeks; all 8 Week non-responders commenced open-label QBECO for 8 weeks.
To account for imbalances in important baseline variables, change in CDAI score from baseline through Week 8 was modeled using a linear regression model that included the following criteria: CDAI, disease severity at baseline (≥250 vs. <250), use of concomitant immunosuppressive medication (Y/N), disease duration (years) and prior exposure to anti-TNF agents (Y/N). These variables were selected prior to the regression analysis based on scientific and clinical judgement; no model selection was performed. Population marginal means for QBECO and placebo (i.e., assuming a balanced population) were generated using least-square means analysis and statistically compared using a
Cytokines were evaluated by change in concentration over time with exposure to study treatment (using one-sample Mann-Whitney test of the paired differences) and by differential change over time by QBECO clinical response status (in QBECO treated subjects only). Linear mixed effect model of cytokine concentration was computed with
Genetic analysis used generalized linear models with an additive genetic model for categorical response and predictor variables. Kruskal-Wallis analysis of variance was used for continuous and ordinal response variables. Benjamini-Hochberg procedure was used to adjust for multiple comparisons across the 113 SNPs that passed quality control. An algorithm combining the top three SNPs linked to QBECO response was formulated using methodology previously described in a genetic association study of CD and ulcerative colitis phenotypes (
All authors had access to the study data and reviewed and approved the final manuscript.
Sixty-eight subjects were randomly assigned (1:1) to receive blinded QBECO or placebo for 8 weeks. Demographic and baseline characteristics are shown for both treatment groups in
Baseline and demographic variables.
Male | 38 (55.9) | 20 (58.8) | 18 (52.9) |
Female | 30 (44.1) | 14 (41.2) | 16 (47.1) |
Caucasian | 59 (86.8) | 30 (88.2) | 29 (85.3) |
Black | 1 (1.5) | 0 (0.0) | 1 (2.9) |
Hispanic | 2 (2.9) | 2 (5.9) | 0 (0.0) |
Asian | 5 (7.4) | 2 (5.9) | 3 (8.8) |
Other | 1 (1.5) | 0 (0.0) | 1 (2.9) |
Median (IQR) | 36.1 (27.5, 50.5) | 42.4 (30.6, 50.6) | 31.8 (26.3, 47.7) |
Mean (SD) | 39.2 (14.0) | 41.0 (12.3) | 37.5 (15.4) |
Range | (19.2, 80.1) | (21.0, 72.7) | (19.2, 80.1) |
Median (IQR) | 7.9 (3.7, 13.0) | 9.2 (3.8, 13.2) | 6.0 (3.7, 10.9) |
Mean (SD) | 9.8 (8.4) | 10.2 (7.6) | 9.3 (9.2) |
Range | (0.5, 49.3) | (0.5, 30.4) | (0.8, 49.3) |
Median (IQR) | 28.0 (20.3, 36.0) | 30.0 (20.2, 39.2) | 24.7 (20.3, 31.4) |
Mean (SD) | 29.5 (12.7) | 30.8 (12.8) | 28.1 (12.6) |
Range | (9.6, 70.0) | (11.9, 70.0) | (9.6, 61.9) |
Median (IQR) | 265.0 (238, 328) | 268.0 (241, 331) | 260.0 (233, 323) |
Mean (SD) | 288.4 (64.4) | 290.7 (57.1) | 286.0 (71.7) |
Range | (210.0, 449.0) | (210.0, 445.0) | (220.0, 449.0) |
Mean (SD) | 25.0 (5.8) | 25.1 (5.8) | 24.8 (5.9) |
Median (IQR) | 24.3 (21.0, 28.4) | 24.4 (20.5, 29.1) | 24.1 (21.0, 28.1) |
Range | (16.0, 40.3) | (16.4, 39.9) | (16.0, 40.3) |
Median (IQR) | 481.2 (258, 706) | 450.0 (260, 641) | 518.9 (242, 782) |
Mean (SD) | 574.7 (448.4) | 523.2 (365.8) | 626.2 (518.5) |
Range | (15.6, 2000.0) | (15.6, 1519.5) | (24.9, 2000.0) |
Median (IQR) | 10.0 (4.4, 24.0) | 8.5 (4.0, 21.4) | 11.5 (5.4, 24.0) |
Mean (SD) | 17.4 (18.2) | 15.8 (17.4) | 18.9 (19.0) |
Range | (0.1, 77.1) | (0.1, 59.5) | (3.1, 77.1) |
Yes | 8 (11.8) | 4 (11.8) | 4 (11.8) |
No | 36 (52.9) | 17 (50.0) | 19 (55.9) |
Not done | 24 (35.3) | 13 (38.2) | 11 (32.4) |
Prior anti-TNFα treatment |
27 (39.7) | 20 (58.8) | 7 (20.6) |
Concomitant therapy for CD, |
52 (76.5) | 27 (79.4) | 25 (73.5) |
Aminosalicylates | 12 (17.6) | 7 (20.6) | 5 (14.7) |
Antibiotics | 3 (4.4) | 2 (5.9) | 1 (2.9) |
Anti-diarrheals | 19 (27.9) | 9 (26.5) | 10 (29.4) |
Corticosteroids | 23 (33.8) | 12 (35.3) | 11 (32.4) |
Immunomodulators | 12 (17.6) | 5 (14.7) | 7 (20.6) |
Others | 5 (7.4) | 4 (11.8) | 1 (2.9) |
Overall, 56 of the 68 subjects (82.4%) completed the study through Week 24, including 27 (79.4%) subjects initially randomized to QBECO and 29 (85.3%) to placebo.
Mean reduction in CDAI score from baseline to Week 8 was greater for QBECO vs. placebo subjects in both the ITT (
Mean change in Crohn's Disease Activity Index (CDAI) score from baseline to Week 8 by treatment group. The mean reduction in CDAI from baseline to Week 8 in patients with moderate-to-severe Crohn's disease blinded to QBECO (red bar) or Placebo (blue bar) treatment. ITT, Intention to Treat analysis; PP, Per Protocol analysis.
Clinical response, improvement, and remission rates at Week 8 by treatment.
Response | 14 (41.2%) | 9 (26.5%) | 14.7% [−10, 39] | 13 (48.1%) | 9 (29.0%) | 19.1% [−7, 43] |
Improvement | 11 (32.4%) | 8 (23.5%) | 8.8% [−16, 33] | 11 (40.7%) | 8 (25.8%) | 14.9% [−11, 39] |
Remission | 10 (29.4%) | 8 (23.5%) | 5.9% [−19, 30] | 10 (37%) | 8 (25.8%) | 11.2% [−15, 36] |
Response | 9 (64.3%) | 7 (26.9%) | 37.4% [5, 65] | 9 (64.3%) | 7 (29.2%) | 35.1% [2, 63] |
Improvement | 7 (50.0%) | 6 (23.1%) | 26.9% [−5, 57] | 7 (50.0%) | 6 (25.0%) | 25.0% [−8, 55] |
Remission | 7 (50.0%) | 6 (23.1%) | 26.9% [−5, 57] | 7 (50.0%) | 6 (25.0%) | 25.0% [−8, 55] |
Mean change in Crohn's Disease Activity Index (CDAI) score in study groups Week 8 and Week 16. Mean change in CDAI score for subjects randomized to QBECO (solid red line) and placebo (solid blue line) from baseline to Week 8 and Weeks 16 of study treatment. Those responding to allocated blinded treatment at week 8 continued blinded treatment for another 8 weeks [light blue solid line for responders originally blinded to placebo treatment (
Patients naïve to anti-TNFα agents achieved a 64% response rate at Week 8 with QBECO vs. 26% placebo (
In subjects with baseline CDAI ≥ 250 (
QBECO treatment was well-tolerated. Adverse events experienced by >5% of blinded participants for weeks 1–8 of the study (
Adverse events affecting at least 5% of subjects receiving study drug.
Any Adverse Event | 45 (66.2) | 25 (73.5) | 20 (58.8) |
Common Adverse Events |
|||
Abdominal tenderness | 3 (4.4) | 1 (2.9) | 2 (5.9) |
Mouth ulceration | 2 (2.9) | 2 (5.9) | 0 (0.0) |
Nausea | 8 (11.8) | 6 (17.6) | 2 (5.9) |
Fatigue | 8 (11.8) | 4 (11.8) | 4 (11.8) |
Influenza like illness | 14 (20.6) | 10 (29.4) | 4 (11.8) |
Injection site bruising | 2 (2.9) | 0 (0.0) | 2 (5.9) |
Injection site pain | 2 (2.9) | 2 (5.9) | 0 (0.0) |
Injection site pruritus | 5 (7.4) | 5 (14.7) | 0 (0.0) |
Pyrexia | 11 (16.2) | 8 (23.5) | 3 (8.8) |
Dizziness | 2 (2.9) | 2 (5.9) | 0 (0.0) |
Headache | 6 (8.8) | 2 (5.9) | 4 (11.8) |
Cough | 2 (2.9) | 2 (5.9) | 0 (0.0) |
Oropharyngeal pain | 2 (2.9) | 2 (5.9) | 0 (0.0) |
Adverse events affecting at least 5% of subjects receiving study drug.
Any Adverse Event | 29 (47.5) | 5 (35.7) | 7 (43.8) | 5 (55.6) | 12 (54.5) |
Common Adverse Events |
|||||
Abdominal pain | 2 (3.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (9.1) |
Abdominal tenderness | 2 (3.3) | 0 (0.0) | 0 (0.0) | 1 (11.1) | 1 (4.5) |
Abnormal feces | 1 (1.6) | 1 (7.1) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Crohn's disease | 2 (3.3) | 0 (0.0) | 1 (6.3) | 0 (0.0) | 1 (4.5) |
Haematochezia | 1 (1.6) | 1 (7.1) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Hemorrhoids | 1 (1.6) | 0 (0.0) | 0 (0.0) | 1 (11.1) | 0 (0.0) |
Large intestine perforation | 1 (1.6) | 0 (0.0) | 1 (6.3) | 0 (0.0) | 0 (0.0) |
Nausea | 2 (3.3) | 0 (0.0) | 1 (6.3) | 0 (0.0) | 1 (4.5) |
Paraesthesia oral | 1 (1.6) | 0 (0.0) | 1 (6.3) | 0 (0.0) | 0 (0.0) |
Vomiting | 2 (3.3) | 1 (7.1) | 1 (6.3) | 0 (0.0) | 0 (0.0) |
Chest discomfort | 1 (1.6) | 0 (0.0) | 1 (6.3) | 0 (0.0) | 0 (0.0) |
Fatigue | 4 (6.6) | 0 (0.0) | 2 (12.5) | 1 (11.1) | 1 (4.5) |
Influenza like illness | 10 (16.4) | 1 (7.1) | 3 (18.8) | 0 (0.0) | 6 (27.3) |
Injection site bruising | 1 (1.6) | 0 (0.0) | 0 (0.0) | 1 (11.1) | 0 (0.0) |
Pain | 1 (1.6) | 1 (7.1) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Pyrexia | 4 (6.6) | 1 (7.1) | 1 (6.3) | 1 (11.1) | 1 (4.5) |
Hepatic lesion | 1 (1.6) | 0 (0.0) | 1 (6.3) | 0 (0.0) | 0 (0.0) |
Hepatitis | 1 (1.6) | 0 (0.0) | 1 (6.3) | 0 (0.0) | 0 (0.0) |
Candidiasis | 1 (1.6) | 0 (0.0) | 1 (6.3) | 0 (0.0) | 0 (0.0) |
Folliculitis | 1 (1.6) | 0 (0.0) | 1 (6.3) | 0 (0.0) | 0 (0.0) |
Contusion | 1 (1.6) | 0 (0.0) | 1 (6.3) | 0 (0.0) | 0 (0.0) |
Exposure to toxic agent | 1 (1.6) | 0 (0.0) | 0 (0.0) | 1 (11.1) | 0 (0.0) |
C-reactive protein increased | 1 (1.6) | 0 (0.0) | 1 (6.3) | 0 (0.0) | 0 (0.0) |
Decreased appetite | 1 (1.6) | 0 (0.0) | 1 (6.3) | 0 (0.0) | 0 (0.0) |
Dehydration | 1 (1.6) | 1 (7.1) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Back pain | 1 (1.6) | 1 (7.1) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Groin pain | 1 (1.6) | 1 (7.1) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Myalgia | 2 (3.3) | 1 (7.1) | 1 (6.3) | 0 (0.0) | 0 (0.0) |
Headache | 5 (8.2) | 0 (0.0) | 2 (12.5) | 0 (0.0) | 3 (13.6) |
Tremor | 1 (1.6) | 1 (7.1) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Libido decreased | 1 (1.6) | 0 (0.0) | 0 (0.0) | 1 (11.1) | 0 (0.0) |
Renal failure | 1 (1.6) | 0 (0.0) | 1 (6.3) | 0 (0.0) | 0 (0.0) |
Pelvic pain | 1 (1.6) | 1 (7.1) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Cough | 1 (1.6) | 0 (0.0) | 1 (6.3) | 0 (0.0) | 0 (0.0) |
Oropharyngeal pain | 1 (1.6) | 0 (0.0) | 1 (6.3) | 0 (0.0) | 0 (0.0) |
Rhinorrhoea | 1 (1.6) | 0 (0.0) | 1 (6.3) | 0 (0.0) | 0 (0.0) |
Acne | 1 (1.6) | 0 (0.0) | 0 (0.0) | 1 (11.1) | 0 (0.0) |
Erythema | 1 (1.6) | 0 (0.0) | 1 (6.3) | 0 (0.0) | 0 (0.0) |
Hot flush | 1 (1.6) | 1 (7.1) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Hypotension | 1 (1.6) | 1 (7.1) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Severe Adverse Events (SAE) were uncommon with 6.4 and 2.3% of all reported events reported as Grade 3 for those receiving QBECO and placebo, respectively. Seven of these eight (87.5%) individuals had past exposure to anti-TNFα therapies. Five of eight SAEs were considered to be unlikely related or unrelated to treatment, with 3 (fever/chills, liver/kidney issues, exacerbations of benign lung nodules) possibly related to treatment. The only SAE in an anti-TNFα-naïve subject was a
Serious adverse events experienced over the course of study.
1–8 | 11106 | QBECO (blinded) | Mechanical bowel obstruction | Severe | Discontinued | Not related |
1–8 | 11148 | QBECO (blinded) | Fever and chills | Severe | Discontinued | Possibly |
1–8 | 11154 | Placebo (blinded) | Severe | Discontinued | Not related | |
1–8 | 11168 | QBECO (blinded) | Multiple pulmonary nodules (present before treatment; reactivation during study) | Severe | Discontinued | Possibly |
9–16 | 11109 | QBECO (open-label) | Hepatitis, renal failure | Severe | Discontinued | Possibly |
9–16 | 11140 | QBECO (open-label) | Perforated sigmoid | Severe | Discontinued | Not related |
9–16 | 11144 | QBECO (open-label) | Electrolyte abnormalities | Severe | Discontinued | Unlikely |
9–16 | 11164 | QBECO (open-label) | Exacerbation Crohn's disease | Moderate | Discontinued | Unlikely |
Forty-two serum immune factors were assessed at baseline, Week 8, 16, and 24. Interleukin-18 (IL-18) increased from baseline to Week 8 and 16 with QBECO treatment (median change 24 pg/mL, adjusted
Among QBECO treated subjects, IFNγ, IL-12p70, IL-17A, and TGFα were significantly elevated in QBECO responders vs. QBECO non-responders (adjusted
Serum cytokines that differed in QBECO responders and non-responders. A 42-plex cytokine/chemokine analysis was performed on serum. Four cytokines- IFNγ, IL-12p70, IL-17A, and TGFα- differentiated QBECO responders from non-responders over the study period after adjusting for multiple comparisons.
Week 8 clinical remission with QBECO treatment occurred more frequently in patients with lower baseline serum Eotaxin-1 levels (adjusted
CRP, an acute phase response protein upregulated in response to bacterial infections, and FCP, a cation-binding protein released by granulocytes in response to infection, were not anticipated to be reduced during active QBECO treatment given its mechanism of action. We assessed levels of these immune biomarkers leading up to Week 24 (when subjects were off study treatments). At Week 24, 44% of those who had been on QBECO from the beginning of the study, 42% of those who had switched to QBECO from placebo at Week 8, and 0% of those who were on placebo since the beginning had CRP levels < 5 mg/L (
One hundred and thirteen SNPs reported to be linked to IBD were analyzed for response to QBECO treatment. A gene risk score, which is a weighted value based on variation in multiple genetic loci, was computed to assess the ability to stratify subjects' response to QBECO.
Gene risk score separates QBECO responders from non-responders. One hundred and thirteen inflammatory bowel disease (IBD)-related SNPs were included in computing the gene risk score for response to QBECO to assess the potential contribution of subjects' genetics to treatment outcome. The derived gene risk score could successfully distinguish QBECO responders from non-responders,
In this proof-of-concept study assessing QBECO, a first-in-class microbial-based immunotherapy, for the treatment of CD, a greater reduction in disease was observed by Week 8 in subjects randomized to QBECO compared to placebo. For the pre-specified Week 8 primary analysis in this 68-patient study, the difference did not reach statistical significance, but secondary analyses suggest that the biological effect induced by QBECO may be of benefit to patients with moderate-to-severe CD and warrants further study.
Notably, patients with prior exposure to anti-TNFα agents, who are known to generally be more difficult to treat (
The current treatment approach for CD largely targets the overzealous adaptive immune response to invading bacteria in the GI tract, but accumulating evidence suggests patients with CD have impaired or deficient innate immunity that predisposes to defective barrier function (
Patients with lower baseline levels of Eotaxin-1, IL-10, and IL-12p40 were more likely to achieve response and remission with 8 weeks of QBECO treatment. Of note, these cytokines tended to be higher in those who had previously been treated with anti-TNFα therapy and may reflect greater immune dysregulation in patients (
A personalized approach to CD treatment has been elusive to date, possibly because current treatments focus on symptom management (
This proof-of-concept study is limited by its small size, short treatment duration, lack of stratification for previous TNFα inhibitor use, and lack of endoscopic and histological assessment. The therapeutic paradigm has now moved from symptom-based assessment to objective measures of disease activity (
In conclusion, QBECO warrants further study as a novel immunotherapy approach for the management of CD. This approach not only provides a new way of thinking about the treatment of the disease, but also sheds more light on the heterogeneity of CD pathogenesis. QBECO may be the optimal choice for those patients with disease characterized by innate immune dysfunction rather than other underlying etiologies. The data from this trial will inform the design of larger definitive Phase II trials, which will include evaluation of endoscopic and histological endpoints, assessment of the impact of prior TNFα inhibitor exposure on QBECO response, evaluation of patients over a longer treatment period, microbiome assessment, and confirmation of the genetic and immune biomarker findings.
This was a Phase 1/2 randomized, double-blind, placebo-controlled study (NCT01809275; Health Canada approval 27-02-2013) for the treatment of moderate-to-severe CD. All study subjects provided written informed consent and the trial was conducted in compliance with the Declaration of Helsinki and Good Clinical Practice guidelines. The study protocol was approved by the institutional research ethics boards at the four study sites.
HG, SS, BB, and AC: study concept and design, analysis and interpretation of data, drafting and review of manuscript. SK, JP, MBa, GV, RF, RP, JA, JM, DMu, and DMc: analysis and interpretation of data, drafting manuscript, critical revision of manuscript, and acquisition of data. DT: statistical analysis of the trial. BK: statistical analysis of the genetic study. RG, JC, MBo, and JJ: acquisition of data, conduct of study, and patient engagement. All authors read and approved the final draft of the manuscript.
SS, DT, RF, RP, DMu, BK, DMc, AC, and BB have served as consultants and/or advisors to Qu Biologics. SK, JP, JC, RG, MBo, MBa, JJ, and GV are (or were) employees of Qu Biologics. HG is the CEO and major shareholder of Qu Biologics. Qu Biologics owns patents across all the major markets (including U.S. Patent No. 8,980,279) relating to the use of Site Specific Immunomodulators derived from components of
The Supplementary Material for this article can be found online at: