AIM-IBD: A Microbiome-Targeted Supplement in Mild-to-Moderate Ulcerative Colitis (AIM-IBD)
AIM-IBD: A Phase 2b Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial of a Microbiome-Targeted Food Supplement Versus Placebo in Adults With Mild-to-Moderate, Objectively Active Ulcerative Colitis
This Phase 2b randomized, double-blind, placebo-controlled, multicenter trial will evaluate the efficacy and safety of a once-daily oral microbiome-targeted food supplement compared with matching placebo in adults with mild-to-moderate, objectively active ulcerative colitis. The supplement is food-grade and is intended for use either alongside stable standard ulcerative colitis therapy (5-aminosalicylic acid/mesalamine) or in participants not currently on any inflammatory bowel disease therapy.
Approximately 162 participants will be enrolled at university hospital centers in Turkey and randomized in a 1:1 ratio to receive either the food supplement or matching placebo for 24 weeks, in addition to their existing background therapy as defined by eligibility.
The primary objective is to determine whether the supplement increases the proportion of participants achieving composite clinical-plus-biochemical remission at Week 24. This composite endpoint requires absence of rectal bleeding, improvement in stool frequency, fecal calprotectin ≤250 micrograms/g, and no rescue therapy, prohibited treatment escalation, ulcerative colitis-related hospitalization, colectomy, or discontinuation for lack of efficacy before Week 24.
Key secondary endpoints include endoscopic improvement, deep biochemical remission, change in fecal calprotectin, change in partial Mayo score, corticosteroid-free composite remission, change in quality of life, change in C-reactive protein, time to treatment failure, and safety. Exploratory analyses will assess stool microbiome composition, eukaryotic carriage including Blastocystis, and associations between baseline microbiome features and treatment response.
연구 개요
상태
상세 설명
Ulcerative colitis is a chronic inflammatory disease of the colonic mucosa characterized by relapsing and remitting symptoms including rectal bleeding, increased stool frequency, urgency, and impaired quality of life. Although 5-aminosalicylic acid (5-ASA, mesalamine) is the foundation of treatment for mild-to-moderate disease, a meaningful proportion of patients have persistent symptoms or ongoing objective inflammation despite optimized therapy, and many wish to defer immunosuppressive or biologic therapy. The intestinal microbiota of patients with active ulcerative colitis differ from those of healthy individuals, with depletion of short-chain fatty acid-producing taxa, reduced diversity, and altered microbial metabolism. Food-grade microbiome-targeted interventions therefore offer a non-immunosuppressive option to modify intestinal microbial ecology and inflammatory activity in this gap.
AIM-IBD is designed as a Phase 2b, randomized, double-blind, placebo-controlled, parallel-group, multicenter proof-of-concept trial. Randomization is centralized and stratified by study site and baseline 5-ASA status. Participants, investigators, site staff, outcome assessors, endoscopy readers, central laboratory personnel, microbiome and metabolomics analysts, and the primary trial statistician remain blinded to allocation until database lock, except where emergency unblinding is required for participant safety. Blinding integrity is formally assessed at Weeks 12 and 24 using participant and investigator treatment-guess questionnaires summarized with Bang's and James's blinding indices.
The Week 24 endoscopic assessment is by protocol-mandated flexible sigmoidoscopy with dual independent blinded reading and adjudication of discordant scores. Fecal calprotectin and other biomarkers are measured in a central laboratory. Stool samples for microbiome and metabolomics analyses are collected at baseline, Week 12, and Week 24 under a harmonized study procedure.
The planned sample size of 162 participants (81 per arm) provides approximately 90% power to detect a 23-percentage-point absolute difference in the Week 24 primary endpoint (placebo 12% vs active 35%), with two-sided alpha 0.05 and approximately 15% attrition. This ambitious effect size is defensible only because the trial is designed as a high-signal proof-of-concept study: the enrolled population is enriched for objectively active disease (fecal calprotectin ≥250 µg/g and rectal bleeding subscore ≥1 at screening), background therapy is held constant (stable 5-ASA at unchanged dose for ≥8 weeks, or no inflammatory bowel disease therapy), and patients with recent advanced-therapy exposure or current corticosteroids are excluded. Sensitivity analyses across a range of placebo and active response assumptions are prespecified in the Statistical Analysis Plan.
The intention-to-treat population is the primary analysis population. The primary composite endpoint is analyzed using stratified Cochran-Mantel-Haenszel methodology adjusted for randomization stratification factors. Key secondary endpoints are tested in a fixed-sequence hierarchical procedure controlling the family-wise error rate at two-sided alpha 0.05. The estimand framework follows ICH E9(R1): treatment failures (rescue therapy, prohibited escalation, ulcerative colitis-related hospitalization, colectomy, discontinuation for lack of efficacy) are handled under a composite strategy, with a supplementary treatment-policy estimand and prespecified sensitivity analyses (multiple imputation, tipping-point analysis, pattern-mixture).
An independent Data Safety Monitoring Board with a written charter oversees safety, with scheduled reviews after approximately 25%, 50%, and 75% of planned enrollment and ad hoc reviews for predefined safety signals. An independent Endpoint Adjudication Committee adjudicates ulcerative colitis-related hospitalizations, colectomies, and any deaths. Rescue therapy is permitted at any time when clinically necessary; participants requiring rescue therapy or any prohibited treatment escalation before Week 24 are classified as treatment failures for the primary endpoint and continue safety follow-up whenever feasible.
The trial is conducted in accordance with the Declaration of Helsinki and ICH-GCP E6(R3). Reporting follows the CONSORT statement, the SPIRIT protocol framework, and the STORMS reporting checklist for the microbiome workstream.
연구 유형
등록 (추정된)
단계
- 해당 없음
연락처 및 위치
연구 연락처
- 이름: Varol TUNALI, Dr.
- 전화번호: +905556303231
- 이메일: vtunali@enbiosis.com
연구 장소
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Izmir, 터키 (Türkiye)
- 모병
- Ege university
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연락하다:
- Nalan G. Ünal, Prof. Dr.
- 전화번호: +90 232 343 4 343
- 이메일: drnalanunal@gmail.com
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참여기준
자격 기준
공부할 수 있는 나이
- 성인
- 고령자
건강한 자원 봉사자를 받아들입니다
설명
Inclusion Criteria:
- Adults aged 18 to 75 years inclusive at screening.
- Documented diagnosis of ulcerative colitis established at least 3 months before screening, based on standard clinical, endoscopic, and histologic criteria.
- Mild-to-moderate active ulcerative colitis defined by a partial Mayo score of 4 to 8 at screening.
- Rectal bleeding subscore of at least 1 at screening.
- Objective intestinal inflammation defined by fecal calprotectin of at least 250 micrograms per gram at screening, measured by the central laboratory or by a validated harmonized assay.
- Eligible disease extent: left-sided colitis or extensive/pancolitis. Proctosigmoiditis is eligible if inflammation extends beyond isolated proctitis and is measurable by study endoscopy. Isolated ulcerative proctitis (E1 only) is eligible only within a prespecified cap not exceeding 10 percent of total enrollment.
- Either no current ulcerative colitis-directed therapy, or stable oral and/or rectal 5-aminosalicylate (5-ASA, mesalamine) therapy at unchanged dose for at least 8 weeks before randomization, with intent to continue at the same unchanged dose through Week 24 unless rescue therapy is clinically required.
- Able and willing to provide written informed consent.
- Able and willing to comply with study visits, stool sampling, endoscopy, medication restrictions, and diary/patient-reported outcome completion.
- Participants of childbearing potential must agree to use a highly effective method of contraception during dosing and for at least 4 weeks after the last dose, in accordance with EMA/CTFG guidance and local ethics requirements.
Exclusion Criteria:
- Crohn disease, inflammatory bowel disease-unclassified, microscopic colitis, ischemic colitis, infectious colitis, radiation colitis, or any other non-ulcerative-colitis form of colitis.
- Severe ulcerative colitis, acute severe ulcerative colitis, fulminant colitis, toxic megacolon, or any disease severity requiring immediate hospitalization or treatment escalation in the investigator's judgment.
- Isolated ulcerative proctitis (E1 only) outside the prespecified 10 percent enrollment cap.
- Use of biologics, Janus kinase (JAK) inhibitors, sphingosine-1-phosphate (S1P) receptor modulators, or systemic immunosuppressants within 8 weeks before randomization, or planned use of any of these during the trial.
- Systemic corticosteroids within 4 weeks before randomization.
- Current budesonide-class therapy at baseline.
- Rectal or topical corticosteroids unless discontinued at least 2 weeks before randomization.
- Antibiotic use within 4 weeks before randomization, except topical antibiotics not expected to affect the gut microbiota.
- Probiotic, prebiotic, synbiotic, postbiotic, fermented microbiome-directed supplement, or other non-study microbiome-directed product within 4 weeks before randomization, or planned use during the trial.
- Active or recent Clostridioides difficile infection within 12 weeks before screening (screening uses a two-step algorithm: glutamate dehydrogenase plus toxin A/B enzyme immunoassay, with reflex nucleic acid amplification testing for discordant results).
- Positive stool test for any clinically relevant enteric infection at screening, per local diagnostic standard operating procedures.
- Prior colectomy, planned colectomy, known dysplasia requiring intervention, or colorectal cancer.
- Pregnancy, breastfeeding, or planned pregnancy during the trial.
- Uncontrolled clinically significant comorbidity, including but not limited to uncontrolled diabetes, advanced liver or renal disease, unstable cardiovascular disease, immunodeficiency, active malignancy other than adequately treated non-melanoma skin cancer, or any other condition compromising participant safety or interpretation of study results.
- Known allergy, intolerance, or contraindication to any component of the investigational product or matching placebo.
- Participation in another interventional clinical trial within 30 days before screening.
- Any other condition that, in the investigator's judgment, would make participation unsafe or compromise protocol adherence.
공부 계획
연구는 어떻게 설계됩니까?
디자인 세부사항
- 주 목적: 지지 요법
- 할당: 무작위
- 중재 모델: 병렬 할당
- 마스킹: 네 배로
무기와 개입
참가자 그룹 / 팔 |
개입 / 치료 |
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실험적: Microbiome-Targeting Investigational Product
Participants assigned to this arm will receive the microbiome-targeting investigational product orally once daily for 24 weeks, in addition to either no background ulcerative colitis therapy or stable 5-aminosalicylic acid/mesalamine therapy at an unchanged dose, according to eligibility criteria.
Rescue therapy or treatment escalation is permitted at any time if clinically needed.
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The investigational product is an oral microbiome-targeting preparation administered once daily for 24 weeks.
It is intended to modulate gut microbial ecology and/or microbial metabolite production in adults with mild-to-moderate ulcerative colitis.
The dosage form, dose, composition class, storage conditions, and batch-release specifications are documented in the study protocol and investigational product dossier reviewed by the ethics committee and relevant regulatory authority.
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위약 비교기: Placebo
Participants assigned to this arm will receive matching placebo orally once daily for 24 weeks, in addition to either no background ulcerative colitis therapy or stable 5-aminosalicylic acid/mesalamine therapy at an unchanged dose, according to eligibility criteria.
Rescue therapy or treatment escalation is permitted at any time if clinically needed.
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The placebo is an oral matching preparation administered once daily for 24 weeks.
It contains inactive excipients only and is matched to the investigational product in appearance, packaging, administration schedule, and organoleptic characteristics, including color, taste, smell, and mouthfeel, as closely as technically feasible.
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연구는 무엇을 측정합니까?
주요 결과 측정
결과 측정 |
측정값 설명 |
기간 |
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Proportion of Participants Achieving Composite Clinical-Plus-Biochemical Remission at Week 24
기간: Baseline to Week 24
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Responder defined by all four criteria at Week 24: (1) rectal bleeding subscore = 0 on the Mayo 0-3 scale (lower = less bleeding; 0 = no blood seen); (2) stool frequency subscore ≤1 on the Mayo 0-3 scale (lower = fewer stools above the participant's normal) with at least a 1-point decrease from baseline; (3) fecal calprotectin ≤250 µg/g (lower = less mucosal inflammation), measured centrally; (4) no rescue therapy, prohibited escalation, UC-related hospitalization, colectomy, or discontinuation for lack of efficacy through Week 24.
Participants not meeting any criterion, or with missing Week 24 data, are counted as non-responders (non-responder imputation).
Higher proportion = greater treatment benefit.
Analyzed in the intention-to-treat population using stratified Cochran-Mantel-Haenszel adjusted for randomization stratification factors, reporting absolute risk difference with Newcombe 95% CI.
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Baseline to Week 24
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2차 결과 측정
결과 측정 |
측정값 설명 |
기간 |
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Proportion of Participants With Endoscopic Improvement at Week 24
기간: Baseline to Week 24
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Responder defined as Mayo endoscopic subscore ≤1 at Week 24 (scale 0-3; lower = less inflammation; 0 = normal, 1 = mild erythema/decreased vascular pattern, 2 = marked erythema/friability/erosions, 3 = spontaneous bleeding/ulceration). Week 24 assessment is by protocol-mandated flexible sigmoidoscopy of the most inflamed segment with standardized image/video capture, scored by two independent blinded readers; discordant scores or scores crossing the ≤1 vs >1 threshold are adjudicated by a third blinded reader (adjudicator score = trial-of-record).
Participants meeting any treatment-failure criterion before Week 24, or not undergoing the Week 24 endoscopy without documented medical exception, are counted as non-responders.
A completer-only sensitivity analysis is prespecified.
Higher proportion = greater treatment benefit.
Analyzed in the intention-to-treat population using stratified Cochran-Mantel-Haenszel; effect estimate is absolute risk difference (Newcombe 95% CI).
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Baseline to Week 24
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Proportion of Participants With Deep Biochemical Remission at Week 24
기간: Baseline to Week 24
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Responder defined as fecal calprotectin ≤150 µg/g at Week 24, measured centrally using a validated assay.
Fecal calprotectin is a stool neutrophil-derived biomarker of intestinal inflammation: healthy adults typically <50 µg/g; well-controlled UC <150-250 µg/g; active disease often several hundred to several thousand µg/g.
The 150 µg/g threshold is stricter than the 250 µg/g threshold used in the primary composite endpoint and corresponds to the deep biochemical remission target in STRIDE-II treat-to-target guidance.
Participants meeting any treatment-failure criterion before Week 24, or with missing Week 24 calprotectin, are counted as non-responders (non-responder imputation).
A completer-only sensitivity analysis is prespecified.
Higher proportion = greater treatment benefit.
Analyzed in the intention-to-treat population using stratified Cochran-Mantel-Haenszel adjusted for randomization stratification factors; effect estimate is absolute risk difference (Newcombe 95% CI).
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Baseline to Week 24
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Change in Fecal Calprotectin From Baseline to Week 24
기간: Baseline to Week 24
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Continuous endpoint quantifying treatment effect on intestinal inflammation.
Fecal calprotectin is a stool neutrophil-derived biomarker measured centrally using a validated assay at baseline and Week 24; healthy adults typically <50 µg/g, well-controlled UC <150-250 µg/g, active disease often several hundred to several thousand µg/g, with no fixed upper limit.
Lower values indicate less mucosal inflammation.
Values are log-transformed (natural log, after substituting half the lower limit of quantification for any below-LLOQ result), and the treatment effect is summarized as the geometric mean ratio of active vs placebo at Week 24 with 95% confidence interval, derived from a mixed model for repeated measures with treatment, visit, treatment-by-visit interaction, log baseline calprotectin, and randomization stratification factors as fixed effects.
A geometric mean ratio below 1 indicates a greater reduction in fecal calprotectin in the active arm relative to placebo.
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Baseline to Week 24
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Change in Fecal Calprotectin From Baseline to Week 12
기간: Baseline to Week 12
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Continuous endpoint quantifying early treatment effect on intestinal inflammation, prespecified as an interim biomarker readout midway through the 24-week treatment period.
Fecal calprotectin is a stool neutrophil-derived biomarker measured centrally using a validated assay at baseline and Week 12; healthy adults typically <50 µg/g, well-controlled UC <150-250 µg/g, active disease often several hundred to several thousand µg/g.
Lower values indicate less mucosal inflammation.
Values are log-transformed (natural log, after substituting half the lower limit of quantification for any below-LLOQ result) and the treatment effect is summarized as the geometric mean ratio of active vs placebo at Week 12 with 95% confidence interval, derived from a mixed model for repeated measures with treatment, visit, treatment-by-visit interaction, log baseline calprotectin, and randomization stratification factors as fixed effects.
A ratio below 1 indicates greater reduction in the active arm vs placebo.
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Baseline to Week 12
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Proportion of Participants With Corticosteroid-Free Composite Remission at Week 24
기간: Baseline to Week 24
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Responder defined by meeting both: (1) the primary composite clinical-plus-biochemical remission endpoint at Week 24 (rectal bleeding subscore = 0; stool frequency subscore ≤1 with at least a 1-point decrease from baseline; fecal calprotectin ≤250 µg/g; and no rescue therapy, prohibited escalation, UC-related hospitalization, colectomy, or discontinuation for lack of efficacy through Week 24); and (2) no use of systemic or rectal corticosteroids (including budesonide-class) at any time between randomization and the Week 24 assessment.
Corticosteroid exposure is captured from concomitant medication records and reconciled with rescue therapy documentation.
Participants not meeting either criterion, or with missing Week 24 data, are counted as non-responders (non-responder imputation).
Higher proportion = greater treatment benefit.
Analyzed in the intention-to-treat population using stratified Cochran-Mantel-Haenszel; effect estimate is absolute risk difference (Newcombe 95% CI).
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Baseline to Week 24
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Change in Partial Mayo Score From Baseline to Week 24
기간: Baseline to Week 24
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Continuous endpoint quantifying treatment effect on clinical disease activity.
The partial Mayo score is the sum of three Mayo subscores - stool frequency (0-3, lower = fewer stools above the participant's normal), rectal bleeding (0-3, lower = less bleeding; 0 = no blood seen), and physician global assessment (0-3, lower = less overall disease severity in the physician's judgment) - yielding a total score from 0 to 9, with lower scores indicating less disease activity.
Assessed at baseline and Week 24.
Treatment effect is summarized as the least-squares mean difference between active and placebo in change from baseline to Week 24 with 95% confidence interval, derived from a mixed model for repeated measures with treatment, visit, treatment-by-visit interaction, baseline partial Mayo, and randomization stratification factors as fixed effects.
A more negative change indicates greater reduction in disease activity; a between-arm difference favoring active = greater treatment benefit.
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Baseline to Week 24
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Change in Inflammatory Bowel Disease Questionnaire-32 Total Score From Baseline to Week 24
기간: Baseline to Week 24
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Continuous endpoint quantifying treatment effect on disease-specific quality of life.
The Inflammatory Bowel Disease Questionnaire-32 (IBDQ-32) is a 32-item validated patient-reported instrument covering four domains: bowel symptoms, systemic symptoms, emotional function, and social function.
Each item is rated 1-7 (1 = worst, 7 = best); the total score ranges from 32 to 224, with higher scores indicating better quality of life.
A change of 16 points or more is generally considered clinically meaningful.
A locally validated Turkish translation is administered at baseline and Week 24.
Treatment effect is summarized as the least-squares mean difference between active and placebo in change from baseline to Week 24 with 95% confidence interval, derived from a mixed model for repeated measures with treatment, visit, treatment-by-visit interaction, baseline IBDQ-32, and randomization stratification factors as fixed effects.
A larger positive change in the active arm = greater benefit.
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Baseline to Week 24
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Change in C-Reactive Protein From Baseline to Week 24
기간: Baseline to week 24
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Continuous endpoint quantifying treatment effect on systemic inflammation.
C-reactive protein (CRP) is a serum acute-phase reactant of hepatic origin, measured in mg/L by the central laboratory using a high-sensitivity assay at baseline and Week 24.
Healthy adults typically have CRP <3 mg/L; lower values indicate less systemic inflammation.
Note that CRP can be normal in a sizeable subset of UC patients with active mucosal disease, particularly those with distal/left-sided disease.
Values are log-transformed and the treatment effect is summarized as the geometric mean ratio of active vs placebo at Week 24 with 95% confidence interval, derived from a mixed model for repeated measures adjusting for log baseline CRP and randomization stratification factors.
A ratio below 1 indicates greater reduction with active treatment.
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Baseline to week 24
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Incidence of Treatment-Emergent Adverse Events
기간: From first dose through 4 weeks after the last dose (up to approximately Week 28)
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Safety endpoint summarizing the cumulative incidence and exposure-adjusted rates of adverse events over the treatment period.
A treatment-emergent adverse event (TEAE) is any adverse event with onset, or worsening, on or after the first dose of study product through 4 weeks after the last dose.
Reported by treatment arm: number and proportion of participants with any TEAE; any serious adverse event (SAE); any TEAE leading to study product discontinuation; and any adverse event of special interest (AESI).
AESI: new-onset Clostridioides difficile infection; serious enteric or opportunistic infection; UC worsening requiring hospitalization; colectomy; hepatobiliary events; severe allergic or anaphylactic reactions; gastrointestinal perforation; death.
Coded with MedDRA (version current at database lock); severity graded per CTCAE v5.0; relatedness assessed by the investigator.
Higher numbers and proportions indicate more frequent events.
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From first dose through 4 weeks after the last dose (up to approximately Week 28)
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Change in Stool Microbiome Composition From Baseline to Weeks 12 and 24
기간: Baseline, Week 12, and Week 24
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Exploratory endpoint characterizing treatment-associated shifts in gut microbial communities.
Stool samples are collected at baseline, Week 12, and Week 24 under a harmonized SOP and processed centrally.
Sequencing is by 16S rRNA gene profiling and/or shotgun metagenomics (final choice locked in the microbiome analysis plan before database lock), with negative controls, mock communities, and batch randomization.
Outputs include alpha diversity (Shannon index, Faith's phylogenetic diversity; higher = more diverse), beta diversity (Aitchison and weighted/unweighted UniFrac distances; quantifying between-sample compositional difference), differential abundance of taxa using compositionally appropriate transformations (CLR/ILR) with Benjamini-Hochberg false discovery rate control at q<0.05, and treatment-associated taxonomic and functional shifts.
As an exploratory endpoint, no formal hypothesis testing within the confirmatory hierarchy is performed.
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Baseline, Week 12, and Week 24
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공동 작업자 및 조사자
협력자
수사관
- 수석 연구원: Varol TUNALI, Enbiosis Biotechnology Limited
연구 기록 날짜
연구 주요 날짜
연구 시작 (추정된)
기본 완료 (추정된)
연구 완료 (추정된)
연구 등록 날짜
최초 제출
QC 기준을 충족하는 최초 제출
처음 게시됨 (실제)
연구 기록 업데이트
마지막 업데이트 게시됨 (실제)
QC 기준을 충족하는 마지막 업데이트 제출
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추가 정보
이 연구와 관련된 용어
키워드
기타 연구 ID 번호
- Enbiosis_AIM-IBD
개별 참가자 데이터(IPD) 계획
개별 참가자 데이터(IPD)를 공유할 계획입니까?
IPD 계획 설명
IPD 공유 기간
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- 연구_프로토콜
- 수액
- CSR
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