Data Safety Monitoring Board Charter (TILA278-201)

Trial Master File operational document for Study TILA278-201.

Change History

1. Introduction and Purpose

This charter defines the composition, authority, operating procedures, and communication pathways of the Data Safety Monitoring Board (DSMB; synonymous herein with an independent Data Monitoring Committee [DMC]) established by Virtual Biopharma Inc. (the Sponsor) for Protocol TILA278-201, a Phase 2b, randomized, double-blind, placebo-controlled, parallel-group, 12-week induction study of TILA-278 in adults with moderate-to-severe ulcerative colitis (UC).

TILA-278 is a humanized IgG1 bispecific monoclonal antibody administered subcutaneously (SC); one antigen-binding arm is an anti-TL1A (TNFSF15) antagonist and the second arm is an interleukin-22 receptor (IL-22R) agonist. The intended pharmacology couples dampening of TH1/TH17-driven mucosal inflammation and intestinal fibrosis (TL1A antagonism) with promotion of epithelial regeneration and mucosal-barrier repair (IL-22R agonism). Because the dual mechanism is novel and combines immunomodulation with an epithelial-proliferative signal, prospective independent safety oversight is warranted throughout the conduct of TILA278-201.

The DSMB is an independent, multidisciplinary group of experts constituted to safeguard the interests and safety of enrolled subjects, to preserve the integrity and credibility of the trial, and to protect the validity of trial results. The DSMB is the only body with routine access to accumulating unblinded safety data organized by treatment group during the conduct of the study. It is advisory to the Sponsor; the Sponsor retains ultimate decision-making responsibility but will not overrule a DSMB safety recommendation without documented justification and, where applicable, consultation with health authorities and Institutional Review Boards / Independent Ethics Committees (IRB/IEC).

This charter is a controlled document of the Trial Master File (TMF) and has been prepared in a manner consistent with the U.S. FDA guidance Establishment and Operation of Clinical Trial Data Monitoring Committees (2006), ICH E6(R3) Good Clinical Practice (GCP), ICH E9 Statistical Principles for Clinical Trials and its R1 addendum, and the EMA Guideline on Data Monitoring Committees (EMEA/CHMP/EWP/5872/03 Corr). It is finalized and executed before the first subject is randomized.

1.1 Abbreviations

2. Scope and Governing Principles

The DSMB's remit is limited to Protocol TILA278-201. Its focus is subject safety and the ongoing acceptability of the benefit–risk balance in the context of a short-duration (12-week) induction study.

Governing principles:

• Independence. DSMB voting members are external to the Sponsor and are free of significant financial, scientific, or professional conflicts of interest with respect to TILA-278, the Sponsor, or the trial outcome.
• Confidentiality. Unblinded, treatment-group-level data reviewed by the DSMB are confidential and are not disclosed to the Sponsor's study team, investigators, or subjects during the conduct of the study, except as expressly provided in this charter (Section 9).
• Trial integrity. All procedures are designed to prevent inadvertent unblinding of individuals who influence trial conduct or endpoint ascertainment.
• Advisory authority. The DSMB issues recommendations; the Sponsor implements or formally documents its response to each recommendation.
• Subject protection primacy. Where subject safety and trial-integrity considerations conflict, subject safety prevails.

No formal group-sequential interim efficacy analysis for stopping for benefit is pre-planned in TILA278-201. Accordingly, the DSMB does not conduct efficacy hypothesis testing and does not issue stop-for-benefit recommendations except in the exceptional circumstance of an unequivocal, clinically compelling safety–benefit imbalance (Section 8.4). Efficacy summaries are provided to the DSMB by treatment group solely to allow interpretation of safety findings within the benefit–risk context.

3. DSMB Composition, Membership, and Independence

3.1 Composition

The DSMB comprises three (3) independent voting members with expertise appropriate to the indication, the modality, and the statistical design. Members are appointed by the Sponsor on the basis of relevant expertise and freedom from conflict of interest, and serve for the duration of the study.

At least one member has substantive experience with monoclonal-antibody safety, including immunogenicity and infection risk; at least one member is a practicing physician in the therapeutic area able to judge the clinical relevance of accruing UC and colonic findings. The Chair is a physician.

3.2 Independence, conflict of interest, and confidentiality undertakings

Prior to appointment, each member discloses financial interests (equity, consultancy, honoraria, research funding), intellectual involvement in competing programs, and any personal or professional relationships that could be perceived as a conflict with respect to TILA-278 or Virtual Biopharma Inc. Members:

• Are not employees of the Sponsor or of any contract organization performing trial-critical functions;
• Are not investigators or site personnel on TILA278-201 and enroll no subjects into the study;
• Hold no financial interest in the Sponsor that could be materially affected by the trial outcome;
• Do not participate in a DSMB or steering role for a directly competing UC induction program during their tenure, absent Sponsor and Chair agreement.

Each member and each non-voting participant executes a confidentiality agreement and a conflict-of-interest disclosure before receiving any trial data. Disclosures are updated at least annually and whenever circumstances change. Perceived conflicts are reviewed by the Chair and Sponsor; material unresolved conflicts result in recusal or replacement.

3.3 Non-voting participants

• Independent Unblinded Statistician / Statistical Data Analysis Center (USS/SDAC): an independent statistician and programming group, functionally and organizationally separated from the Sponsor study team, who receive unblinded randomization data, generate the closed (unblinded) reports, and attend closed sessions to present and clarify data. The USS/SDAC does not vote.
• DSMB Coordinator / Sponsor liaison: facilitates logistics, agendas, and open-session materials. This individual remains blinded and does not attend closed sessions.

3.4 Quorum, voting, and replacement

Full attendance by all three voting members is the norm and is expected for any meeting at which a stop, pause, arm-termination, or study-termination recommendation may be formulated. The minimum quorum is two of the three voting members, one of whom must be the Chair. Where a meeting proceeds with two members because the third is unavoidably unavailable, the absent member provides written input in advance, and no stop, pause, or arm-/study-termination recommendation is finalized without the participation (in person or in writing) of the biostatistician. Recommendations are reached by consensus wherever possible. Where consensus cannot be reached, a majority vote is recorded together with any minority position and rationale. In the event of a persistent tie (e.g., a two-member session), the Chair's determination governs, and the matter is re-reviewed at the earliest opportunity with full membership. A member who cannot continue is replaced by the Sponsor following the same independence and conflict criteria; incoming members are oriented to this charter and to prior meeting outcomes.

4. Roles and Responsibilities

4.1 DSMB (collective)

• Review accumulating safety data at the intervals and by the triggers defined in Section 6.
• Assess the adequacy and completeness of the data presented and the timeliness of AE/SAE reporting.
• Evaluate whether the safety profile, and the benefit–risk balance, remain acceptable for continued enrollment and continued dosing.
• Issue one of the recommendations defined in Section 8 after each review.
• Recommend protocol, monitoring, or informed-consent modifications where indicated by emerging safety data.
• Maintain the confidentiality of unblinded data and of its deliberations.

4.2 Chair

• Sets agendas in consultation with the Sponsor liaison and USS/SDAC; chairs open, closed, and executive sessions.
• Serves as the DSMB's point of contact with the Sponsor and communicates recommendations.
• Determines the need for, and convenes, ad hoc meetings.
• Ensures minutes are prepared, reviewed, and archived appropriately (open vs. closed).

4.3 Voting members

• Prepare for and attend meetings; review pre-distributed reports before each session.
• Contribute domain expertise (clinical, immunologic, statistical) to interpretation and recommendations.
• Declare any newly arising conflicts.

4.4 Independent Unblinded Statistician / SDAC

• Receive the unblinded treatment assignment from the interactive response technology (IRT) vendor under a firewall separating them from the Sponsor study team.
• Produce closed (unblinded) safety reports per the pre-specified DSMB reporting plan and to a consistent, reproducible specification.
• Present and clarify closed-session data; perform any ad hoc unblinded analyses requested by the DSMB.
• Maintain unblinded data securely and ensure no unblinded output reaches the blinded study team.

4.5 Sponsor

• Constitute the DSMB, execute agreements, and provide the resources and blinded (open) data required.
• Ensure timely, accurate, and complete data flow to the USS/SDAC.
• Receive, act on, and document its response to DSMB recommendations, including notification of investigators, IRB/IECs, and health authorities as required.
• Maintain the firewall between the USS/SDAC and the blinded study team.
• Not attend closed sessions and not request or receive unblinded, treatment-group-level data during the study except as provided in Section 9.

5. Data to Be Reviewed

Reports are prepared in two parts. Open (blinded) reports contain pooled or by-blinded-group data and are available to the full DSMB and, where appropriate, to the Sponsor. Closed (unblinded) reports present data by actual treatment group (TILA-278 High, TILA-278 Low, Placebo) and are restricted to the DSMB voting members and the USS/SDAC.

5.1 Open (blinded) session content

• Enrollment, randomization, and disposition against the target of 900 randomized subjects (planned 1:1:1 allocation to TILA-278 High / TILA-278 Low / Placebo), including screen-failure context relative to the approximately 1,700 subjects planned to be screened.
• Baseline demographics and disease characteristics, including stratification factors (baseline modified Mayo severity; prior biologic exposure).
• Protocol deviations, data completeness, and eCRF/query status.
• Aggregate, treatment-blinded AE and SAE counts and site-level safety-reporting timeliness.

5.2 Closed (unblinded) session content — by treatment group

The closed report presents the following by TILA-278 High, TILA-278 Low, and Placebo. Given the 12-week induction duration and scheduled visits at Weeks 0, 2, 4, 8, and 12, particular attention is paid to on-treatment emergence and dose-ordering of events.

Individual-subject data listings (SAEs, deaths, discontinuations, marked lab abnormalities, and AESIs) are provided to support case-level review.

5.3 Data flow, cutoff, and quality

For each scheduled review, a data cutoff date is pre-specified (typically 2–4 weeks before the meeting) to allow cleaning and report generation. Reports are distributed to voting members securely at least five (5) business days in advance. The report specifies the cutoff, data-maturity caveats, and the extent of medical coding and source verification achieved. SAEs and deaths are reported to the DSMB on an expedited basis irrespective of the scheduled review cycle (Section 6.1).

5.4 Adverse events of special interest

AESIs are pre-defined in light of the mechanism and modality of TILA-278 and are tabulated and reviewed at every closed session:

1. Serious and opportunistic infections, reflecting the immunomodulatory action of TL1A antagonism; upper-respiratory and other common infections (e.g., nasopharyngitis) are monitored for frequency, severity, and any dose-ordering.
2. Injection-site reactions — the principal drug-attributable local finding anticipated for an SC monoclonal antibody.
3. Systemic hypersensitivity / anaphylactic reactions.
4. Hepatic injury, including potential Hy's-law cases.
5. Colonic epithelial proliferative events / dysplasia or neoplasia — a theoretical, mechanism-based concern arising from the IL-22R agonist arm's epithelial-proliferative signal; reviewed together with any colonoscopy/biopsy findings and worsening-UC events.
6. Immunogenicity-associated events temporally linked to ADA formation.
7. Major adverse cardiovascular events and malignancy of any type.

6. Meeting Schedule and Format

6.1 Types of meetings

• Organizational meeting — held after this charter is executed and before the first subject is randomized. The DSMB reviews the protocol, statistical analysis plan, this charter, the reporting plan, and safety-monitoring conventions, and confirms the review schedule and stopping guidance.
• Periodic safety reviews — scheduled unblinded reviews of accumulating data (Section 6.2).
• Ad hoc meetings — convened at the Chair's discretion, or at Sponsor request, in response to a safety signal, an SAE cluster, a death, a SUSAR, or an external safety finding relevant to the class or mechanism. The DSMB may also be consulted expeditiously between meetings on specific SAEs/deaths by written procedure.

6.2 Schedule and triggers

Given the compressed 12-week induction design and anticipated enrollment cadence toward 900 randomized subjects, periodic reviews are governed by enrollment milestones and by a calendar minimum, whichever occurs first. Proposed schedule (thresholds confirmable at the organizational meeting):

The interval between periodic reviews will not ordinarily exceed three (3) months while subjects are on treatment. The DSMB may increase or decrease the frequency of reviews based on the accruing data and will document any change.

6.3 Session structure

Each meeting is organized into up to three sequential parts:

1. Open session — full DSMB with Sponsor liaison and USS/SDAC; blinded data, logistics, conduct, and data-quality matters.
2. Closed session — voting members and USS/SDAC only; unblinded, by-treatment-group data and deliberation.
3. Executive session — voting members only; final formulation of the recommendation, including any minority position.

Meetings may be held by secure teleconference/videoconference. Materials are handled on validated, access-controlled systems.

7. Statistical Considerations and Safety Monitoring Approach

Safety monitoring is primarily descriptive and clinical rather than inferential. The USS/SDAC presents by-group frequencies, rates adjusted for exposure where appropriate, severity/relatedness distributions, laboratory shift and marked-abnormality tables, and case-level listings. Because TILA278-201 does not implement a pre-planned group-sequential efficacy analysis, no alpha is spent on interim efficacy testing and no efficacy stopping boundary is defined.

For safety, formal statistical stopping rules are intentionally limited; the DSMB relies on clinical judgment informed by pre-specified quantitative triggers (Section 8.3). Where the DSMB wishes to characterize a numerical imbalance, the USS/SDAC may provide descriptive confidence intervals or between-group comparisons, understood as flags for clinical review rather than as hypothesis tests. The dose-ordered design (High vs. Low vs. Placebo) is used to assess whether any safety finding is dose-related; the anticipated pharmacology predicts no dose-dependent systemic safety signal, with injection-site reactions as the principal drug-attributable finding, and the DSMB monitors for deviations from this expectation.

8. Decision / Recommendation Framework

After each closed and executive session, the DSMB issues a single primary recommendation to the Sponsor from the categories below.

8.1 Recommendation categories

8.2 Considerations informing the recommendation

• Frequency, severity, seriousness, relatedness, reversibility, and dose-ordering of events.
• Whether findings are consistent with the known safety expectations for SC monoclonal antibodies and the TL1A/IL-22R mechanism, or represent unexpected signals.
• Data completeness and maturity, and the plausibility of confounding (e.g., worsening UC vs. drug effect; events more frequent on placebo attributable to disease/lack of efficacy).
• The short, fixed 12-week treatment duration and the availability of established rescue/standard-of-care options.
• The benefit–risk balance in light of by-group efficacy context.

8.3 Safety stopping / pause guidelines

The following pre-specified quantitative triggers do not mandate a specific action but require explicit DSMB deliberation and a documented rationale for whichever recommendation is chosen (thresholds confirmable at the organizational meeting):

• Any treatment-related death, or a clustering of deaths on an active arm exceeding placebo beyond chance.
• Any confirmed Hy's-law case, or ≥2 cases of drug-attributable serious hepatic injury on an active arm.
• Any anaphylaxis / serious hypersensitivity event assessed as related, or a rate of related serious hypersensitivity meaningfully exceeding placebo.
• A serious/opportunistic infection rate on an active arm that is dose-ordered and materially exceeds placebo.
• Any confirmed case of colonic dysplasia or neoplasia plausibly attributable to the IL-22R agonist mechanism, or a mechanism-consistent increase in proliferative colonic findings.
• A serious injection-site or systemic reaction pattern incompatible with continued SC administration.
• Any other unanticipated serious safety finding that, in the DSMB's judgment, renders the benefit–risk balance unacceptable.

8.4 Stop-for-benefit

Consistent with Section 2, the DSMB will not recommend early termination for efficacy. Only in the exceptional case of an unequivocal, clinically overwhelming safety–benefit imbalance rendering continued placebo or continued lower-dose exposure ethically untenable would the DSMB raise a benefit-driven consideration, and then only in conjunction with a safety rationale and full documentation.

9. Communication Procedures

9.1 Recommendations to the Sponsor

After each meeting, the Chair communicates the DSMB's primary recommendation to a designated senior Sponsor representative, ordinarily in writing within five (5) business days, using a standard recommendation memorandum. A recommendation to continue without modification (Category 1) contains no unblinded data. Recommendations in Categories 2–5 provide the rationale in terms sufficient for the Sponsor to act while disclosing the minimum unblinded information necessary; where feasible, the rationale is framed to avoid unblinding the study team. Urgent recommendations (pause, arm termination, study termination, or any recommendation arising from a death or serious signal) are communicated to the Sponsor by the Chair without delay, ahead of the written memorandum.

9.2 Sponsor response and onward notification

The Sponsor documents its decision and rationale in response to each recommendation and retains both in the TMF. Where the Sponsor implements a Category 2–5 recommendation, or otherwise as required, it notifies investigators, IRB/IECs, and health authorities in accordance with regulatory obligations and reporting timelines. Should the Sponsor decline to follow a DSMB safety recommendation, the basis is documented and discussed with the DSMB Chair, and health authorities are informed as appropriate.

9.3 Documentation, minutes, and archival

Two sets of minutes are maintained:

• Open minutes — record attendance, blinded discussion, conduct/quality items, and the recommendation category, without unblinded data; shared with the Sponsor and filed in the accessible TMF.
• Closed minutes — record unblinded deliberations, data reviewed, votes (including any minority opinion), and the detailed basis for the recommendation; held confidentially and released only after final database lock and study unblinding, or earlier if required by a health authority.

All materials are version-controlled, dated, and retained per the Sponsor's records-retention policy and applicable regulation.

9.4 Confidentiality, firewall, and unblinding control

• Unblinded, treatment-group-level data and closed-session deliberations are confidential to the DSMB voting members and the USS/SDAC.
• The USS/SDAC operates behind a documented firewall from the blinded Sponsor study team; no unblinded output is transmitted to the blinded team.
• DSMB members do not communicate unblinded findings to investigators, subjects, or the blinded study team.
• Individual-subject emergency unblinding for medical management remains the responsibility of the investigator via the IRT system and is independent of DSMB processes; expedited safety reporting (SAEs, SUSARs) to health authorities proceeds through the Sponsor's pharmacovigilance system and is not delayed pending a DSMB meeting.

9.5 Interface with pharmacovigilance and regulatory reporting

The DSMB's periodic review does not replace the Sponsor's ongoing expedited safety-reporting obligations (e.g., SUSAR reporting consistent with ICH E2A and applicable regional requirements, and aggregate safety reports). The DSMB is informed of relevant expedited reports and of any external safety information affecting the TILA-278 program or the TL1A/IL-22R class, and may factor these into its recommendations.

10. Charter Administration

This charter takes effect on execution by all voting members and the Sponsor and remains in force until the last subject completes the study and the database is locked, or until the study is terminated. Amendments require the agreement of the DSMB Chair and the Sponsor, are version-controlled, and are documented in the TMF; substantive changes (e.g., to composition, review schedule, or stopping guidance) are agreed before implementation and, where they affect subject safety or trial integrity, discussed with health authorities as appropriate. In the event of conflict between this charter and the protocol regarding safety oversight, the DSMB Chair and Sponsor resolve the discrepancy and record the resolution.

11. Approval and Signatures

The signatories confirm that they have read this charter, agree to its provisions, and will discharge their responsibilities in accordance with it.

Protocol TILA278-201 — TILA-278 (anti-TL1A × IL-22R bispecific humanized IgG1 monoclonal antibody), moderate-to-severe ulcerative colitis. Sponsor: Virtual Biopharma Inc. This Data Safety Monitoring Board Charter is a controlled document of the Trial Master File.