📚 Part of the TILA-278 Regulatory Dossier — Reader's Guide. This article shows the live document; edits to the source appear here automatically.

---

Randomization & IWRS Plan (TILA278-201)

Document ID: TMF-012
Version: 1.0
Change History: 1.0 — Initial issue.
Standard(s): ICH E6(R3) / E9

Randomization & IWRS Plan — TILA278-201

The randomization specification for TILA278-201: allocation 1:1:1, stratification factors, block structure, the IWRS/IRT workflow for assignment and drug supply, and emergency unblinding. The randomization schedule is generated under access control and held independent of the study team, and treatment assignment is executed by a validated Interactive Web Response System (IWRS/IRT) that also governs investigational product (IP) allocation and cold-chain supply logistics for the subcutaneously administered bispecific antibody. ICH E6(R3); E9.

1. Purpose and Scope

This plan defines the randomization methodology, stratification, allocation-concealment controls, and IWRS/IRT operational workflow for TILA278-201, a Phase 2b, randomized, double-blind, placebo-controlled, parallel-group study of TILA-278 — an anti-TL1A (antagonist) × IL-22R (agonist) bispecific humanized IgG1 monoclonal antibody produced by Chinese hamster ovary (CHO) cell culture and administered subcutaneously — in adults with moderately to severely active Ulcerative Colitis (UC) over a 12-week induction period. It covers the process from screening identifier assignment through randomized treatment allocation, IP dispensing and resupply, maintenance of the blind, and emergency code-break. The plan is written to be consistent with the protocol, the Statistical Analysis Plan, and the IWRS User Requirements and Functional Specifications, and operates under the trial's overarching quality management framework in accordance with ICH E6(R3) and the design/analysis principles of ICH E9.

Three treatment groups are studied — TILA-278 High-dose, TILA-278 Low-dose, and matching placebo — administered by subcutaneous injection at the protocol-defined induction visits through Week 12. The active groups deliver TL1A antagonism (anti-inflammatory and anti-fibrotic signaling) together with IL-22R agonism (epithelial and mucosal repair); the placebo group receives the identical formulation vehicle without active bispecific antibody. The dose designations "High" and "Low" refer to the two active regimens specified in the protocol and encoded as distinct IWRS medication strata.

2. Trial Design Context

TILA278-201 is a 1:1:1 randomized allocation across the three groups. Approximately 1700 subjects were screened to achieve 900 randomized subjects, distributed as 299 to TILA-278 High-dose, 300 to TILA-278 Low-dose, and 301 to placebo. The Full Analysis Set (FAS) comprised 840 subjects (284 High-dose, 283 Low-dose, 273 placebo), defined as all randomized subjects who received at least one dose of study treatment and had at least one post-baseline efficacy assessment, analyzed according to randomized treatment. Randomization occurs after eligibility confirmation at the baseline (Day 1) visit and is irreversible once the IWRS returns a treatment/medication assignment; the randomization number is retained as the subject's primary key for the remainder of the study and is not reissued under any circumstance.

3. Randomization Methodology

Subjects meeting all inclusion and no exclusion criteria are randomized in a 1:1:1 ratio to TILA-278 High-dose, TILA-278 Low-dose, or placebo. Randomization is performed centrally through the IWRS using a pre-generated randomization schedule, ensuring that neither site personnel, subjects, the sponsor study team, monitors, nor the bioanalytical laboratories performing pharmacokinetic (PK) and anti-drug antibody (ADA) assays can predict or infer upcoming assignments. Allocation concealment is absolute prior to the IWRS transaction: the sequence is neither visible nor derivable at the site, and the system returns only a medication (kit) identifier, never the treatment name or dose level.

Because the primary endpoint is clinical remission (modified Mayo score ≤ 2 with no individual subscore > 1) at Week 12, and key secondary endpoints include modified Mayo LS-mean change from baseline and endoscopic improvement, allocation is balanced across the prognostic factors that most influence UC induction response so that between-group comparisons are protected from confounding. Balance is enforced within stratum by permuted-block randomization (Section 5) rather than by dynamic minimization, preserving the unpredictability required for allocation concealment while maintaining close 1:1:1 balance overall and within each stratum.

4. Stratification Factors

Randomization is stratified to control the recognized baseline drivers of induction response in moderate-to-severe UC and to ensure comparability of the three arms with respect to those factors. The stratification factors are:

• Prior exposure to biologic or targeted advanced therapy (exposed vs. naïve) — including prior anti-TNF agents, anti-integrin therapy, anti-IL-12/23 or anti-IL-23 agents, and JAK inhibitors. Prior-exposed (including primary/secondary non-responders and intolerant subjects) constitute a distinct response population and are balanced across arms.
• Baseline disease activity by modified Mayo score category — reflecting the more-severe versus less-severe strata within the moderate-to-severe eligibility range, so that baseline endoscopic and clinical burden is evenly distributed.
• Baseline concomitant corticosteroid use (yes vs. no) — given the impact of background steroids on remission and endoscopic outcomes.
• Geographic region — to account for regional differences in standard of care, endoscopy reading practice, and prior-therapy landscape across participating regions.

The IWRS collects and locks the stratum values at randomization from responses entered by the site; stratum assignment cannot be edited post-randomization. Central endoscopy reading of the baseline endoscopic subscore, where used to confirm eligibility and the disease-activity stratum, is completed and returned to the IWRS prior to the randomization transaction so that the correct stratum is applied.

5. Block Structure and Randomization List Generation

Within each stratum, treatment is assigned using randomly permuted blocks to maintain 1:1:1 balance throughout enrollment while keeping the sequence unpredictable. Block sizes are chosen as small multiples of three (consistent with the three-arm 1:1:1 ratio), varied and randomly ordered within strata, and are not disclosed to any site or sponsor study-team personnel; the specific block sizes are documented only in the controlled, access-restricted randomization specification held by the independent biostatistics function. Varied block length prevents deterministic prediction of the final assignment within any block.

The randomization schedule is generated by an independent (unblinded) statistician or delegated randomization group using validated software with a documented, reproducible random seed. The generation, review, and approval of the schedule follow a controlled procedure with dual verification: the schedule is independently checked for the correct allocation ratio, stratum structure, block behavior, absence of duplicate randomization numbers, and correct linkage between randomization numbers and medication (kit) numbers before it is loaded into the IWRS. The approved schedule and its generation documentation (parameters, seed, program, and QC evidence) are stored under access control, segregated from the blinded study team, and released to unblinded personnel only. Loading of the schedule into the IWRS is verified by comparison against the source list, and the load is formally released for production only after successful verification.

6. IWRS/IRT System Description and Workflow

Treatment assignment and IP management are executed by a validated web-based Interactive Response Technology system (IWRS/IRT, also termed RTSM). The system supports the following core transactions:

• Screening registration — assignment of a unique screening number at the screening visit; the IWRS tracks screening status and screen-failure disposition.
• Randomization — at the baseline visit, after the site confirms eligibility and enters the stratification responses, the IWRS assigns the next sequential randomization number within the appropriate stratum and returns a blinded medication (kit) number corresponding to the allocated treatment. The transaction is atomic and logged with user, date, and time.
• IP dispensing and re-dispensing — at each dosing visit the IWRS selects and releases the appropriate blinded kit(s) from site inventory to cover the subcutaneous administration schedule through Week 12, ensuring the subject continues on the originally allocated (blinded) treatment.
• Inventory and resupply — the IWRS maintains real-time site and depot inventory, triggers automated resupply shipments against predictive and threshold-based algorithms, and manages kit status transitions (available, allocated, dispensed, quarantined, returned, destroyed, expired).
• Visit and status management — recording of dosing visits, treatment discontinuation, and study completion/withdrawal, with corresponding release or hold of inventory.

The system is accessible 24/7 to authorized site users via role-based credentials, with a validated Interactive Voice Response (IVR) or help-desk fallback path. All transactions are captured in a secure, time-stamped, non-editable audit trail. Interfaces to the EDC system (for demographic/screening reconciliation) and to the clinical supply/distribution systems are validated and reconciled on a defined cadence.

7. Investigational Product Supply Management

TILA-278 is a CHO-derived humanized IgG1 bispecific monoclonal antibody supplied as a sterile subcutaneous presentation; matching placebo is the identical formulation vehicle without active antibody, indistinguishable in presentation. Because the product is a temperature-sensitive protein biologic, the IWRS enforces cold-chain and product-integrity controls throughout the supply chain:

• Storage and handling — kits are stored refrigerated at 2–8 °C, protected from light, and must not be frozen or shaken; the IWRS records depot and site storage conditions and blocks dispensing of any kit whose status is not "available."
• Temperature-excursion handling — on report of a temperature excursion, affected kits are automatically placed in quarantine status by the IWRS pending sponsor/quality disposition, and are excluded from allocation until released or destroyed. This prevents dispensing of potentially compromised biologic material and preserves product-quality traceability.
• Expiry and shelf-life management — consistent with the limited shelf life of a biologic and its stability profile (see ICH Q5C/Q6B), the IWRS applies expiry/retest dates at the kit level, prevents allocation of expired material, and factors remaining shelf life into resupply so that dispensed kits cover the induction schedule without expiry during use. Where a retest/relabel of extended-dating material applies, the updated dating is reflected in IWRS kit records under change control.
• Kit identity and blinding — each kit carries a unique medication number with no external indication of active versus placebo or of dose level; the linkage between medication number and treatment resides only in the controlled randomization/packaging code.

Distribution, packaging, labeling, and reconciliation of the biologic IP follow GMP and ICH good-distribution expectations for a cold-chain protein product, with full chain-of-custody from depot to site to subject and controlled return/destruction of used and unused kits.

8. Blinding and Maintenance of the Blind

The study is double-blind. Subjects, investigators and site staff, the sponsor clinical study team, clinical monitors, and personnel performing efficacy, endoscopy, PK, and immunogenicity (ADA) assessments remain blinded to individual treatment assignment until database lock and formal unblinding. The identical presentation of active and placebo subcutaneous injections, the blinded medication numbering, and the concealment of the randomization schedule and block sizes together maintain the blind. Neutral, blinded terminology (medication number) is used in all site- and sponsor-facing IWRS outputs.

Given the product's target-mediated drug disposition (TMDD) pharmacokinetics and the relevance of immunogenicity, the bioanalytical laboratories analyzing PK and ADA samples operate under blinded sample handling, and any potentially unblinding data (e.g., measurable drug concentrations) are firewalled from the blinded study team until the pre-specified analysis. Only designated unblinded roles — the independent statistician/randomization group, unblinded pharmacists/preparers where applicable, and, where constituted, an unblinded pharmacovigilance function and independent data monitoring committee support group — have controlled access to treatment assignment for their defined purpose. Any unblinding event, whether individual (emergency) or programmatic, is documented with rationale, scope, and timing.

9. Emergency Unblinding

Emergency unblinding is available at all times through the IWRS to protect subject safety when knowledge of the treatment assignment is essential to clinical management of a medical emergency. Key features:

• Access — the investigator (or authorized designee) initiates a code-break transaction in the IWRS; the system provides the individual subject's treatment assignment directly, without requiring sponsor pre-authorization, so that care is not delayed.
• Justification and documentation — the initiator records the reason for unblinding; the IWRS captures user identity, date, and time, and the event is retained in the immutable audit trail. The investigator documents the medical rationale in source and, per procedure, notifies the sponsor and pharmacovigilance promptly.
• Scope containment — unblinding is restricted to the single subject concerned; the study team's overall blind and the integrity of the remaining assignments are preserved. Where possible, expedited safety reporting to health authorities is managed by the unblinded pharmacovigilance function so that the blinded study team remains blinded.
• Continuity — a validated IVR/help-desk fallback ensures code-break availability during any IWRS web outage.

Emergency unblinding does not, by itself, discontinue study treatment; continuation or discontinuation follows the protocol and the investigator's medical judgment.

10. Roles, Responsibilities, and Independence

Clear separation of blinded and unblinded functions is maintained throughout:

• Independent (unblinded) biostatistics/randomization group — generates, QCs, approves, and controls the randomization schedule; loads and verifies it in the IWRS; holds the treatment code.
• IWRS vendor — develops, validates, hosts, and supports the system; executes controlled changes and manages the audit trail under a quality agreement.
• Sponsor clinical study team (blinded) — oversees conduct without access to treatment assignments.
• Investigational sites — perform eligibility confirmation, enter stratification data, execute randomization and dispensing transactions, and administer the blinded subcutaneous IP.
• Clinical supply/quality (unblinded where required) — manage packaging, labeling, distribution, quarantine disposition, and reconciliation of the cold-chain biologic.
• Independent pharmacovigilance / DMC support (as constituted) — access treatment assignment only for safety oversight and expedited reporting, firewalled from the blinded team.

Access provisioning is role-based, individually credentialed, periodically reviewed, and revoked on role change or study exit. The randomization schedule and the treatment code are held independent of the study team at all times prior to planned unblinding.

11. System Validation, Security, and 21 CFR Part 11 Compliance

The IWRS is a validated computerized system developed and maintained under a documented software development life cycle consistent with GAMP-5 risk-based principles. Validation deliverables include user requirements, functional and design specifications, requirements-based testing (IQ/OQ/PQ or equivalent), traceability, and a validation summary released prior to production go-live. The randomization schedule load, dispensing logic, stratification handling, resupply algorithms, and code-break function are specifically verified against source specifications through User Acceptance Testing.

The system complies with 21 CFR Part 11 and Annex 11 expectations for electronic records and signatures: unique individual logins, role-based authorization, enforced password/credential controls, session controls, and a secure, computer-generated, time-stamped, non-alterable audit trail for all safety- and allocation-relevant transactions. Data are hosted in a controlled environment with validated backup, disaster recovery, and business-continuity provisions, and all production changes proceed under formal change control with regression testing. These controls preserve data integrity (attributable, legible, contemporaneous, original, accurate) for the randomization and IP-management records.

12. Contingency and Manual Procedures

Documented contingency procedures ensure continuity of randomization, dispensing, and emergency unblinding during any planned or unplanned IWRS unavailability. The primary fallback is the validated IVR/help-desk channel, which can execute randomization, dispensing, and code-break transactions and reconcile them into the system on restoration. A controlled manual (offline) randomization and code-break envelope process is defined as a last-resort backup, with sealed materials held under access control and full documentation on use. All contingency transactions are logged, reconciled against the IWRS on recovery, and reviewed to confirm that allocation concealment and the blind were not compromised.

13. Documentation, Reconciliation, and Archival

The randomization specification, the generated schedule and its QC evidence, the IWRS validation and user-requirement documents, access logs, transaction and audit-trail exports, IP shipment/dispensing/return/destruction records, temperature-excursion dispositions, and all emergency-unblinding records are retained as controlled Trial Master File records. Randomization and dispensing data are reconciled against the EDC and clinical-supply systems at defined intervals and at end of study; discrepancies are investigated and resolved under change control before database lock. At the pre-specified time, unblinding of the study team is performed as a controlled, documented event, and the final treatment code is released for analysis in accordance with the Statistical Analysis Plan. All records are archived per the sponsor's retention requirements and applicable regulations. ICH E6(R3); E9.