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π Part of the TILA-278 Regulatory Dossier β Reader's Guide. This article shows the live document; edits to the source appear here automatically.
This is a mock / simulation document, made for a portfolio and for learning. The drug (GLPI-103), the sponsor, the people, and the data are all fictional. It is not a real regulatory submission and has no clinical, legal, or regulatory standing. What is real is the shape of the thing β the document structure, the standards it follows, and the analysis methods; the content inside is illustrative.
What it is. Patient Narratives (TILA278-201)
Why it exists. Clinical study documentation supporting the efficacy and safety of the program.
How it is produced here. The numbers come straight from the study's simulated Phase 3 dataset β they are calculated from the data, not typed in by hand. That is why you see the same figures repeated across the protocol, the analysis plan, the report, and the summaries: they all read from the same source.
Format & governing standard. β
Document ID: CSR-201-16.3
Version: 1.0
Change History: 1.0 β Initial issue.
Standard(s): ICH E3 Β§16.3
Narratives for each death, serious adverse event, and other significant adverse event in TILA278-201, giving subject, treatment, event term, onset/course, management, outcome, and causality assessment, per ICH E3 Β§16.3.
These narratives cover every death, every other serious adverse event (SAE), and other significant adverse events (adverse events leading to permanent discontinuation of study drug and protocol-defined events of special interest) observed during the double-blind induction period of Study TILA278-201, in accordance with ICH E3 Β§16.3. Study TILA278-201 was a Phase 2b, randomised, double-blind, placebo-controlled, parallel-group induction study of TILA-278, a humanised bispecific IgG1 monoclonal antibody with anti-TL1A (TNFSF15) antagonist and IL-22 receptor agonist activity, in adults with moderately to severely active ulcerative colitis (UC). Of 1700 subjects screened, 900 were randomised 1:1:1 to TILA-278 High (299), TILA-278 Low (300), or Placebo (301) and are described relative to the Safety Analysis Set (TILA-278 High 284; TILA-278 Low 283; Placebo 273).
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Study drug was TILA-278 150 mg/mL solution for subcutaneous injection, supplied as identical single-use prefilled syringes each delivering 2 mL (300 mg). The TILA-278 High dose was 600 mg (two 300 mg injections), the TILA-278 Low dose was 300 mg (one 300 mg TILA-278 injection plus one matching placebo injection), and placebo was two matching injections; all were administered subcutaneously at Weeks 0, 2, 4, and 8. To preserve blinding, every subject received two subcutaneous injections of identical appearance at each dosing visit. Onset is expressed as study day relative to the first dose (Week 0 = Day 1; Week 2 = Day 15; Week 4 = Day 29; Week 8 = Day 57; the Week 12 assessment corresponds to Day 85).
Narratives were prepared after database lock and unblinding; treatment assignments are therefore disclosed. Adverse events were coded using MedDRA version 26.1 and are cited by System Organ Class and Preferred Term. Seriousness was assessed against the ICH E2A criteria (death, life-threatening, inpatient hospitalisation or prolongation of hospitalisation, persistent or significant disability/incapacity, congenital anomaly, or other medically important event). Severity was graded per the protocol grading convention, and causality (related or not related to study drug) was assigned by the investigator and independently reviewed by the Sponsor's medical monitor.
Immunogenicity was evaluated with a validated, tiered anti-drug antibody (ADA) method (screening, confirmatory, and titre steps) and a separate cell-based neutralising-antibody (NAb) assay; treatment-emergent ADA status at the time of each event is reported where a contemporaneous sample was available. Because TILA-278 exhibits target-mediated drug disposition (TMDD) against soluble and membrane TL1A and against the IL-22 receptor, exposure was interpreted in that context. Consistent with the monoclonal-antibody modality and ICH S6(R1), cardiac safety was monitored by scheduled 12-lead electrocardiography; a dedicated thorough QT/QTc study is not warranted for a monoclonal antibody of this class, and no QT/QTc signal was identified.
Three deaths occurred during the study (TILA-278 High 2; TILA-278 Low 0; Placebo 1). Each was assessed by the investigator as not related to study drug, and the Sponsor's medical monitor concurred in every case following independent review, including consideration of immunogenicity status and the anti-TL1A/IL-22R mechanism.
Narrative 1 β Subject 1042-0087, TILA-278 High, fatal acute myocardial infarction. A 68-year-old man with a history of coronary artery disease (prior percutaneous coronary intervention 4 years earlier), hypertension, type 2 diabetes mellitus, dyslipidaemia, and former tobacco use was randomised to TILA-278 High for moderately to severely active UC (baseline modified Mayo severity 7β9; biologic-experienced). Concomitant medications included oral mesalazine, aspirin, atorvastatin, ramipril, and metformin. He received 600 mg subcutaneously at Weeks 0, 2, and 4 (three doses; last dose Day 29) without infusion- or injection-related complaint. On Day 53 he developed acute central chest pain with diaphoresis and presented to the emergency department. Electrocardiography showed ST-segment elevation in the inferior leads, and troponin was markedly elevated; coronary angiography demonstrated acute thrombotic occlusion of the right coronary artery. Despite emergency reperfusion he sustained cardiogenic shock and died on Day 53. No autopsy was performed. The event met seriousness criteria (death, life-threatening, hospitalisation). The investigator assessed the acute myocardial infarction (MedDRA Preferred Term: Acute myocardial infarction) as not related to study drug, attributing it to established atherosclerotic coronary disease and multiple cardiovascular risk factors; the Sponsor concurred. Outcome: fatal.
Narrative 2 β Subject 1108-0026, TILA-278 High, fatal sepsis secondary to pneumonia. A 71-year-old woman with a history of chronic obstructive pulmonary disease (long-term inhaled bronchodilator and corticosteroid therapy), remote breast carcinoma in sustained remission, and long-standing UC (baseline modified Mayo severity 7β9; biologic-experienced) was randomised to TILA-278 High. Concomitant medications included oral mesalazine, a tapering course of oral prednisolone, tiotropium, and an inhaled corticosteroid/long-acting beta-agonist combination. She received 600 mg subcutaneously at Weeks 0, 2, and 4 (three doses; last dose Day 29). On Day 40 she developed fever, productive cough, and dyspnoea; chest radiography confirmed a right lower-lobe consolidation (MedDRA Preferred Term: Pneumonia) and she was hospitalised. Despite broad-spectrum intravenous antibiotics she progressed to respiratory failure and septic shock (Preferred Term: Sepsis) and died on Day 47. Blood cultures grew a Gram-negative organism. The contemporaneous ADA sample was negative and there was no evidence of neutralising antibody. This infection was reviewed as an event of special interest. The investigator assessed both the pneumonia and the fatal sepsis as not related to study drug, citing advanced age, chronic obstructive pulmonary disease, and background corticosteroid exposure; the Sponsor concurred, noting that IL-22 receptor agonism supports epithelial and mucosal host defence and that TL1A antagonism confers limited systemic immunosuppression, and that the clinical course was consistent with a community-acquired infection in a predisposed host. Outcome: fatal.
Narrative 3 β Subject 1231-0054, Placebo, fatal pulmonary embolism. A 62-year-old man with obesity, hypertension, and extensive, active UC (baseline modified Mayo severity 7β9; biologic-experienced) was randomised to Placebo. Concomitant medications included oral mesalazine and antihypertensive therapy. He received matching placebo subcutaneously at Weeks 0, 2, 4, and 8 (four doses). His UC remained active during induction. On Day 68 he collapsed acutely with dyspnoea and pleuritic chest pain; computed tomography pulmonary angiography demonstrated bilateral pulmonary emboli, and lower-limb ultrasonography confirmed proximal deep-vein thrombosis. He deteriorated haemodynamically despite anticoagulation and supportive care and died on Day 70 (MedDRA Preferred Terms: Pulmonary embolism; Deep vein thrombosis). The event met seriousness criteria (death, life-threatening, hospitalisation). The investigator assessed the pulmonary embolism as not related to study drug β the subject received placebo β and attributed it to the recognised prothrombotic state associated with active UC together with immobility and obesity; the Sponsor concurred. Outcome: fatal.
Four non-fatal serious adverse events were reported (TILA-278 High 1; TILA-278 Low 0; Placebo 3). Together with the three fatal serious adverse events described in Β§16.3.1, the total number of serious adverse events was 3 in the TILA-278 High group, 0 in the TILA-278 Low group, and 4 in the Placebo group.
Narrative 4 β Subject 1076-0141, TILA-278 High, systemic hypersensitivity reaction. A 44-year-old woman with UC (baseline modified Mayo severity 4β6; biologic-experienced) and a history of seasonal allergic rhinitis was randomised to TILA-278 High. Concomitant medications included oral mesalazine. She tolerated the Week 0 and Week 2 doses. On Day 29, within approximately 45 minutes of the Week 4 (third) 600 mg subcutaneous administration, she developed generalised urticaria, facial flushing, wheeze, and mild dyspnoea (MedDRA Preferred Terms: Hypersensitivity; Urticaria; Bronchospasm). She remained haemodynamically stable without hypotension or airway compromise. She was treated with intramuscular adrenaline, an intravenous antihistamine, and intravenous corticosteroid and was admitted for overnight observation, meeting seriousness criteria (hospitalisation, medically important event). Symptoms resolved fully within 24 hours. Study drug was permanently discontinued (positive dechallenge; no rechallenge). Treatment-emergent ADA were confirmed on the Week 4 sample at a titre of 1:320; the neutralising-antibody assay was negative, and TILA-278 exposure was within the expected range for the dose. The investigator assessed the hypersensitivity reaction as related to study drug, and the Sponsor concurred, characterising it as an immunogenicity-associated systemic hypersensitivity reaction. Outcome: recovered/resolved.
Narrative 5 β Subject 1188-0203, Placebo, worsening of ulcerative colitis (severe flare). A 39-year-old man with moderately to severely active UC (baseline modified Mayo severity 7β9; biologic-experienced) was randomised to Placebo. Concomitant medications included oral mesalazine. From approximately Day 25 his stool frequency and rectal bleeding increased progressively despite continued dosing. On Day 35 he was hospitalised with a severe UC flare (MedDRA Preferred Term: Colitis ulcerative), meeting seriousness criteria (hospitalisation). He was managed with intravenous corticosteroids and supportive care; sigmoidoscopy confirmed severe endoscopic activity without perforation or toxic dilatation. Study drug was discontinued and he was referred for rescue medical therapy. The investigator assessed the worsening of UC as not related to study drug β the subject received placebo β and consistent with the natural course of inadequately controlled disease; the Sponsor concurred. Outcome: recovering/resolving at last contact.
Narrative 6 β Subject 1203-0175, Placebo, symptomatic anaemia requiring transfusion. A 57-year-old woman with active UC (baseline modified Mayo severity 7β9; biologic-naΓ―ve) and chronic gastrointestinal blood loss was randomised to Placebo. Concomitant medications included oral mesalazine and oral iron. Over the induction period she developed progressive fatigue and exertional dyspnoea, and on Day 44 was found to have symptomatic anaemia with a markedly reduced haemoglobin attributable to ongoing UC-related colonic blood loss (MedDRA Preferred Term: Anaemia). She was hospitalised (seriousness criterion: hospitalisation) and received red-cell transfusion and intravenous iron, with intensification of UC therapy. The investigator assessed the anaemia as not related to study drug β the subject received placebo β and as secondary to active UC; the Sponsor concurred. Outcome: recovered/resolved.
Narrative 7 β Subject 1259-0098, Placebo, Clostridioides difficile colitis. A 66-year-old man with active UC (baseline modified Mayo severity 4β6; biologic-experienced) and recent antibiotic exposure for a dental infection was randomised to Placebo. Concomitant medications included oral mesalazine. On Day 51 he presented with increased watery diarrhoea, abdominal cramping, and low-grade fever; stool testing was positive for Clostridioides difficile toxin (MedDRA Preferred Term: Clostridium difficile colitis). He was hospitalised (seriousness criterion: hospitalisation) and treated with oral vancomycin, with clinical resolution. The investigator assessed the event as not related to study drug β the subject received placebo β and attributed it to recent systemic antibiotic exposure superimposed on active colonic disease; the Sponsor concurred. Outcome: recovered/resolved.
This section describes other significant adverse events per ICH E3 Β§16.3, namely adverse events that led to permanent discontinuation of study drug but did not meet seriousness criteria, and non-serious events of special interest (injection-site reactions, infections, and immunogenicity-associated events) relevant to a subcutaneously administered anti-TL1A/IL-22R bispecific monoclonal antibody. Overall study discontinuation was reported for 17 subjects (6.0%) in the TILA-278 High group, 17 subjects (6.0%) in the TILA-278 Low group, and 29 subjects (10.6%) in the Placebo group; discontinuation in the Placebo group was driven mainly by lack of efficacy. Representative narratives are provided below; the complete listing of these events is presented in Appendix 16.2.
Subject 1055-0119, TILA-278 High, injection-site reaction leading to discontinuation. A 51-year-old woman receiving TILA-278 High (baseline modified Mayo severity 4β6; biologic-experienced) developed recurrent, moderate injection-site erythema, induration, and pruritus (MedDRA Preferred Term: Injection site reaction) after the Week 2 and Week 4 doses, without systemic hypersensitivity features. The reactions were managed conservatively with topical measures and oral antihistamine and resolved within several days on each occasion. Because of subject preference and recurrence, study drug was permanently discontinued after Week 4. The investigator assessed the injection-site reactions as related to study drug; the Sponsor concurred, consistent with injection-site reactions being the principal drug-attributable finding in this study. Outcome: recovered/resolved.
Subject 1147-0162, TILA-278 Low, treatment-emergent immunogenicity without clinical sequelae. A 48-year-old man receiving TILA-278 Low (baseline modified Mayo severity 7β9; biologic-experienced) developed treatment-emergent ADA detected from the Week 4 sample, with a rising titre through Week 8; the neutralising-antibody assay was negative on a subset of samples and positive on the Week 8 sample. Serial pharmacokinetic sampling showed reduced TILA-278 exposure in the later induction period, consistent with ADA-associated enhanced clearance in the context of target-mediated drug disposition. No hypersensitivity, injection-site reaction, or other clinical adverse event accompanied the immunogenicity finding, and the subject completed induction dosing. This immunogenicity event of special interest did not meet seriousness criteria and did not require intervention. The investigator assessed the finding as related to study drug; the Sponsor concurred. Outcome: not applicable (laboratory immunogenicity finding without clinical event); the subject remained clinically stable.
Subject 1092-0134, TILA-278 High, localised herpes zoster (event of special interest). A 59-year-old woman receiving TILA-278 High (baseline modified Mayo severity 4β6; biologic-experienced) developed a unidermatomal vesicular rash with localised pain on Day 58 (MedDRA Preferred Term: Herpes zoster). The event was moderate in severity and did not meet seriousness criteria. She was treated with oral valaciclovir with complete resolution and without dissemination or post-herpetic neuralgia; study drug was continued. As a protocol-defined infection of special interest, the event underwent Sponsor medical review. The investigator assessed the herpes zoster as possibly related to study drug in the context of immunomodulation; the Sponsor concurred that a contributory role could not be excluded. Outcome: recovered/resolved.