Phase 2 Dose-finding IMU-838 for Ulcerative Colitis

Phase 2

Terminated

Conditions: Ulcerative Colitis

Interventions: Drug: IMU-838
Drug: Placebo

Registration Number: NCT03341962

Lead Sponsor: Immunic AG

Brief Summary: This is a phase 2, multicenter, randomized, double-blind, placebo-controlled, dose-finding study to evaluate the efficacy and safety of IMU-838 for induction and maintenance therapy with an option for open-label treatment extension in moderate-to-severe ulcerative colitis (CALDOSE-1).

Detailed Description: The investigational medicinal product (IMP) IMU-838 (vidofludimus calcium) is a new compound that selectively inhibits the human enzyme dihydroorotate dehydrogenase (DHODH). Dihydroorotate dehydrogenase plays a major role in the de-novo pyrimidine synthesis and is specifically expressed at high levels in proliferating or activated lymphocytes. Resting lymphocytes satisfy their pyrimidine requirements through a DHODH-independent salvage pathway. Thus, IMU-838-mediated DHODH inhibition selectively affects activated, rapidly proliferating lymphocytes. The metabolic stress secondary to DHODH inhibition leads to a reduction of pro-inflammatory cytokine release including interleukin (IL)-17 (IL-17A and IL-17F) and interferon gamma (IFNγ), and to an increased apoptosis in activated lymphocytes.

This is a phase 2, multicenter, randomized, double-blind, and placebo-controlled trial in patients with moderate-to-severe UC with an option for open-label treatment extension. The study comprises a blinded induction phase to establish the optimal dose of IMU-838 to induce response and remission, a blinded maintenance phase to evaluate the potential of IMU-838 to maintain remission until Week 50, and an open-label treatment extension arm for all patients who discontinue the blinded phase as scheduled or prematurely, subject to certain restrictions. A subset of patients will undergo a pharmacokinetic (PK) period at the start of the open-label period to establish a full single-dose PK profile.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 263

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
10 mg IMU-838 (Maintenance)	IMU-838	Two 5 mg tablets once daily of IMU-838 until Week 50 or ulcerative colitis relapse.
placebo (Induction)	Placebo	The placebo tablets will be identical to the IMU-838 tablets in terms of appearance, constitution of inactive ingredients, and packaging.
10 mg IMU-838 (Induction)	IMU-838	Two 5 mg tablets once daily of IMU-838 for 10 to 22 weeks depending on symptomatic remission at Weeks 10 or 22. Patients will receive only half of their assigned full dose during the first week of treatment.
30 mg IMU-838 (Maintenance)	IMU-838	Two 15 mg tablets once daily of IMU-838 until Week 50 or ulcerative colitis relapse.
placebo (Maintenance)	Placebo	The placebo tablets will be identical to the IMU-838 tablets in terms of appearance, constitution of inactive ingredients, and packaging. Patients who have received placebo during the induction phase will be 're-randomized' to continue to receive placebo (in a blinded fashion).
30 mg IMU-838 (Open-label)	IMU-838	Two 15 mg tablets once daily of IMU-838 or one 30 mg tablet IMU-838 once daily for up to 10 years and up to 3 years in UK sites
30 mg IMU-838 (Induction)	IMU-838	Two 15 mg tablets once daily of IMU-838 for 10 to 22 weeks depending on symptomatic remission at Weeks 10 or 22. Patients will receive only half of their assigned full dose during the first week of treatment.
45 mg IMU-838 (Induction)	IMU-838	Two 22.5 mg tablets once daily of IMU-838 for 10 to 22 weeks depending on symptomatic remission at Weeks 10 or 22. Patients will receive only half of their assigned full dose during the first week of treatment.

Primary Outcome Measures

Name	Time	Method
Induction Phase: Symptomatic Remission and Endoscopic Healing at Week 10	10 weeks	Composite endpoint: Proportion of patients with both, symptomatic remission (Mayo rectal bleeding subscore = 0, and Mayo stool frequency subscore of 0 or 1) and endoscopic healing (Modified Mayo endoscopy subscore of 0 or 1) at Week 10. All patients who were randomized to 30 mg/day and 45 mg/day were used for the assessment of the primary efficacy endpoint

Secondary Outcome Measures

Name	Time	Method
Open-label Phase: fCP	Baseline, Week 4 OLE, Week 8 OLE, EoT up to 4 years (variable)	Timecourse of biomarker fCP in stool samples. Visits were scheduled every 4 weeks (+/-7 days) until 50 weeks of total study participation (ie induction + extended induction, if applicable, maintenance + open-label part) and every 10 weeks (+/-7 days) thereafter. The visit schedule in the OLE after 50 weeks of overall study treatment was changed from a 10-week schedule to a 24 week (+/-14 days) schedule after Protocol Version 6.0 came into force. Because the study was terminated early, EoT varied between patients depending on when patients entered the study and the time a patient participated in the induction and maintenance phases before switching to the OLE.
Induction Phase: Symptomatic Remission and Endoscopic Healing at Different Doses at Week 10	10 weeks	Proportion of patients with both symptomatic remission and endoscopic healing at Week 10 (all individual IMU-838 doses were compared with one another and to placebo)
Induction Phase: Symptomatic Remission	22 weeks	Proportion of patients achieving symptomatic remission (Mayo rectal bleeding subscore = 0, and Mayo stool frequency subscore of 0 or 1) during the induction phase
Induction Phase: Time to Achieving Symptomatic Remission	22 weeks	Time to achieving symptomatic remission (Mayo rectal bleeding subscore = 0 and Mayo stool frequency subscore of 0 or 1) within the extended induction phase
Induction Phase: Proportion of Patients With Clinical Response	10 weeks	Proportion of patients with clinical response (decrease from Baseline in the full Mayo score of at least 3 points and at least 30%, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or an absolute subscore for rectal bleeding of 0 or 1) at Week 10
Induction Phase: Proportion of Patients With Endoscopic Healing	10 weeks	Proportion of patients with endoscopic healing (Modified Mayo endoscopy subscore of 0 or 1) at Week 10
Induction Phase: Proportion of Patients With Symptomatic Response	22 weeks	Proportion of patients with symptomatic response (≥1-point decrease from Baseline in Mayo PRO-2 score) during the induction phase (including extended induction phase)
Induction Phase: Full Mayo Score	10 weeks	Change in full Mayo Score from Baseline to Week 10. The full Mayo score is composed of 4 categories (bleeding, stool frequency, physician assessment, and endoscopic appearance) each rated from 0 to 3 that are added up to give a total score that ranges from 0 to 12. A higher score indicates a worse outcome.
Induction Phase: Partial Mayo Score	22 weeks	Change in partial mayo score over 10 or 22 weeks. The partial Mayo score includes only the non-invasive Mayo subscores, ie, stool frequency, rectal bleeding, and physician's global assessment (each rated from 0 to 3 that are added up to give a total score that ranges from 0 to 9). A higher score indicates a worse outcome.
Induction Phase: Patient Reported Outcome (PRO)-2 Mayo Score	22 weeks	Change in PRO-2 Mayo score over 10 or 22 weeks. Mayo PRO-2 score, ie, stool frequency and rectal bleeding score each rated from 0 to 3 that are added up to give a total score that ranges from 0 to 6. A higher score indicates a worse outcome.
Induction Phase: Fecal Calprotectin (fCP)	22 weeks	Time course of biomarker fCP in stool samples during extended induction phase
Induction Phase: C-reactive Protein (CRP)	22 weeks	Time course of biomarker CRP in blood samples during extended induction phase
Safety: Adverse Events	50 weeks	Incidence and Severity of AEs during the induction and maintenance phases
Safety: Number of Participants With Clinically Significant Findings During Physical Examination	50 weeks	The emergence of any clinically significant findings compared to screening captured during the induction and maintenance phases
Safety: Body Weight	50 weeks	Changes in body weight during the induction and maintenance phases
Safety: Blood Pressure	50 weeks	Changes in blood pressure (mm Hg) during the induction and maintenance phases
Safety: Heart Rate	50 weeks	Changes in heart rate (beats per minute) during the induction and maintenance phases
Safety: 12-lead Electrocardiogram (ECG)	50 weeks	Number of patients with clinically significant changes in ECG
Safety: Hematology	up to Week 50	Number of participants with abnormal hematology laboratory values (treatment-emergent adverse events \[TEAEs\] related to hematological abnormalities)
Safety: Blood Chemistry	50 weeks	Number of participants with abnormal blood chemistry laboratory values (TEAES related to clinical chemistry abnormalities)
Safety: Coagulation	10 weeks	Number of participants with clinically significant abnormal coagulation laboratory values
Safety: Urinalysis	50 weeks	Number of participants with abnormal urinalysis laboratory values (TEAEs related to urinalysis)
Safety: Micro Ribonucleic Acid-122 Expression	24 hours	Micro ribonucleic acid-122 (miR-122) expression (before first dose and 24 hours after first dose - foldchange of normalized expression values )
PK: IMU-838 Plasma Level	2 weeks	Measurement of post-dose blood plasma levels of IMU-838 at Week 2
PK: Time to Cmax (Tmax)	pre-dose, 1, 2, 3, 4, 5, 6 hours post PK dose; 24 hours post PK dose; 48 hours post PK dose; 72 hours post PK dose	Single-dose PK measurement of Tmax in a subset of patients in the open-label phase
Pharmacodynamics (PK): IMU-838 Trough Level	Day 0, Day 1, Day 7, Week 2 and Week 10	Measurement of pre-dose (trough) blood plasma levels of IMU-838 throughout the induction period
PK: Area Under the Drug Concentration-time Curve (AUC) From Time Zero to 24 Hours (AUC0-24h)	pre-dose, 1, 2, 3, 4, 5, 6 hours post PK dose; 24 hours post PK dose; 48 hours post PK dose; 72 hours post PK dose	Single-dose PK measurement of AUC0-24h in a subset of patients in the open-label phase
PK: AUC Time Zero to Infinity (AUC0-inf)	pre-dose, 1, 2, 3, 4, 5, 6 hours post PK dose; 24 hours post PK dose; 48 hours post PK dose; 72 hours post PK dose	Single-dose PK measurement of AUC0-inf in a subset of patients in the open-label phase
PK: AUC Time Zero to Last Measurable Concentration (AUC0-t)	pre-dose, 1, 2, 3, 4, 5, 6 hours post PK dose; 24 hours post PK dose; 48 hours post PK dose; 72 hours post PK dose	Single-dose PK measurement of AUC0-t in a subset of patients in the open-label phase
PK: Maximum Plasma Concentration (Cmax)	pre-dose, 1, 2, 3, 4, 5, 6 hours post PK dose; 24 hours post PK dose; 48 hours post PK dose; 72 hours post PK dose	Single-dose PK measurement of Cmax in a subset of patients in the open-label phase
Maintenance Phase: Proportion of Patients in Symptomatic Remission	Week 14, Week 30, Week 50	Proportion of patients in symptomatic remission (Mayo rectal bleeding subscore = 0, and Mayo stool frequency subscore of 0 or 1) by visit up to Week 50 in maintenance phase
Maintenance Phase: Time to Relapse	50 weeks	Time to symptomatic ulcerative colitis (UC) relapse
Maintenance Phase: Proportion of Patients Without Relapse	50 weeks	Proportion of patients without symptomatic UC relapse until Week 50
Maintenance Phase: fCP	50 weeks	Timecourse of biomarker fCP in stool samples
Maintenance Phase: CRP	50 weeks	Timecourse of biomarker CRP in blood samples
Maintenance Phase: Proportion of Patients With Endoscopic Healing	50 weeks	Proportion of patients with endoscopic healing (Modified Mayo endoscopy subscore of 0 or 1) at Week 50 of maintenance phase
Maintenance Phase: Proportion of Patients With Microscopic Healing	50 weeks	Proportion of patients with microscopic healing (Geboes score of =\< 3.1) at Week 50 of maintenance phase
Maintenance Phase: Corticosteroid-free Remission	50 weeks	Corticosteroid-free clinical remission (clinical remission and no receipt of systemic or local corticosteroids) at Week 50 in patients receiving corticosteroids at Baseline
Open-label Phase: Symptom Control	up to 4 years	Proportion of patients with symptom control
Open-label Phase: CRP	Baseline, Week 4 OLE, Week 8 OLE, Week 10 OLE, Week 12 OLE, Week 16 OLE, Week 20 OLE, Week 24 OLE, Week 28 OLE, Week 32 or 38 OLE (depending if entry was after extended induction phase), EoT up to 4 years (variable)	Timecourse of biomarker CRP in blood samples. Visits were scheduled every 4 weeks (+/-7 days) until 50 weeks of total study participation (ie induction + extended induction, if applicable, maintenance + open-label part) and every 10 weeks (+/-7 days) thereafter. The visit schedule in the OLE after 50 weeks of overall study treatment was changed from a 10-week schedule to a 24 week (+/-14 days) schedule after Protocol Version 6.0 came into force. Because the study was terminated early, EoT varied between patients depending on when patients entered the study and the time a patient participated in the induction and maintenance phases before switching to the OLE.
Maintenance Phase: Mayo PRO-2 Score	50 weeks	Time course of Mayo PRO-2 score until Week 50. Mayo patient-reported outcome score, ie, stool frequency and rectal bleeding score each rated from 0 to 3 3 that are added up to give a total score that ranges from 0 to 6. A higher score indicates a worse outcome.

Trial Locations

Locations (130): Del Sol Research Management, LLC
🇺🇸
Tucson, Arizona, United States
Axis Clinical Trials
🇺🇸
Los Angeles, California, United States
Ventura Clinical Trials
🇺🇸
Ventura, California, United States
Alliance Medical Research, LLC
🇺🇸
Lighthouse Point, Florida, United States
Medley Research Associates
🇺🇸
Medley, Florida, United States
Global Life Research LLC
🇺🇸
Miami, Florida, United States
Family Clinical Trials
🇺🇸
Pembroke Pines, Florida, United States
Clinical Research Trials of Florida, Inc.
🇺🇸
Tampa, Florida, United States
Atlanta Gastroenterology Associates, LLC
🇺🇸
Atlanta, Georgia, United States
McFarland Clinic, P.C.
🇺🇸
Ames, Iowa, United States
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Del Sol Research Management, LLC
🇺🇸Tucson, Arizona, United States