Double-Blinded, Placebo-Controlled Phase 1b Study for Safety, PK, Efficacy, PD of RO7049665 in Participants With Ulcerative Colitis (UC)

A Multicenter, Randomized, Double-Blind, Placebo Controlled Phase Ib Study to Investigate the Safety, Tolerability, Pharmacokinetics, Preliminary Efficacy, and Pharmacodynamics of Subcutaneously Administered RO7049665 in Participants With Active Ulcerative Colitis

The principal aim of this study is to evaluate the safety and tolerability of RO7049665 in participants with active ulcerative colitis (UC).

Study Overview

• Status: Terminated
• Conditions: Ulcerative Colitis
• Intervention / Treatment: Drug: RO7049665; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 1

Contacts and Locations

Study Locations

• Georgia
  • Tbilisi, Georgia, 112
    • The Research Institute of Clinical Medicine
• Hungary
  • Balatonfüred, Hungary, 8230
    • Drug Research Centre Gyogyszervizsgalo Kozpontot Kft.
  • Budapest, Hungary, 1083
    • SE ÁOK I. sz. Belgyógyászati Klinika
• Moldova, Republic of
  • Chisinau, Moldova, Republic of, MD-2025
    • ARENSIA Phase 1 Unit- Spitalul Clinic Republican Location
• Ukraine
  • KIEV Governorate
    • Kapitanovka Village, KIEV Governorate, Ukraine, 08112
      • Medical center of Yuriy Spizhenko LLC
• United States
  • Florida
    • Jacksonville, Florida, United States, 32216
      • Jacksonville Center for Clinical Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 66 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosed with UC for at least 12 weeks prior to screening
• Screening colonoscopy for colorectal cancer conducted within the prior two years if a history of pancolitis with disease duration ≥ 8 years or history of left-sided colitis and disease duration ≥12 years
• Evidence of disease activity at time of screening
• Insufficient clinical response to standard of care (SOC) therapy or intolerance to SOC

Exclusion Criteria:

• Diagnosis of Crohn's disease or indeterminate colitis
• History of infection with hepatitis B, human immunodeficiency virus (HIV), active hepatitis C virus (HCV) infection, or other chronic infection
• Active infections requiring systemic therapy with antibiotic, antiviral or antifungal or febrile illness within 7 days before Day -1
• History of primary or acquired immunodeficiency
• Abnormal hematologic values
• Abnormal hepatic enzyme or hepatic function values

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: RO7049665; Participants will receive a subcutaneous (SC) dose of RO7049665 every 2 weeks for 4 doses.	Drug: RO7049665; Multiple ascending doses of RO7049665 will be administered SC.
Placebo Comparator: Placebo; Participants will receive a SC dose of matching placebo every 2 weeks for 4 doses.	Drug: Placebo; Matching placebo will be administered SC.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE was defined as any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity or is a congenital anomaly/birth defect. Severity of AEs were graded according to NCI CTCAE v4.0.	From baseline up to safety follow-up visit on Day 99

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Maximum Concentration (Tmax) of RO7049665		Day 1 to Day 15 (predose) and Day 43 (post-dose)
Maximum Serum Concentration Observed (Cmax) of RO7049665		Days 1 and 43: Pre-dose, 6 h and 12 h post-dose
Area Under the Serum Concentration-time Curve Extrapolated to Infinity (AUCinf) of RO7049665		Days 1 and 43: Pre-dose, 6 h and 12 h post-dose
Change From Baseline in the Endoscopy Subscore of the Mayo Clinic Score (MCS-ES)	The Mayo Clinic Score (MCS) ranges from 0 to 12 and is a composite of 4 assessments, each rated from 0-3: stool frequency, rectal bleeding, endoscopy (i.e., centrally read MCS-ES) and Physician Global Assessment (PGA). Flexible sigmoidoscopy (or colonoscopy) was centrally read and scored using the MCS-ES scoring systems. The disease was considered as endoscopic normal or inactive if the MCS-ES (centrally read) was 0, mild (erythema, decreased vascular pattern) if MCS-ES was 1, moderate (marked erythema, absent vascular pattern, erosions) if MCS-ES was 2 and severe (spontaneous bleeding, ulceration) if MCS-ES was 3. The Endoscopy Subscore of the Mayo Score was modified so that a value of 1 did not include friability. A negative change from baseline indicates improvement.	Baseline, Days 29 and 57
Change From Baseline in the Ulcerative Colitis Endoscopic Index of Severity (UCEIS)	Flexible sigmoidoscopy (or colonoscopy) were centrally read and scored using the UCEIS scoring systems. The UCEIS total score is a sum of 3 assessments: Bleeding (scored 0-3), Erosion and Ulcers (scored 0-3), and Vascular Pattern (scored 0-2). The total score ranges from 0-8, with higher score indicating more severe disease. A negative change from baseline indicates improvement.	Baseline, Days 29 and 57
Change From Baseline in Histology Score of Sigmoid Colon Biopsies Using Geboes Score (GS)	Mucosal biopsies were obtained during flexible sigmoidoscopy from the most affected area 10 to 20 centimeters (cm) from the anal verge. Biopsies were assessed by standard histology for changes in the inflammatory activity as measured using GS. The GS is a stepwise grading system used for the evaluation of microscopic inflammation and histopathologic disease activity in UC. The microscopic appearance of the mucosa is categorized into 6 grades: Grade 0: architectural changes, Grade 1: chronic inflammatory infiltrate, Grade 2: lamina propria neutrophils and eosinophils, Grade 3: neutrophils in epithelium, Grade 4: crypt destruction and erosions or Grade 5: ulcerations, and each grade of the score is divided in 4 subcategories. A decrease of the Geboes grading system to Grades 0 or 1 would indicate mucosal healing.	Baseline, Days 29 and 57
Change From Baseline in Histology Score of Sigmoid Colon Biopsies Using Robarts Histology Index (RHI)	Mucosal biopsies were obtained during flexible sigmoidoscopy from the most affected area 10 to 20 cm from the anal verge. Biopsies were assessed by standard histology for changes in the inflammatory activity as measured using RIH. The RHI is an evaluative index, derived from the Geboes score and is designed to be reproducible and responsive to clinically meaningful change in disease activity over time. The total RHI score ranges from 0 (no disease activity) to 33 (severe disease activity). A negative change from baseline indicates improvement.	Baseline, Days 29 and 57
Change From Baseline in Histology Score of Sigmoid Colon Biopsies Using Nancy Histology Index (NHI)	Mucosal biopsies were obtained during flexible sigmoidoscopy from the most affected area 10 to 20 cm from the anal verge. Biopsies were assessed by standard histology for changes in the inflammatory activity as measured using NHI. NHI is a validated index for assessing histological disease activity in UC. It is composed of three histological items defining five grades of disease activity: absence of significant histological disease (Grade 0), chronic inflammatory infiltrate with no acute inflammatory infiltrate (Grade 1), mildly active disease (Grade 2), moderately active disease (Grade 3), and severely active disease (Grade 4). The presence of ulceration on the biopsy specimen corresponds to severely active disease (Grade 4). A decrease of the NHI grading system to Grades 0 or 1 would indicate improvement.	Baseline, Days 29 and 57
Percentage of Participants With Mayo Clinic Score (MCS) Clinical Response	The MCS ranges from 0 to 12 and is a composite of 4 assessments: stool frequency, rectal bleeding, endoscopy (i.e., centrally read MCS-ES) and Physician Global Assessment (PGA). Each assessment was rated from 0-3, with higher score indicating more severe disease. Clinical response was defined as a decrease in the MCS of at least 3 points and at least 30% decrease from baseline.	Baseline, Days 29 and 57
Number of Participants With Anti-Drug Antibodies (ADAs)	ADA assays was used to detect anti-drug antibodies against RO7049665. Samples which were positive for anti-drug antibodies were further assessed using a neutralizing antibody assay. Participants were considered ADA positive if they were ADA negative at baseline but developed an ADA response following study drug administration (treatment-induced ADA response), or if they were ADA positive at baseline and the titer of one or more post-baseline samples was greater than the titer of the baseline sample by a scientifically reasonable margin such as at least 4-fold (treatment-enhanced ADA response).	Baseline; Post-dose on Days 8, 22, 57, 71 and 99; Pre-dose on Days 15, 29 and 43
Change From Baseline in White Blood Cells (Tregs, Teffs)		Baseline; Pre-dose: Days 15, 29 and 43; Post-dose: Days 2, 6, 8, 10, 22, 36, 48, 50, 52, 57, 71
Change From Baseline in White Blood Cells (Natural Killer (NK) Cells)		Baseline; Pre-dose: Days 15, 29 and 43; Post-dose: Days 2, 6, 8, 10, 22, 36, 48, 50, 52, 57, 71
Change From Baseline in White Blood Cells (B Cells)		Baseline; Pre-dose: Days 15, 29 and 43; Post-dose: Days 2, 6, 8, 10, 22, 36, 48, 50, 52, 57, 71
Change From Baseline in Eosinophils		Baseline; Pre-dose: Days 15, 29 and 43; Post-dose: Days 2, 8, 22, 36, 57, 71 and follow-up visit on Day 99

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche
• Investigators: Study Director: Clinical Trials, Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (Actual): May 13, 2019
• Primary Completion (Actual): July 22, 2021
• Study Completion (Actual): July 22, 2021

Study Registration Dates

• First Submitted: May 7, 2019
• First Submitted That Met QC Criteria: May 8, 2019
• First Posted (Actual): May 9, 2019

Study Record Updates

• Last Update Posted (Estimated): February 15, 2024
• Last Update Submitted That Met QC Criteria: June 22, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Gastrointestinal Diseases; Gastroenteritis; Colonic Diseases; Intestinal Diseases; Inflammatory Bowel Diseases; Ulcer; Colitis; Colitis, Ulcerative
• Other Study ID Numbers: WP40161; 2017-004599-74 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No