TerminatedNCT03478956FENNELUpdated Dec 27, 2024Results posted

A Phase I Study of Etrolizumab Followed by Open-Label Extension and Safety Monitoring in Pediatric Patients With Moderate to Severe Ulcerative Colitis or Moderate to Severe Crohn's Disease

A Phase 1 interventional study of Etrolizumab in Ulcerative Colitis and Crohn's Disease, sponsored by Hoffmann-La Roche. Terminated at 5 sites in 4 countries. Open to participants aged 4 Years to 17 Years. Per ClinicalTrials.gov, last updated 2024-12-27.

Sponsored by Hoffmann-La Roche · Phase 1, Interventional, and Treatment

Why this study was terminated

The study was terminated due to program discontinuation, based on mixed efficacy results in the adult ulcerative colitis and Crohn's disease studies. There were no safety concerns.

Phase: Phase 1
Study type: Interventional
Enrollment: 24
Allocation: Randomized
Ages: 4 Years to 17 Years
Sex: All

Study summary

This study will evaluate pharmacokinetics, pharmacodynamics and safety of etrolizumab in pediatric patients of 4 to \<18 years of age with moderate to severe ulcerative colitis (UC) or with moderate to severe Crohn's disease (CD).

Conditions studied

Ulcerative Colitis
Crohn's Disease

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Who can participate

Ages eligible: 4 Years to 17 Years
Sexes eligible: All
Accepts healthy volunteers: No

Eligibility criteria

Inclusion Criteria:

Age of 4 years to \<18 years at the time of signing the Informed Consent Form.
Weight of 13 kilograms (kg) or more
Diagnosis of ulcerative colitis (UC) or Crohn's Disease (CD) confirmed by biopsy and established for ≥3 months (i.e., after first diagnosis by a physician according to American College of Gastroenterology [ACG] guidelines) prior to screening
Inadequate response, loss of response or intolerance to prior immunosuppressants and/or corticosteroid treatment and/or anti-tumor necrosis factor (TNF) therapy
For postpubertal females of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use acceptable contraceptive methods during the treatment period and for at least 24 weeks after the last dose of etrolizumab.
For male patients: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm

Exclusion Criteria:

Pregnant or lactating
Lack of peripheral venous access
Congenital or acquired immune deficiency
Neurological conditions or diseases that may interfere with monitoring for progressive multifocal leukoencephalopathy (PML)
History of demyelinating disease
History of cancer, including hematologic malignancy, solid tumors, and carcinoma in situ, within 5 years before screening

Exclusion Criteria Related to Inflammatory Bowel Disease:

Prior extensive colonic resection, subtotal or total colectomy, or planned surgery
Past or present ileostomy or colostomy
Diagnosis of indeterminate colitis
Suspicion of ischemic colitis, radiation colitis, or microscopic colitis
Diagnosis of toxic megacolon within 12 months of initial screening visit
Abdominal abscess
A history or current evidence of colonic mucosal dysplasia
Patients with fixed symptomatic stenosis of the intestine
Patients with history or evidence of adenomatous colonic polyps that have not been removed

Exclusion Criteria Related to Ulcerative Colitis:

Severe extensive colitis per investigator judgment that colectomy is imminent

Exclusion Criteria Related to Crohn's Disease:

Sinus tract with evidence for infection (e.g., purulent discharge) in the clinical judgment of the investigator
Short-bowel syndrome
Evidence of abdominal or perianal abscess
Expected to require surgery to manage CD-related complications during the study

Exclusion Criteria Related to Prior or Concomitant Therapy:

Any prior treatment with anti-integrin agents (including natalizumab, vedolizumab, and efalizumab), ustekinumab, anti-adhesion molecules (e.g., anti-MAdCAM-1), or rituximab
Use of IV steroids within 30 days prior to screening with the exception of a single administration of IV steroid
Use of agents that deplete B or T cells (e.g., alemtuzumab or visilizumab) within 12 months prior to Day 1, with the exception of AZA and 6-MP
Use of cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil (MMF) within 4 weeks prior to Day 1
Use of other biologics (e.g. anti-TNF) within 8 weeks before dosing (unless drug level is below detectability before completion of the 8-week interval)
Chronic nonsteroidal anti-inflammatory drug (NSAID) use
Patients who are currently using anticoagulants
Apheresis (i.e., Adacolumn apheresis) within 2 weeks prior to Day 1
Received any investigational treatment including investigational vaccines within 12 weeks prior to Day 1 of the study or 5 half-lives of the investigational product, whichever is greater
History of moderate or severe allergic or anaphylactic/anaphylactoid reactions to chimeric, human, or humanized antibodies, fusion proteins, or murine proteins or hypersensitivity to etrolizumab (active drug substance) or any of the excipients (L-histidine, L-arginine, succinic acid, polysorbate 20)

Study design

Phase: Phase 1
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel assignment
Masking: None (open label)
Enrollment: 24 participants (actual)

Study arms

Experimental
Etrolizumab Q4W
Etrolizumab 1.5 milligrams per kilogram of body weight (mg/kg) was administered by subcutaneous (SC) injection once every 4 weeks (Q4W) for a total of 4 doses over the course of the 24-week randomized treatment phase (16-week treatment period plus 8-week safety follow-up). Participants were then given the option to participate in the 312-week open-label extension (OLE) treatment phase with etrolizumab 1.5 mg/kg SC Q4W followed by the 104-week safety surveillance phase (no etrolizumab treatment) to monitor for progressive multifocal leukoencephalopathy (PML). All participants who chose not to enter the OLE phase after the 24-week randomized treatment phase entered the 104-week PML monitoring phase.
Drug: Etrolizumab
Experimental
Etrolizumab Q8W
Etrolizumab 3.0 mg/kg was administered by subcutaneous (SC) injection once every 8 weeks (Q8W) for a total of 2 doses over the course of the 24-week randomized treatment phase (16-week treatment period plus 8-week safety follow-up). Participants were then given the option to participate in the 312-week open-label extension (OLE) treatment phase with etrolizumab 1.5 mg/kg SC Q4W followed by the 104-week safety surveillance phase (no etrolizumab treatment) to monitor for progressive multifocal leukoencephalopathy (PML). All participants who chose not to enter the OLE phase after the 24-week randomized treatment phase entered the 104-week PML monitoring phase.
Drug: Etrolizumab

Interventions

DrugEtrolizumab
Etrolizumab was administered by subcutaneous (SC) injection as described for each treatment arm.
Also known as: RG7413, RO5490261, PRO145223, rhuMAb Beta7

What researchers measure

Primary outcomes

Maximum Serum Concentration (Cmax) of Etrolizumab After First and Last Dose During the Randomized Treatment Phase
Etrolizumab concentrations in all pharmacokinetics (PK) samples were measured using a validated assay method. Non-compartmental analysis methods were employed to calculate PK parameters.
Time frame: Arm Etro Q4W: Day 1, 84 and Arm Etro Q8W: Day 1, 56
Time to Maximum Serum Concentration (Tmax) of Etrolizumab After First and Last Dose During the Randomized Treatment Phase
Etrolizumab concentrations in all pharmacokinetics (PK) samples were measured using a validated assay method. Non-compartmental analysis methods were employed to calculate PK parameters.
Time frame: Arm Etro Q4W: Days 1, 84 and Arm Etro Q8W: Days 1, 56
Area Under the Concentration-Time Curve Within the Last Dosing Interval (AUC-tau) of Etrolizumab During the Randomized Treatment Phase
Etrolizumab concentrations in all pharmacokinetics (PK) samples were measured using a validated assay method. Non-compartmental analysis methods were employed to calculate PK parameters.
Time frame: Arm Etro Q4W: Days 56, 84, 88, 98, 112 and Arm Etro Q8W: Day 56, 60, 70, 84, 88, 98, 112
Elimination Half-Life (t1/2) of Etrolizumab After Last Dose During the Randomized Treatment Phase
Etrolizumab concentrations in all pharmacokinetics (PK) samples were measured using a validated assay method. Non-compartmental analysis methods were employed to calculate PK parameters.
Time frame: Arm Etro Q4W: Days 84, 88, 98, 112, 126, 140, 168 and Arm Etro Q8W: Days 56, 60, 70, 84, 88, 98, 112, 126, 140, 168
Serum Trough Concentration (Ctrough) of Etrolizumab at the End of Each Dosing Interval During the Randomized Treatment Phase
Etrolizumab concentrations in all pharmacokinetics (PK) samples were measured using a validated assay method.
Time frame: Arm Etro Q4W: Predose on Days 28, 56, 84, 112 and Arm Etro Q8W: Predose on Days 56, 112
Percentage of Baseline Absolute Numbers of Beta7 Receptor-Expressing Gut Homing CD3, CD4, and CD8 T Cells and CD19 B Cells With Unoccupied Beta7 Receptors in Peripheral Blood, Assessed by Flow Cytometry, During the Randomized Treatment Phase
Target engagement of etrolizumab was assessed via measurement of Beta7 receptor occupancy on Beta7 receptor-expressing gut homing lymphocyte subsets in peripheral blood, including CD3, CD4, and CD8 T cells and CD19 B cells, using qualified flow cytometry methods. A decrease to 0% of baseline (BL) in median absolute cell counts of Beta7 receptor-expressing T and B cell subsets with unoccupied Beta7 receptors following etrolizumab treatment indicated maximal receptor occupancy by etrolizumab.
Time frame: Predose (dosing days only) at Baseline (Day 1) and on Days 4, 56, 84, 98, and 112 (Treatment Period), and Days 126, 140, and 168 (Follow-Up Period)

Secondary outcomes

Number of Participants With Adverse Events by Highest Severity Grade, Assessed According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI-CTCAE v4.0), During the Randomized Treatment Phase
All adverse events (AEs) were graded for severity using the NCI-CTCAE v4.0. Any AE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to AE. Not all grades are appropriate for all AEs; some AEs have fewer than 5 options. The terms "severe" and "serious" are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade.
Time frame: From Baseline until 12 weeks (Q4W arm only) or 16 weeks (Q8W arm only) after the last dose of study drug during the randomized treatment phase (up to 24 weeks)
Number of Participants With Serious Infection-Related Adverse Events During the Randomized Treatment Phase
Serious infection-related AEs were assessed using NCI-CTCAE v4.0.
Time frame: From Baseline until 12 weeks (Q4W arm only) or 16 weeks (Q8W arm only) after the last dose of study drug during the randomized treatment phase (up to 24 weeks)
Number of Participants With Hypersensitivity Reactions During the Randomized Treatment Phase
Hypersensitivity reactions were assessed using NCI-CTCAE v4.0.
Time frame: From Baseline until 12 weeks (Q4W arm only) or 16 weeks (Q8W arm only) after the last dose of study drug during the randomized treatment phase (up to 24 weeks)
Number of Participants With Malignancies During the Randomized Treatment Phase
Malignancies were assessed using NCI-CTCAE v4.0.
Time frame: From Baseline until 12 weeks (Q4W arm only) or 16 weeks (Q8W arm only) after the last dose of study drug during the randomized treatment phase (up to 24 weeks)
Number of Participants With Anti-Drug Antibodies (ADAs) to Etrolizumab at Baseline and Post-Baseline During the Randomized Treatment Phase
Participants were considered to be etrolizumab anti-drug antibody (ADA) positive if they were ADA negative or had missing data at Baseline (BL) but developed an ADA response following study drug exposure (i.e., treatment-induced ADA positive), or if they were ADA positive at baseline and the titer of one or more postbaseline samples was at least 0.60 titer unit greater than the titer of the baseline sample (i.e., treatment-enhanced ADA positive); these ADA positive responses are summarized together (induced + enhanced) in the 'treatment-emergent ADA positive' category. Participants were considered to be ADA negative if they were ADA negative or had missing data at Baseline (BL) and all postbaseline samples were negative (i.e., treatment-emergent ADA negative).
Time frame: Predose (dosing days only) on Days 1, 28, 84, 112, and 168 (up to the end of the randomized treatment phase at Week 24)
Long-Term Safety of Etrolizumab: Number of Participants With Adverse Events by Highest Severity Grade, Assessed According to NCI-CTCAE v4.0
All adverse events (AEs) were graded for severity using the NCI-CTCAE v4.0. Any AE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to AE. Not all grades are appropriate for all AEs; some AEs have fewer than 5 options. The terms "severe" and "serious" are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade.
Time frame: OLE Period: From end of Week 24 to end of 12-week safety follow-up (up to 195 weeks); PML Period: After completion of safety follow up in Randomized Treatment phase or after completion of safety follow up after OLE treatment, up to approximately 92 weeks
Long-Term Safety of Etrolizumab: Number of Participants With Serious Infection-Related Adverse Events
Serious infection-related AEs were assessed using NCI-CTCAE v4.0.
Time frame: OLE Period: From end of Week 24 to end of 12-week safety follow-up (up to 195 weeks); PML Period: After completion of safety follow up in Randomized Treatment phase or after completion of safety follow up after OLE treatment, up to approximately 92 weeks
Long-Term Safety of Etrolizumab: Number of Participants With Hypersensitivity Reactions
Hypersensitivity reactions were assessed using NCI-CTCAE v4.0.
Time frame: OLE Period: From end of Week 24 to end of 12-week safety follow-up (up to 195 weeks); PML Period: After completion of safety follow up in Randomized Treatment phase or after completion of safety follow up after OLE treatment, up to approximately 92 weeks
Long-Term Safety of Etrolizumab: Number of Participants With Malignancies
Malignancies were assessed using NCI-CTCAE v4.0.
Time frame: OLE Period: From end of Week 24 to end of 12-week safety follow-up (up to 195 weeks); PML Period: After completion of safety follow up in Randomized Treatment phase or after completion of safety follow up after OLE treatment, up to approximately 92 weeks
Long-Term Safety of Etrolizumab: Number of Participants With Anti-Drug Antibodies (ADAs) to Etrolizumab at Baseline and Post-Baseline
Participants were considered to be etrolizumab anti-drug antibody (ADA) positive if they were ADA negative or had missing data at Baseline (BL) but developed an ADA response following study drug exposure (i.e., treatment-induced ADA positive), or if they were ADA positive at baseline and the titer of one or more postbaseline samples was at least 0.60 titer unit greater than the titer of the baseline sample (i.e., treatment-enhanced ADA positive); these ADA positive responses are summarized together (induced + enhanced) in the 'treatment-emergent ADA positive' category. Participants were considered to be ADA negative if they were ADA negative or had missing data at Baseline (BL) and all postbaseline samples were negative (i.e., treatment-emergent ADA negative).
Time frame: Predose (dosing days only) at Baseline (Day 1), Days 28, 84, and 112, Weeks 24, 36, 72, and 120, and every 12 weeks thereafter for up to 4.25 years
Number of Participants With Confirmed Progressive Multifocal Leukoencephalopathy (PML) During the Post-Treatment PML Monitoring Phase
The safety surveillance PML-monitoring phase (no etrolizumab treatment) consisted of telephone calls approximately every 6 months with administration of the protocol's PML Subjective Checklist. If there were any signs or symptoms suggestive of PML identified on this subjective checklist during the telephone call, the participant was asked to come into the clinic for a neurologic examination. The protocol's PML Algorithm was followed for any suspected case of PML, and any confirmed case of PML would be reported as a serious adverse event.
Time frame: PML Period: After completion of safety follow up in Randomized Treatment period or after completion of safety follow up after OLE treatment, up to approximately 92 weeks

Results

Posted Aug 5, 2020

Participant flow

Randomized Treatment Period

Participant flow — Randomized Treatment Period
Milestone	Etrolizumab Q4W	Etrolizumab Q8W
Started	12	12
Received at least one dose of study drug	12	12
Completed treatment	11	10
Completed	11	11
Not completed	1	1
Withdrew: Adverse event	1	0
Withdrew: Withdrawal by subject	0	1

Open Label Extension Period

Participant flow — Open Label Extension Period
Milestone	Etrolizumab Q4W	Etrolizumab Q8W	OLE: Etrolizumab 1.5 mg Q4W	PML Safety Monitoring
Started	0	0	21	0
Completed	0	0	0	0
Not completed	0	0	21	0
Withdrew: Adverse event	0	0	4	0
Withdrew: Lack of efficacy	0	0	8	0
Withdrew: Reason not provided	0	0	1	0
Withdrew: Study terminated by sponsor	0	0	6	0
Withdrew: Withdrawal by subject	0	0	2	0

PML Safety Monitoring Period

Participant flow — PML Safety Monitoring Period
Milestone	Etrolizumab Q4W	Etrolizumab Q8W	OLE: Etrolizumab 1.5 mg Q4W	PML Safety Monitoring
Started	0	0	0	13
Completed	0	0	0	4
Not completed	0	0	0	9
Withdrew: Study terminated by sponsor	0	0	0	9

Outcome measures

PrimaryMaximum Serum Concentration (Cmax) of Etrolizumab After First and Last Dose During the Randomized Treatment Phase

Etrolizumab concentrations in all pharmacokinetics (PK) samples were measured using a validated assay method. Non-compartmental analysis methods were employed to calculate PK parameters.

Time frame:: Arm Etro Q4W: Day 1, 84 and Arm Etro Q8W: Day 1, 56
Reported as:: Mean · micrograms per millilitre (μg/mL)

Maximum Serum Concentration (Cmax) of Etrolizumab After First and Last Dose During the Randomized Treatment Phase
micrograms per millilitre (μg/mL)	Etrolizumab Q4W	Etrolizumab Q8W
After First Dose (Day 1)	7.73 ± 2.18	19.0 ± 8.21
After Last Dose (Q4W Day 84, Q8WDay 56)	9.80 ± 4.86	18.1 ± 6.25

PrimaryTime to Maximum Serum Concentration (Tmax) of Etrolizumab After First and Last Dose During the Randomized Treatment Phase

Etrolizumab concentrations in all pharmacokinetics (PK) samples were measured using a validated assay method. Non-compartmental analysis methods were employed to calculate PK parameters.

Time frame:: Arm Etro Q4W: Days 1, 84 and Arm Etro Q8W: Days 1, 56
Reported as:: Mean · Day

Time to Maximum Serum Concentration (Tmax) of Etrolizumab After First and Last Dose During the Randomized Treatment Phase
Day	Etrolizumab Q4W	Etrolizumab Q8W
After First Dose (Day 1)	4.65 ± 1.43	4.00 ± 1.48
After Last Dose (Q4W Day 84, Q8WDay 56)	5.04 ± 2.92	4.94 ± 3.28

PrimaryArea Under the Concentration-Time Curve Within the Last Dosing Interval (AUC-tau) of Etrolizumab During the Randomized Treatment Phase

Etrolizumab concentrations in all pharmacokinetics (PK) samples were measured using a validated assay method. Non-compartmental analysis methods were employed to calculate PK parameters.

Time frame:: Arm Etro Q4W: Days 56, 84, 88, 98, 112 and Arm Etro Q8W: Day 56, 60, 70, 84, 88, 98, 112
Reported as:: Mean · Day*μg/mL

Area Under the Concentration-Time Curve Within the Last Dosing Interval (AUC-tau) of Etrolizumab During the Randomized Treatment Phase
Day*μg/mL	Etrolizumab Q4W	Etrolizumab Q8W
AUC56-112	—	521 ± 306
AUC84-112	167 ± 86.9	—

PrimaryElimination Half-Life (t1/2) of Etrolizumab After Last Dose During the Randomized Treatment Phase

Etrolizumab concentrations in all pharmacokinetics (PK) samples were measured using a validated assay method. Non-compartmental analysis methods were employed to calculate PK parameters.

Time frame:: Arm Etro Q4W: Days 84, 88, 98, 112, 126, 140, 168 and Arm Etro Q8W: Days 56, 60, 70, 84, 88, 98, 112, 126, 140, 168
Reported as:: Mean · Day

Elimination Half-Life (t1/2) of Etrolizumab After Last Dose During the Randomized Treatment Phase
Day	Etrolizumab Q4W	Etrolizumab Q8W
Elimination Half-Life (t1/2) of Etrolizumab After Last Dose During the Randomized Treatment Phase	7.31 ± 1.76	8.65 ± 3.74

PrimarySerum Trough Concentration (Ctrough) of Etrolizumab at the End of Each Dosing Interval During the Randomized Treatment Phase

Etrolizumab concentrations in all pharmacokinetics (PK) samples were measured using a validated assay method.

Time frame:: Arm Etro Q4W: Predose on Days 28, 56, 84, 112 and Arm Etro Q8W: Predose on Days 56, 112
Reported as:: Mean · micrograms per millilitre (μg/mL)

Serum Trough Concentration (Ctrough) of Etrolizumab at the End of Each Dosing Interval During the Randomized Treatment Phase
micrograms per millilitre (μg/mL)	Etrolizumab Q4W	Etrolizumab Q8W
Day 28	1.87 ± 1.32	—
Day 56	3.22 ± 2.24	1.82 ± 1.99
Day 84	3.00 ± 2.38	—
Day 112	2.79 ± 2.01	3.70 ± 4.64

PrimaryPercentage of Baseline Absolute Numbers of Beta7 Receptor-Expressing Gut Homing CD3, CD4, and CD8 T Cells and CD19 B Cells With Unoccupied Beta7 Receptors in Peripheral Blood, Assessed by Flow Cytometry, During the Randomized Treatment Phase

Target engagement of etrolizumab was assessed via measurement of Beta7 receptor occupancy on Beta7 receptor-expressing gut homing lymphocyte subsets in peripheral blood, including CD3, CD4, and CD8 T cells and CD19 B cells, using qualified flow cytometry methods. A decrease to 0% of baseline (BL) in median absolute cell counts of Beta7 receptor-expressing T and B cell subsets with unoccupied Beta7 receptors following etrolizumab treatment indicated maximal receptor occupancy by etrolizumab.

Time frame:: Predose (dosing days only) at Baseline (Day 1) and on Days 4, 56, 84, 98, and 112 (Treatment Period), and Days 126, 140, and 168 (Follow-Up Period)
Reported as:: Median · Percentage of BL Unoccupied Beta7 Cells

Percentage of Baseline Absolute Numbers of Beta7 Receptor-Expressing Gut Homing CD3, CD4, and CD8 T Cells and CD19 B Cells With Unoccupied Beta7 Receptors in Peripheral Blood, Assessed by Flow Cytometry, During the Randomized Treatment Phase
Percentage of BL Unoccupied Beta7 Cells	Etrolizumab Q4W	Etrolizumab Q8W
CD3 T Cells: Baseline	100 ± 0.0	100 ± 0.0
CD3 T Cells: Day 4	0.18 ± 0.2	0.40 ± 0.4
CD3 T Cells: Day 56	1.92 ± 1.9	13.74 ± 13.5
CD3 T Cells: Day 84	7.43 ± 6.0	1.06 ± 1.1
CD3 T Cells: Day 98	0.36 ± 0.4	1.06 ± 1.1
CD3 T Cells: Day 112	4.06 ± 2.6	6.01 ± 5.6
CD3 T Cells: Day 126	12.00 ± 12.0	27.24 ± 24.6
CD3 T Cells: Day 140	47.47 ± 21.9	56.82 ± 22.2
CD3 T Cells: Day 168	71.64 ± 22.4	51.79 ± 23.1
CD4 T Cells: Baseline	100 ± 0.0	100 ± 0.0
CD4 T Cells: Day 4	0.17 ± 0.2	0.00 ± 0.0
CD4 T Cells: Day 56	3.33 ± 3.3	16.56 ± 16.1
CD4 T Cells: Day 84	7.14 ± 7.1	1.28 ± 1.0
CD4 T Cells: Day 98	0.24 ± 0.2	1.28 ± 1.3
CD4 T Cells: Day 112	3.60 ± 3.1	6.74 ± 6.4
CD4 T Cells: Day 126	13.33 ± 13.3	37.03 ± 33.7
CD4 T Cells: Day 140	55.34 ± 23.9	62.01 ± 20.3
CD4 T Cells: Day 168	74.49 ± 26.1	50.00 ± 16.3
CD8 T Cells: Baseline	100 ± 0.0	100 ± 0.0
CD8 T Cells: Day 4	0.00 ± 0.0	0.00 ± 0.0
CD8 T Cells: Day 56	1.56 ± 1.6	8.41 ± 8.4
CD8 T Cells: Day 84	2.72 ± 2.7	0.00 ± 0.0
CD8 T Cells: Day 98	1.10 ± 1.1	2.33 ± 2.3
CD8 T Cells: Day 112	0.97 ± 1.0	2.46 ± 2.5
CD8 T Cells: Day 126	20.00 ± 20.0	14.51 ± 14.5
CD8 T Cells: Day 140	54.17 ± 18.8	40.98 ± 24.7
CD8 T Cells: Day 168	63.34 ± 40.1	55.56 ± 21.1
CD19 B Cells: Baseline	100 ± 0.0	100 ± 0.0
CD19 B Cells: Day 4	0.00 ± 0.0	0.00 ± 0.0
CD19 B Cells: Day 56	3.57 ± 3.6	19.14 ± 17.1
CD19 B Cells: Day 84	10.71 ± 10.7	0.00 ± 0.0
CD19 B Cells: Day 98	0.00 ± 0.0	0.00 ± 0.0
CD19 B Cells: Day 112	7.14 ± 7.1	7.14 ± 7.1
CD19 B Cells: Day 126	42.86 ± 21.4	33.93 ± 32.3
CD19 B Cells: Day 140	68.00 ± 30.5	77.78 ± 32.6
CD19 B Cells: Day 168	73.21 ± 17.7	40.00 ± 13.2

SecondaryNumber of Participants With Adverse Events by Highest Severity Grade, Assessed According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI-CTCAE v4.0), During the Randomized Treatment Phase

All adverse events (AEs) were graded for severity using the NCI-CTCAE v4.0. Any AE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to AE. Not all grades are appropriate for all AEs; some AEs have fewer than 5 options. The terms "severe" and "serious" are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade.

Time frame:: From Baseline until 12 weeks (Q4W arm only) or 16 weeks (Q8W arm only) after the last dose of study drug during the randomized treatment phase (up to 24 weeks)
Reported as:: Count of participants · Participants

Number of Participants With Adverse Events by Highest Severity Grade, Assessed According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI-CTCAE v4.0), During the Randomized Treatment Phase
Participants	Etrolizumab Q4W	Etrolizumab Q8W
Any Adverse Event - Any Grade	9	10
Any Adverse Event - Grade 1	2	2
Any Adverse Event - Grade 2	4	5
Any Adverse Event - Grade 3	3	3
Any Adverse Event - Grade 4	0	0
Any Adverse Event - Grade 5	0	0

SecondaryNumber of Participants With Serious Infection-Related Adverse Events During the Randomized Treatment Phase

Serious infection-related AEs were assessed using NCI-CTCAE v4.0.

Time frame:: From Baseline until 12 weeks (Q4W arm only) or 16 weeks (Q8W arm only) after the last dose of study drug during the randomized treatment phase (up to 24 weeks)
Reported as:: Count of participants · Participants

Number of Participants With Serious Infection-Related Adverse Events During the Randomized Treatment Phase
Participants	Etrolizumab Q4W	Etrolizumab Q8W
Number of Participants With Serious Infection-Related Adverse Events During the Randomized Treatment Phase	0	0

SecondaryNumber of Participants With Hypersensitivity Reactions During the Randomized Treatment Phase

Hypersensitivity reactions were assessed using NCI-CTCAE v4.0.

Time frame:: From Baseline until 12 weeks (Q4W arm only) or 16 weeks (Q8W arm only) after the last dose of study drug during the randomized treatment phase (up to 24 weeks)
Reported as:: Count of participants · Participants

Number of Participants With Hypersensitivity Reactions During the Randomized Treatment Phase
Participants	Etrolizumab Q4W	Etrolizumab Q8W
Number of Participants With Hypersensitivity Reactions During the Randomized Treatment Phase	0	0

SecondaryNumber of Participants With Malignancies During the Randomized Treatment Phase

Malignancies were assessed using NCI-CTCAE v4.0.

Time frame:: From Baseline until 12 weeks (Q4W arm only) or 16 weeks (Q8W arm only) after the last dose of study drug during the randomized treatment phase (up to 24 weeks)
Reported as:: Count of participants · Participants

Number of Participants With Malignancies During the Randomized Treatment Phase
Participants	Etrolizumab Q4W	Etrolizumab Q8W
Number of Participants With Malignancies During the Randomized Treatment Phase	0	0

SecondaryNumber of Participants With Anti-Drug Antibodies (ADAs) to Etrolizumab at Baseline and Post-Baseline During the Randomized Treatment Phase

Participants were considered to be etrolizumab anti-drug antibody (ADA) positive if they were ADA negative or had missing data at Baseline (BL) but developed an ADA response following study drug exposure (i.e., treatment-induced ADA positive), or if they were ADA positive at baseline and the titer of one or more postbaseline samples was at least 0.60 titer unit greater than the titer of the baseline sample (i.e., treatment-enhanced ADA positive); these ADA positive responses are summarized together (induced + enhanced) in the 'treatment-emergent ADA positive' category. Participants were considered to be ADA negative if they were ADA negative or had missing data at Baseline (BL) and all postbaseline samples were negative (i.e., treatment-emergent ADA negative).

Time frame:: Predose (dosing days only) on Days 1, 28, 84, 112, and 168 (up to the end of the randomized treatment phase at Week 24)
Reported as:: Count of participants · Participants

Number of Participants With Anti-Drug Antibodies (ADAs) to Etrolizumab at Baseline and Post-Baseline During the Randomized Treatment Phase
Participants	Etrolizumab Q4W	Etrolizumab Q8W
Baseline (BL): ADA Positive	1	0
BL: ADA Negative	11	12
Post-BL: Treatment-Emergent ADA Positive	4	2
Post-BL: Treatment-Emergent ADA Negative	7	10

SecondaryLong-Term Safety of Etrolizumab: Number of Participants With Adverse Events by Highest Severity Grade, Assessed According to NCI-CTCAE v4.0

Time frame:: OLE Period: From end of Week 24 to end of 12-week safety follow-up (up to 195 weeks); PML Period: After completion of safety follow up in Randomized Treatment phase or after completion of safety follow up after OLE treatment, up to approximately 92 weeks
Reported as:: Count of participants · Participants

Long-Term Safety of Etrolizumab: Number of Participants With Adverse Events by Highest Severity Grade, Assessed According to NCI-CTCAE v4.0
Participants	OLE: Etrolizumab 1.5 mg Q4W	PML Safety Monitoring
Any Adverse Event - Any Grade	20	4
Any Adverse Event - Grade 1	0	2
Any Adverse Event - Grade 2	12	2
Any Adverse Event - Grade 3	8	0
Any Adverse Event - Grade 4	0	0
Any Adverse Event - Grade 5	0	0

SecondaryLong-Term Safety of Etrolizumab: Number of Participants With Serious Infection-Related Adverse Events

Serious infection-related AEs were assessed using NCI-CTCAE v4.0.

Time frame:: OLE Period: From end of Week 24 to end of 12-week safety follow-up (up to 195 weeks); PML Period: After completion of safety follow up in Randomized Treatment phase or after completion of safety follow up after OLE treatment, up to approximately 92 weeks
Reported as:: Count of participants · Participants

Long-Term Safety of Etrolizumab: Number of Participants With Serious Infection-Related Adverse Events
Participants	OLE: Etrolizumab 1.5 mg Q4W	PML Safety Monitoring
Long-Term Safety of Etrolizumab: Number of Participants With Serious Infection-Related Adverse Events	1	0

SecondaryLong-Term Safety of Etrolizumab: Number of Participants With Hypersensitivity Reactions

Hypersensitivity reactions were assessed using NCI-CTCAE v4.0.

Time frame:: OLE Period: From end of Week 24 to end of 12-week safety follow-up (up to 195 weeks); PML Period: After completion of safety follow up in Randomized Treatment phase or after completion of safety follow up after OLE treatment, up to approximately 92 weeks
Reported as:: Count of participants · Participants

Long-Term Safety of Etrolizumab: Number of Participants With Hypersensitivity Reactions
Participants	OLE: Etrolizumab 1.5 mg Q4W	PML Safety Monitoring
Long-Term Safety of Etrolizumab: Number of Participants With Hypersensitivity Reactions	4	1

SecondaryLong-Term Safety of Etrolizumab: Number of Participants With Malignancies

Malignancies were assessed using NCI-CTCAE v4.0.

Time frame:: OLE Period: From end of Week 24 to end of 12-week safety follow-up (up to 195 weeks); PML Period: After completion of safety follow up in Randomized Treatment phase or after completion of safety follow up after OLE treatment, up to approximately 92 weeks
Reported as:: Count of participants · Participants

Long-Term Safety of Etrolizumab: Number of Participants With Malignancies
Participants	OLE: Etrolizumab 1.5 mg Q4W	PML Safety Monitoring
Long-Term Safety of Etrolizumab: Number of Participants With Malignancies	0	0

SecondaryLong-Term Safety of Etrolizumab: Number of Participants With Anti-Drug Antibodies (ADAs) to Etrolizumab at Baseline and Post-Baseline

Time frame:: Predose (dosing days only) at Baseline (Day 1), Days 28, 84, and 112, Weeks 24, 36, 72, and 120, and every 12 weeks thereafter for up to 4.25 years
Reported as:: Count of participants · Participants

Long-Term Safety of Etrolizumab: Number of Participants With Anti-Drug Antibodies (ADAs) to Etrolizumab at Baseline and Post-Baseline
Participants	Etrolizumab Q4W	Etrolizumab Q8W
Baseline (BL): ADA Positive	1	0
BL: ADA Negative	11	12
Post-BL: Treatment-Emergent ADA Positive	4	3
Post-BL: Treatment-Emergent ADA Negative	7	9

SecondaryNumber of Participants With Confirmed Progressive Multifocal Leukoencephalopathy (PML) During the Post-Treatment PML Monitoring Phase

The safety surveillance PML-monitoring phase (no etrolizumab treatment) consisted of telephone calls approximately every 6 months with administration of the protocol's PML Subjective Checklist. If there were any signs or symptoms suggestive of PML identified on this subjective checklist during the telephone call, the participant was asked to come into the clinic for a neurologic examination. The protocol's PML Algorithm was followed for any suspected case of PML, and any confirmed case of PML would be reported as a serious adverse event.

Time frame:: PML Period: After completion of safety follow up in Randomized Treatment period or after completion of safety follow up after OLE treatment, up to approximately 92 weeks
Reported as:: Count of participants · Participants

Number of Participants With Confirmed Progressive Multifocal Leukoencephalopathy (PML) During the Post-Treatment PML Monitoring Phase
Participants	PML Safety Monitoring
Number of Participants With Confirmed Progressive Multifocal Leukoencephalopathy (PML) During the Post-Treatment PML Monitoring Phase	0

Adverse events

Collected over From Baseline up to the last dose of drug in the Randomized Treatment phase (up to 24 weeks); OLE Period: From end of Week 24 up to end of 12-week safety follow-up (up to 195 weeks); PML Period: After completion of safety follow up in the Randomized Treatment phase or after completion of safety follow up after OLE treatment, up to approximately 92 weeks. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Etrolizumab Q4W	0/12 (0%)	2/12 (16.7%)	8/12 (66.7%)
Etrolizumab Q8W	0/12 (0%)	2/12 (16.7%)	9/12 (75%)
OLE: Etrolizumab 1.5 mg/kg Q4W	0/21 (0%)	6/21 (28.6%)	20/21 (95.2%)
PML Safety Monitoring	0/13 (0%)	0/13 (0%)	4/13 (30.8%)

Most frequent serious events

Showing 10 of 12

Most frequent serious events
Event	Etrolizumab Q4W	Etrolizumab Q8W	OLE: Etrolizumab 1.5 mg/kg Q4W	PML Safety Monitoring
Colitis ulcerativeGastrointestinal disorders	0/12	1/12	2/21	0/13
Crohn's diseaseGastrointestinal disorders	0/12	1/12	2/21	0/13
AnaemiaBlood and lymphatic system disorders	1/12	0/12	0/21	0/13
DiarrhoeaGastrointestinal disorders	1/12	0/12	0/21	0/13
GastritisGastrointestinal disorders	1/12	0/12	0/21	0/13
VomitingGastrointestinal disorders	1/12	0/12	0/21	0/13
Anxiety disorderPsychiatric disorders	1/12	0/12	0/21	0/13
SinusitisInfections and infestations	0/12	0/12	1/21	0/13
Idiopathic intracranial hypertensionNervous system disorders	0/12	0/12	1/21	0/13
Drug abusePsychiatric disorders	0/12	0/12	1/21	0/13

Most frequent other events

Showing 10 of 59

Most frequent other events
Event	Etrolizumab Q4W	Etrolizumab Q8W	OLE: Etrolizumab 1.5 mg/kg Q4W	PML Safety Monitoring
Upper respiratory tract infectionInfections and infestations	2/12	0/12	8/21	0/13
Colitis ulcerativeGastrointestinal disorders	2/12	0/12	7/21	0/13
PyrexiaGeneral disorders	4/12	0/12	6/21	1/13
Abdominal painGastrointestinal disorders	3/12	2/12	6/21	0/13
AnaemiaBlood and lymphatic system disorders	3/12	1/12	4/21	0/13
HeadacheNervous system disorders	0/12	3/12	5/21	0/13
Crohn's diseaseGastrointestinal disorders	2/12	2/12	5/21	0/13
PharyngitisInfections and infestations	0/12	0/12	5/21	0/13
Abdominal pain upperGastrointestinal disorders	1/12	0/12	4/21	2/13
Respiratory tract infectionInfections and infestations	1/12	0/12	4/21	0/13

Baseline characteristics

Age, Continuous
Age, Continuous(Years)	Etrolizumab Q4W	Etrolizumab Q8W	Total
Mean	12.25 ± 3.62	13.42 ± 4.46	12.83 ± 4.02

Sex: Female, Male
Sex: Female, Male(Participants)	Etrolizumab Q4W	Etrolizumab Q8W	Total
Female	4	7	11
Male	8	5	13

Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)	Etrolizumab Q4W	Etrolizumab Q8W	Total
Hispanic or Latino	0	1	1
Not Hispanic or Latino	12	11	23
Unknown or Not Reported	0	0	0

Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)	Etrolizumab Q4W	Etrolizumab Q8W	Total
White	12	12	24

Disease Indication: Crohn's Disease or Ulcerative Colitis
Disease Indication: Crohn's Disease or Ulcerative Colitis(Participants)	Etrolizumab Q4W	Etrolizumab Q8W	Total
Crohn's Disease	5	5	10
Ulcerative Colitis	7	7	14

Randomization Stratification Factor: Body Weight <40 kg or ≥40 kg
Randomization Stratification Factor: Body Weight <40 kg or ≥40 kg(Participants)	Etrolizumab Q4W	Etrolizumab Q8W	Total
<40 kg	5	4	9
≥40 kg	7	8	15

Study locations

5 sites

Hôpital Enfants Reine Fabiola
Bruxelles, 1020, Belgium
Gabinet Lekarski, Bartosz Korczowski
Rzeszów, 35-302, Poland
Centrum Zdrowia MDM
Warszawa, 00-189, Poland
Hospital Niño Jesus; Servicio de Pediatria - Gastrenterologia y Nutricion
Madrid, 28009, Spain
Royal Manchester Childrens Hospital
Manchester, M13 9WL, United Kingdom

References and documents

Study documents

Protocol and statistical analysis plan · May 28, 2021

Documents are hosted by the registry — open the source record to download them.

Registry details

Key details

Study ID: NCT03478956
Lead sponsor: Hoffmann-La Roche
Responsible party: Sponsor
First posted: Mar 27, 2018
Start date: Mar 27, 2018
Primary completion: Dec 2, 2019
Completion: Sep 27, 2023
Results posted: Aug 5, 2020
Last update: Dec 27, 2024

Study contacts

Clinical Trials

study director · Hoffmann-La Roche

Oversight

Data monitoring committee: No
FDA-regulated drug: Yes
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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