Clinical trial NCT03478956: 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
Official title: A Phase I, Open-Label, Randomized, Pharmacokinetic, Pharmacodynamic, and Safety Study of Etrolizumab Followed by Open-Label Extension and Safety Monitoring in Pediatric Patients From 4 Years to Less Than 18 Years Of Age With Moderate to Severe Ulcerative Colitis or Moderate To Severe Crohn's Disease
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Ulcerative Colitis
Crohn's Disease
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2018-03-27
Enrollment: 24
Sex: ALL
Minimum age (years): 4
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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).


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)

Primary outcomes:
measure: Maximum Serum Concentration (Cmax) of Etrolizumab After First and Last Dose During the Randomized Treatment Phase
timeFrame: Arm Etro Q4W: Day 1, 84 and Arm Etro Q8W: Day 1, 56
measure: Time to Maximum Serum Concentration (Tmax) of Etrolizumab After First and Last Dose During the Randomized Treatment Phase
timeFrame: Arm Etro Q4W: Days 1, 84 and Arm Etro Q8W: Days 1, 56
measure: Area Under the Concentration-Time Curve Within the Last Dosing Interval (AUC-tau) of Etrolizumab During the Randomized Treatment Phase
timeFrame: Arm Etro Q4W: Days 56, 84, 88, 98, 112 and Arm Etro Q8W: Day 56, 60, 70, 84, 88, 98, 112
measure: Elimination Half-Life (t1/2) of Etrolizumab After Last Dose During the Randomized Treatment Phase
timeFrame: 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
measure: Serum Trough Concentration (Ctrough) of Etrolizumab at the End of Each Dosing Interval During the Randomized Treatment Phase
timeFrame: Arm Etro Q4W: Predose on Days 28, 56, 84, 112 and Arm Etro Q8W: Predose on Days 56, 112
measure: 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
timeFrame: 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:
measure: 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
timeFrame: 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)
measure: Number of Participants With Serious Infection-Related Adverse Events During the Randomized Treatment Phase
timeFrame: 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)
measure: Number of Participants With Hypersensitivity Reactions During the Randomized Treatment Phase
timeFrame: 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)
measure: Number of Participants With Malignancies During the Randomized Treatment Phase
timeFrame: 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)
measure: Number of Participants With Anti-Drug Antibodies (ADAs) to Etrolizumab at Baseline and Post-Baseline During the Randomized Treatment Phase
timeFrame: Predose (dosing days only) on Days 1, 28, 84, 112, and 168 (up to the end of the randomized treatment phase at Week 24)
measure: Long-Term Safety of Etrolizumab: Number of Participants With Adverse Events by Highest Severity Grade, Assessed According to NCI-CTCAE v4.0
timeFrame: 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
measure: Long-Term Safety of Etrolizumab: Number of Participants With Serious Infection-Related Adverse Events
timeFrame: 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
measure: Long-Term Safety of Etrolizumab: Number of Participants With Hypersensitivity Reactions
timeFrame: 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
measure: Long-Term Safety of Etrolizumab: Number of Participants With Malignancies
timeFrame: 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
measure: Long-Term Safety of Etrolizumab: Number of Participants With Anti-Drug Antibodies (ADAs) to Etrolizumab at Baseline and Post-Baseline
timeFrame: 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
measure: Number of Participants With Confirmed Progressive Multifocal Leukoencephalopathy (PML) During the Post-Treatment PML Monitoring Phase
timeFrame: 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
Other outcomes:
Locations:
city: Bruxelles
country: Belgium
facility: Hôpital Enfants Reine Fabiola
city: Rzeszów
country: Poland
facility: Gabinet Lekarski, Bartosz Korczowski
city: Warszawa
country: Poland
facility: Centrum Zdrowia MDM
city: Madrid
country: Spain
facility: Hospital Niño Jesus; Servicio de Pediatria - Gastrenterologia y Nutricion
city: Manchester
country: United Kingdom
facility: Royal Manchester Childrens Hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: