A 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

• Register: EUCTR
• Last refreshed on: 28 February 2019
• Main ID: EUCTR2017-003649-10-DE
• Date of registration: 07/02/2018
• Prospective Registration: Yes
• Primary sponsor: F. Hoffmann-La Roche Ltd
• Public title: A 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
• Scientific 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
• Date of first enrolment: 30/04/2018
• Target sample size: 60
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-003649-10
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, Germany, Poland, Spain, United Kingdom, United States

Contacts

• Name: Trial Information Support Line-TISL
• Affiliation: F.Hoffmann-La Roche Ltd

• Name: Trial Information Support Line-TISL
• Affiliation: F.Hoffmann-La Roche Ltd

Key inclusion & exclusion criteria

Inclusion criteria:
- Age of 4 years to < 18 years
- Weight of 13 kg or more
- Diagnosis of UC or CD confirmed by biopsy and established for >= 3 months prior to screening
- Inadequate response, loss of response or intolerance to prior immunosuppressants and/or corticosteroid treatment and/or anti-TNF therapy
- For patients with UC: moderately to severely active UC as determined by an MCS of 6-12 with an endoscopic subscore >= 2 and a rectal bleeding subscore 3>= 1
- For patients with CD: moderately to severely active CD as determined by a Pediatric Crohn’s Disease Activity Index (PCDAI) score of >30 at baseline
- Patients must meet the surveillance colonoscopy requirements such as document evidence of surveillance for dysplasia every 1 to 2 years, beginning approximately 7 to 10 years after their initial diagnosis
- For postpubertal females of childbearing potential: agreement to remain abstinent 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 or use contraceptive measures, and agreement to refrain from donating sperm for at least 24 weeks after the last dose of study drug to avoid exposing the embryo to study drug
Are the trial subjects under 18? yes
Number of subjects for this age range: 60
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
For IBD
- Prior extensive colonic resection, subtotal or total colectomy, or planned surgery
- Past or present ileostomy or colostomy and a history or current evidence of colonic mucosal dysplasia
- Diagnosis of indeterminate colitis, toxic megacolon within 12 months of initial screening visit
- Suspicion of ischemic colitis, radiation colitis, or microscopic colitis
- Abdominal abscessl
- Patients with any stricture of the colon and having history or evidence of adenomatous colonic polyps that have not been removed and who are not up to date on vaccinations per the local vaccine schedule will be excluded

For UC
- Severe extensive colitis per investigator judgment that colectomy is imminent or the patient has two of the mentioned five symptoms at screening or baseline visit such as 6 bowel movements daily with obvious blood, abdominal examination worrisome for imminent surgery, persistent fever, tachycardia and anemia

For CD
- Sinus tract with evidence for infection in the clinical judgment of the investigator, short-bowel syndrome and evidence of abdominal or perianal abscess
- Expected to require surgery to manage CD-related complications during the study

For Prior or Concomitant Therapy
- Any prior treatment with anti-integrins, ustekinumab,anti-adhesion molecules and rituximab
- Use of intravenous (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 within 12 months prior to Day (D)1, with the exception of azathioprine and 6 mercaptopurine; use of cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil within 4 weeks prior to D1, other biologics within 8 weeks before dosing and use of chronic nonsteroidal anti-inflammatory drug and anticoagulants and apheresis within 2 weeks prior to D1
- Received any investigational treatment including investigational vaccines within 12 weeks prior to D1 of the study or 5 half-lives of the investigational product
- 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 or any of excipients
- Tube feeding, defined formula diets, or parenteral alimentation/nutrition who have not discontinued these treatments > 3 weeks prior to D1

For General Safety
- Lack of peripheral venous access
- Congenital or acquired immune deficiency
- Significant uncontrolled comorbidity, such as cardiac, pulmonary, renal, hepatic, endocrine, or gastrointestoinal disorders (excluding UC and CD) and clinically significant abnormalities on the screening PML Subjective Checklist
- Neurological conditions or diseases that may interfere with PML monitoring
- History of demyelinating disease , major neurological disorder and cancer
- Conditions other than UC or CD that could require treatment with >10 mg/day of prednisone during course of the study

For Infection Risk
- Congenital or acquired immune deficiency
- Patients must undergo screening for HIV and test positive for preliminary, confirmatory tests and hepatitis B virus
- Positive hepatitis C virus (HCV) antibody test result, unless patient who has undetectable HCV RNA levels for >6 months after completing a successful course of HCV anti-viral treatment and an undetectable HCV RNA at screening or who has a known history of HCV antibody positivity with a history of undetectable HCV RNA and undetectable HCV RNA at screening in absence

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Moderate to severe ulcerative colitis (UC); moderate to severe Crohn’s disease (CD)
MedDRA version: 20.0 Level: PT Classification code 10011401 Term: Crohn's disease System Organ Class: 10017947 - Gastrointestinal disorders
MedDRA version: 20.0 Level: PT Classification code 10009900 Term: Colitis ulcerative System Organ Class: 10017947 - Gastrointestinal disorders

Therapeutic area: Diseases [C] - Digestive System Diseases [C06]

Intervention(s)

Product Name: Etrolizumab
Product Code: 549-0261/F02-01
Pharmaceutical Form: Solution for injection
INN or Proposed INN: ETROLIZUMAB
CAS Number: 1044758-60-2
Current Sponsor code: RO5490261/F02-01
Other descriptive name: ETROLIZUMAB
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 150-

Primary Outcome(s)

Secondary Objective: •To evaluate the overall safety and tolerability of etrolizumab in pediatric population (Randomized Treatment Phase)
•To evaluate long-term safety and efficacy of etrolizumab in pediatric population (Open–label Extension Phase)
•Post-trial safety surveillance with focus on progressive multifocal leukoencephalopathy (PML) monitoring in patients who have stopped treatment (PML Monitoring Phase)

Primary end point(s): 1.Maximum concentration observed (Cmax) (Randomized Treatment Phase)
2.Area under the concentration-time curve within a dosing interval (AUCtau) (Randomized Treatment Phase)
3.Elimination half-life (t1/2) (Randomized Treatment Phase)
4.Steady-state concentration at the end of a dosing interval (Ctrough) (Randomized Treatment Phase)
5.PD parameters: ß7 receptor occupancy by flow cytometry on peripheral blood lymphocytes (Randomized Treatment Phase)

Timepoint(s) of evaluation of this end point: 1-4. Treatment period: D1 of Week (W)0;D4;D28 (W4); D56 (W8); D60 and 70; D84 (W12); D88 and 98; D112 (W16) and at unscheduled visit and early withdrawal from treatment or discontinuation
Safety follow-up period: At D126 (W18), D140 (W20) and D168 (W24) or early withdrawal visit
5. Treatment period: D1 (W0), D4, D56 (W8), D84 (W12), D98, D112 (W16) and at unscheduled visit and early withdrawal from treatment or discontinuation
Safety follow-up period: At D126 (W18), D140 (W20) and D168 (W24) or early withdrawal visit

Main Objective: •To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD)of etrolizumab in a pediatric IBD patient population (Randomized Treatment Phase)

Secondary Outcome(s)

Secondary end point(s): 1. Incidence and severity of infection-related adverse events (Randomized Treatment and Open–Label Extension Phase)
2. Incidence of immunogenic responses (anti-drug antibodies [ADAs]) (Randomized Treatment Phase)
3. Incidence and severity of hypersensitivity reaction events (Randomized Treatment and Open–Label Extension Phase)
4. Incidence of other safety events, including adverse events, serious adverse events, and adverse events of special interest (Randomized Treatment and Open–Label Extension Phase)
5. Incidence and severity of malignancies (Open–Label Extension Phase)
6. Incidence of ADAs to etrolizumab (Open–Label Extension Phase)
7. Clinical response at W132, as assessed by the Pediatric Ulcerative Colitis Activity Index (UC) and Pediatric Crohn's Disease Activity Index (CD) (Open–Label Extension Phase)
8. Occurrence of confirmed PML events (PML Monitoring Phase)

Timepoint(s) of evaluation of this end point: 1-5. Up to 5 years
6. At W132
7. Up to 104 weeks

Secondary ID(s)

CA40192

2017-003649-10-ES

Source(s) of Monetary Support

F. Hoffmann-La Roche Ltd

Ethics review

Status: Approved
Approval date:
Contact: