Evaluation of Safety, Efficacy, Pharmacokinetic and Pharmacodynamic of Bertilimumab in Patients With Active Moderate to Severe Ulcerative Colitis

Ulcerative Colitis, Active Moderate Clinical Trial

Official title:

A Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Multi-Center Study Designed to Evaluate the Safety, Efficacy, Pharmacokinetic and Pharmacodynamic Profile of Bertilimumab in Patients With Active Moderate to Severe Ulcerative Colitis

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01671956
• Other study ID #: Immune/BRT/UC-01
• Status: Recruiting
• Phase: Phase 2
• First received: August 9, 2012
• Last updated: January 3, 2018
• Start date: July 2015
• Est. completion date: March 2019

Study information

• Verified date: January 2018
• Source: Immune Pharmaceuticals
• Contact: Tony Fiorino, MD
• Email: tony.fiorino[@]immunepharma.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a randomized, double blind, placebo-controlled, parallel group multi-center study in adult patients with active moderate to severe UC . Eligible patients will be randomly assigned in a 2:1 ratio to one of two treatment groups, bertilimumab 10 mg/kg or matching placebo, respectively

Description:

This is a randomized, double blind, placebo-controlled, parallel group multi-center study in adult patients with active moderate to severe UC . Eligible patients will be randomly assigned in a 2:1 ratio to one of two treatment groups, bertilimumab 10 mg/kg or matching placebo, respectively.

The study will consist of three periods: a screening period of up to two weeks, a 4-week double-blind treatment period (three IV infusions at 2-week intervals), and a safety and efficacy follow-up period of approximately 9 weeks.

Bertilimumab is a recombinant human IgG4 monoclonal antibody that neutralizes human eotaxin-1 (eotaxin). Bertilimumab will be administered every other week for 4-weeks, by IV infusion over 30 minutes.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 42
• Est. completion date: March 2019
• Est. primary completion date: August 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

1. Males or females, 18 to 70 years of age inclusive.

2. Diagnosed with active moderate to severe UC per standard diagnostic criteria for a minimum of 3 months:

• Mayo score of 6-12 (inclusive) at the Screening Visit

• Endoscopic evidence of active mucosal disease, as assessed by flexible sigmoidoscopy, with an Endoscopic Finding Sub-score of =2 (assessed centrally)

• Rectal Bleeding Sub-score of =1

• Physician's Global Assessment (PGA) Sub-score of =2.

3. Levels of eotaxin-1 in biopsied colon tissue of =100 pg/mg protein.

4. Adequate cardiac, renal and hepatic function as determined by the Investigator and demonstrated by screening laboratory evaluations and physical examination results; these findings must all be within normal limits or judged not clinically significant by the Investigator.

Exclusion Criteria:

1. History of colonic or rectal surgery other than hemorrhoidal surgery or appendectomy.

2. Currently receiving total parenteral nutrition (TPN).

3. Positive Clostridium difficile toxin stool assay.

4. Tested positive for active/latent mycobacterium tuberculosis (TB) infection.

5. Pregnant or breast-feeding, or plan to become pregnant during the study.

6. Males who are young and childless or planning to have more children in the future.

7. Known hypersensitivity to bertilimumab or any of the drug excipients.

8. History of infection requiring administration of any IV antibiotic, antiviral or antifungal medication within 30 days of Screening or any oral anti-infective agent within 14 days of Screening.

9. Severe UC evidenced by the following signs of toxicity: heart rate >100 beats/min at rest, temperature >37.8°C, hemoglobin <10.0 g/dL.

10. Ulcerative proctitis, defined as disease limited to less than 15 cm from the anal verge.

11. Received a vaccine or other immunostimulator within 4 weeks prior to screening.

12. Use of >4.8 g mesalazine or equivalent within 2 weeks prior to the screening visit. Mesalazine =4.8 g is allowed if the dose during the 2 weeks prior to the screening visit was stable.

13. Use of systemic corticosteroids exceeding the equivalent of 20 mg/day of prednisone within four weeks prior to the screening visit (see Section 6.9.1).

14. Change in dose of immunosuppressive drugs (e.g., corticosteroids, 6-mercaptopurine [6-MP], azathioprine) within four weeks prior to the screening visit.

15. Use of TNF-blockers (e.g., infliximab or adalimumab) within 60 days of the screening visit.

16. Use of chronic non-steroidal anti-inflammatory (NSAID) therapy. Occasional use of NSAIDs or acetaminophen for headache, arthritis, myalgias, menstrual cramps, etc., or daily use of low dose (81-162 mg) aspirin for cardiovascular prophylaxis is allowed.

17. Patients diagnosed with:

• Crohn's disease

• Diverticulitis or diverticulosis

• Indeterminate colitis (inability to distinguish between UC and Crohn's disease [as assessed by the Investigator])

• Microscopic colitis (collagenous or lymphocytic colitis)

• Ischemic or infectious colitis

• Clostridium difficile colitis within 90 days of the screening visit

• Parasitic disease within 90 days of the screening visit

• Systemic fungal infection within 90 days of the screening visit.

18. History of positive serology of hepatitis B or C, or human immunodeficiency virus (HIV) infection.

19. Congenital or acquired immunodeficiency (e.g., common variable immunodeficiency, organ transplantation).

20. Clinically significant abnormal laboratory test results, unless regarded by the Investigator as related to UC, including but not limited to:

• Hemoglobin level <10.0 g/dL

• White blood cell count < 3 x 103/µL

• Lymphocyte count < 0.5 x 103/µL

• Platelet count <100 x 103/µL or >1200 x 103/µL

• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 the upper limit of normal (ULN)

• Alkaline phosphatase >3 ULN

• Serum creatinine >2 ULN.

21. Active abuse of alcohol or drugs.

22. Known malignancy or history of malignancy that could reduce life expectancy.

23. Any condition, which in the opinion of the Investigator, would place the patient at an unacceptable risk if participating in the study protocol.

24. Participation in a clinical trial of an investigational (unapproved) product

Related Conditions & MeSH terms

• Colitis
• Colitis, Ulcerative
• Ulcer
• Ulcerative Colitis, Active Moderate
• Ulcerative Colitis, Active Severe

Intervention

Biological:
• Bertilimumab
IV infusion over 30 minutes, at Day 0, Day 14 and Day 28
• Placebo
IV infusion over 30 minutes, at Day 0, Day 14 and Day 28

Locations

Country	Name	City	State
Israel	HaEmek Medical Center	Afula
Israel	Wolfson Medical Center	Holon
Israel	Hadassah Ein Kerem	Jerusalem
Israel	Shaare Zedek Medical Central	Jerusalem
Israel	Meir Medical Center	Kfar-Saba
Israel	Sourasky-Ichilov Tel Aviv Medical Center	Tel- Aviv

Sponsors (1)

Lead Sponsor	Collaborator
Immune Pharmaceuticals

Country where clinical trial is conducted

Israel, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	PHARMACOKINETICS	PK analysis for bertilimumab concentration: blood samples will be collected on dosing days (pre-dose and at 30 minutes and 4 hours following initiation of study drug infusion) and at the follow-up visits. The following PK parameters will be calculated, to the degree possible given the number of timepoints: Cmax, Tmax, Cavg, Cmin and t1/2. Additional standard and exploratory PK parameters will be calculated if deemed necessary	Throughout the study
Other	PHARMACODYNAMIC	Fecal calprotectin change from Day 0 (baseline) to all scheduled measurement timepoints.; PD analysis of eosinophil shape change: blood samples will be collected on dosing days (pre-dose and on Day 0 only, at 4 hours following initiation of study drug infusion), and at the follow-up visits.; Change in eosinophil count, serum eotaxin-1 and hs-CRP from Day 0 to all scheduled measurement timepoints.; Change in eotaxin-1 concentration and eosinophil count in biopsy tissue from Screening to Day 56	Throughout the study
Other	Safety	Adverse events (AE); Injection site reactions; Physical examination; Vital signs (blood pressure, heart rate, temperature and respiratory rate); ECG; Concomitant medications; Laboratory evaluation (hematology, biochemistry, anti-bertilimumab antibodies).	Throughout the study
Primary	Clinical response	A decrease in Mayo score from baseline of at least 3 points and at least 30% AND; Either a decrease in the sub-score for rectal bleeding of at least 1 point, or rectal bleeding sub-score of 0 or 1.	Day 56
Secondary	Change in UCEIS score from screening to Day 56		Da 56
Secondary	Clinical remission at Day 56, defined as a total Mayo score of 2 points or lower, with no individual sub-score exceeding 1 point		Day 56
Secondary	Mucosal healing at Day 56, defined as an absolute sub-score for endoscopy of 0 or 1.		Day 56
Secondary	Change in partial Mayo score from Day 0 to all scheduled measurement timepoints (efficacy follow up).		Throughout the study