A randomized, double-blind, multicenter phase 3 study in patients with moderately to severely active ulcerative colitis (UC) to compare the efficacy, safety and immunogenicity of PB016 and Entyvio® for the induction and maintenance of clinical response and remission. (UCESIVE)
- Trial ID
- 2022-502778-18-00
- Protocol
- PB016-03-01
- Sponsor
- Polpharma Biologics S.A.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to demonstrate the **similarity** of effect of induction treatment with intravenous (IV) formulations of PB016 and Entyvio® on the clinical response rate at 6 weeks in patients with moderately to severely active **ulcerative colitis**. This is clinically relevant as it aims to establish whether PB016 can achieve comparable efficacy to the established treatment, Entyvio®, in inducing a clinical response, which is crucial for managing this chronic inflammatory condition.
Secondary objectives include:
- Demonstrating similarity of effect of maintenance treatment with IV formulations of PB016 and Entyvio® on clinical response rate at 52 weeks.
- Demonstrating similarity of effect of IV PB016 and Entyvio® on partial Mayo score, clinical remission rate, mucosal healing rate, and corticosteroid-free remission rate.
- Demonstrating similarity of effect of IV PB016 and Entyvio® on disease-related biomarkers and immunogenicity.
- Comparing the safety profiles of PB016 and Entyvio®.
- Demonstrating similarity of IV PB016 and Entyvio® on pharmacokinetics.
Participants
The clinical trial involves a total of **504 participants** diagnosed with **ulcerative colitis**, a chronic inflammatory bowel disease. The study population includes both male and female subjects, aged between 18 and 80 years, who have been diagnosed with moderate to severe ulcerative colitis for at least six months prior to screening. Participants were selected based on their inadequate response, loss of response, or intolerance to previous treatments such as corticosteroids, immunomodulators, or TNFα antagonists. The trial includes individuals with a body mass index of at least 18 at screening and those who have demonstrated a complete Mayo score of 6 to 12 with an endoscopic sub-score of at least 2. Lifestyle considerations such as the stability of medication doses, including oral 5-aminosalicylic acid compounds, corticosteroids, probiotics, antidiarrheals, azathioprine, or 6-mercaptopurine, were taken into account. The trial population also includes individuals who are up-to-date on colorectal cancer surveillance if they have a family history of colorectal cancer or other risk factors. Both male and female participants of childbearing potential are required to use effective contraception during the study and for a specified period after the last dose of the study drug. The sponsor has not provided information regarding the inclusion of vulnerable populations in this trial.
Plans and Procedures
The clinical trial is a **randomized, double-blind, controlled** study designed to evaluate the efficacy, safety, and immunogenicity of PB016 compared to Entyvio® in patients with moderately to severely active **ulcerative colitis**. The trial is structured as a phase 3 study and aims to demonstrate the similarity of effect between the two treatments on clinical response rate at 6 weeks. The trial is expected to run until September 2026, with recruitment having commenced in June 2023. Participants will be involved in the study for a maximum treatment period of 46 weeks.
The study involves a sequence of visits, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as age, disease severity, and previous treatment history. The screening visit will also include a colonoscopy for certain patients to ensure up-to-date colorectal cancer surveillance. Following successful screening, participants will be randomized to receive either PB016 or Entyvio® via **intravenous infusion**. The primary endpoint is the clinical response rate at Week 6, defined by a reduction in the complete Mayo score and rectal bleeding sub-score.
Subsequent follow-up visits are scheduled at Weeks 2, 6, 14, 22, 30, 38, 46, and 52 to assess secondary endpoints, including clinical remission rates, mucosal healing, and changes in biomarkers such as fecal calprotectin and blood C-reactive protein. Vedolizumab levels and the presence of anti-drug antibodies will also be monitored. The end-of-study visit will occur at Week 52, marking the conclusion of participant involvement.
Participants may be withdrawn from the study early if they experience adverse events or serious adverse events that necessitate discontinuation, or if they fail to adhere to the study protocol. The trial is conducted under strict ethical guidelines, ensuring that all participants provide informed consent and are able to participate in all aspects of the study. The study's design and procedures are meticulously planned to ensure the collection of robust and reliable data to support the trial's objectives.
Treatment
The clinical trial involves the administration of **Entyvio** (vedolizumab), a **powder for concentrate for solution for infusion**. This pharmaceutical form is specifically designed for intravenous (IV) infusion. Each dose contains 300 mg of vedolizumab, a humanized antibody of the IgG1 class, which is classified under the ATC code L04AA33. The maximum daily dose is 300 mg, with a total maximum dose of 2400 mg over the treatment period. The treatment is administered via IV infusion, with a maximum treatment period of 46 weeks. The product is manufactured by Takeda Pharma A/S and is authorized for use in the European Union under the marketing authorization number EU/1/14/923/001. The administration schedule and participant compliance are monitored throughout the trial to ensure adherence to the dosing regimen.
The trial also includes the use of **PB016**, another formulation of vedolizumab, which serves as the comparator treatment. PB016 is also administered as a solution for infusion, with the same dosage and administration route as Entyvio. The maximum daily and total doses are identical to those of Entyvio, ensuring consistency in the treatment protocol. The primary objective of the trial is to compare the efficacy, safety, and immunogenicity of PB016 and Entyvio in patients with moderately to severely active **ulcerative colitis**. Both treatments are administered under a double-blind, randomized, multicenter phase 3 study design, with the aim of demonstrating similarity in clinical response rates at 6 weeks. Compliance with the dosing schedule is closely monitored to maintain the integrity of the trial results.
Efficacy
Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints designed to evaluate the therapeutic impact of PB016 and Entyvio® in patients with moderately to severely active **ulcerative colitis**. The primary endpoint is the clinical response rate at Week 6, defined as the proportion of patients achieving a reduction in the complete Mayo score by at least 3 points and 30% from baseline, along with a decrease in the rectal bleeding sub-score by at least 1 point or an absolute rectal bleeding sub-score of 1 point or less.
Secondary endpoints include the clinical response rate at Week 52, changes from baseline in the partial Mayo score at multiple timepoints (Weeks 2, 6, 14, 22, 30, 38, 46, and 52), and the clinical remission rate at Weeks 6 and 52. Additional secondary measures involve the mucosal healing rate, corticosteroid-free remission rate, changes in fecal calprotectin and blood C-reactive protein levels, and vedolizumab trough levels at specified intervals. The presence of anti-drug antibodies and neutralizing antibodies will also be monitored at baseline and at several subsequent weeks (Weeks 2, 6, 14, 30, and 52).
These efficacy parameters will be collected and analyzed using validated scales and laboratory tests at designated timepoints throughout the study. The assessments will provide comprehensive data on the efficacy of the treatments in inducing and maintaining clinical response and remission in the study population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age ≥18 and ≤80 years at Screening.
- Demonstrated an inadequate response to, loss of response to, or intolerance to at least 1 of the following agents: Corticosteroids Signs and symptoms of persistently active disease despite a history of at least one 4-week induction regimen that included a dose equivalent to prednisone 30 mg daily orally for 2 weeks or intravenously for 1 week. OR Two failed attempts to taper corticosteroids to below a dose equivalent to prednisone 10 mg daily orally (i.e., corticosteroid dependent patients). OR History of intolerance to corticosteroids (including, but not limited to Cushing’s syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, infection). Immunomodulators Signs and symptoms of persistently active disease despite a history of at least one 8-week regimen of oral azathioprine (≥1.5 mg/kg) or 6-mercaptopurine mg/kg (≥0.75 mg/kg). OR History of intolerance to at least one immunomodulator (including, but not limited to, nausea/vomiting, abdominal pain, pancreatitis, liver function test abnormalities, lymphopenia, TPMT genetic mutation, infection). Tumor Necrosis Factor Alpha (TNFα) Antagonists Non-responders/inadequate response despite a history of at least one induction regimen/loading dose of TNFα antagonists as per summary of product characteristics (SmPC). OR Recurrence of symptoms during maintenance dosing following prior clinical benefit (discontinuation despite clinical benefit does not qualify). OR History of intolerance to TNFα antagonists (including, but not limited to site/infusion-related reaction, demyelination, congestive heart failure, infection).
- May be receiving a therapeutic dose of the following drugs: a. Oral 5-aminosalicylic acid (5-ASA) compounds provided that the dose has been stable for the 2 weeks prior to randomization. b. Oral corticosteroid therapy (at a dose of ≤30 mg/day prednisone equivalent) provided that the dose has been stable for the 4 weeks immediately prior to randomization (if corticosteroids have just been initiated), or for the 2 weeks immediately prior to randomization (if corticosteroids are being tapered). c. Probiotics (e.g., Culturelle, Saccharomyces boulardii) provided that the dose has been stable for the 2 weeks immediately prior to randomization. d. Antidiarrheals (e.g., loperamide, diphenoxylate with atropine) for control of chronic diarrhea. e. Azathioprine or 6-mercaptopurine provided that the dose has been stable for the 8 weeks immediately prior to randomization.
- Able to participate in all aspects of this clinical study.
- Male or female patient who is voluntarily able to give informed consent.
- At Screening, females of childbearing potential must be non pregnant and non-lactating; or females should be of non childbearing potential (either surgically sterilized or physiologically incapable of becoming pregnant, or at least 1 year postmenopausal [amenorrhea duration of 12 consecutive months]); non-pregnancy will be confirmed for all females of childbearing potential by a serum pregnancy test conducted at Screening.
- Female patients of childbearing potential, with a fertile male sexual partner, must use highly effective contraception from Screening until 18 weeks after the last dose of study drug.
- Male patients engaging in sexual intercourse with a female of childbearing potential must agree they will use condoms with spermicide or abstain from sexual intercourse for the duration of the study, starting at Screening and for at least 18 weeks after their last dose of study drug if not surgically sterilized at least 6 months before Screening (with a post-vasectomy semen analysis negative for sperm). Male patients must not donate sperm until 18 weeks after the last dose of study drug.
- Diagnosis of moderate to severe UC established at least 6 months prior to Screening by clinical and endoscopic evidence, corroborated by a histopathology report and confirmed by the Investigator.
- Moderately to severely active UC as determined by a complete Mayo score of 6 to 12 with an endoscopic sub-score ≥2, confirmed by a central reader within 28 days prior to randomization.
- Evidence of UC extending proximal to the rectum (≥15 cm of involved colon).
- Patients with extensive colitis or pancolitis of >8 years duration or left-sided colitis of >12 years duration must have documented evidence that a surveillance colonoscopy was performed within 12 months of the initial Screening Visit (may be performed during Screening).
- Patients with a family history of colorectal cancer, personal history of increased colorectal cancer risk, age >45 years, or other known risk factor must be up-to-date on colorectal cancer surveillance (may be performed during Screening).
- Body mass index ≥18 at Screening.
Exclusion Criteria
- Previous exposure to vedolizumab (Entyvio® or any other investigational vedolizumab-containing product).
- Diagnosis of Crohn’s disease, microscopic colitis, ischemic colitis or indeterminate colitis.
- Had any surgical procedure requiring general anesthesia within 30 days prior to randomization or the patient currently requires or is anticipated to require surgical intervention for UC during the study.
- Has history or evidence of adenomatous colonic polyps that have not been removed.
- Has any of the following: Evidence of a serious active or clinically significant infection requiring medical treatment or that in the opinion of the Investigator would confound the study results, during Screening or has been hospitalized or treated for such infection within 60 days of Baseline (e.g., sepsis, cytomegalovirus, listeriosis or opportunistic infections such as progressive multifocal leukoencephalopathy [PML]). OR Evidence of C. difficile or other intestinal pathogen at Screening. If during Screening, patients tested positive for C. difficile or any other stool pathogens, retest for the same pathogen can be performed at the Investigator’s discretion (e.g., if there is a doubt or reasonable expectation for a negative outcome of the retest). In case of screen failure, rescreening of patients with completed treatment against the pathogen with no clinical signs and subsequent negative test results can be allowed at the Investigator’s discretion. OR Other current or recent (within 30 days prior to Screening) clinically significant infection (e.g., pneumonia, pyelonephritis).
- Chronic hepatitis B or C infection. Patients with positive viral serology at Screening for infection with hepatitis B, or hepatitis C virus may be eligible if polymerase chain reaction test is negative, and the patient receives standard of care antiviral prophylaxis (if applicable).
- Known active tuberculosis (TB). OR Positive QuantiFERON® test or 2 successive indeterminate QuantiFERON® tests. OR Chest X-ray within 3 months of randomization in which active or latent pulmonary TB cannot be excluded. OR A tuberculin skin test reaction ≥10 mm (≥5 mm in patients receiving the equivalent of >15 mg/day prednisone). Note: Patients currently receiving treatment for latent TB without active TB, or patients with a positive QuantiFERON® or tuberculin test but where active TB is ruled out and standard of care anti-TB treatment has been initiated will not be excluded from the study.
- Has any identified congenital or acquired immunodeficiency (e.g., common variable immunodeficiency, human immunodeficiency virus infection, organ transplantation).
- Any history of malignancy, except for the following: a. Adequately treated nonmetastatic basal cell skin cancer. b. Squamous cell skin cancer that has been adequately treated and that has not recurred for at least 1 year prior to randomization. c. History of cervical carcinoma in situ that has been adequately treated and that has not recurred for at least 3 years prior to randomization. Note: Patients with remote history of malignancy (e.g., >5 years since completion of curative therapy without recurrence prior to Screening) will be considered based on the nature of the malignancy and the therapy received and must be discussed with the Sponsor on a case-by-case basis prior to randomization.
- Has any live vaccination within 30 days prior to Screening or is planning to receive any live vaccination during participation in the study.
- Has used a topical (rectal) treatment with 5-ASA or corticosteroid enemas/suppositories within 2 weeks prior to randomization unless taken on stable dose for at least 2 weeks before randomization.
- Female patients who are lactating or have a positive serum pregnancy test during the Screening Period or a positive urine pregnancy test on Day 0 prior to study drug administration.
- Has a history of hypersensitivity or allergies to the ingredients of Entyvio®.
- History of any major neurological disorders, including stroke, multiple sclerosis, brain tumor, or neurodegenerative disease that, in the opinion of the Investigator, would confound the study results.
- Positive PML subjective symptom checklist prior to the administration of the first dose of study drug.
- Current or recent history (within 1 year prior to randomization) of alcohol dependence or illicit drug abuse.
- Active psychiatric problems that, in the Investigator’s opinion, may interfere with compliance with the study procedures.
- Any of the following laboratory abnormalities during the Screening Period: a. Hemoglobin level <8 g/dL. b. White blood cell count <3 × 109/L. c. Lymphocyte count <0.5 × 109/L. d. Platelet count <100 × 109/L or >1200 × 109/L. e. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 × the upper limit of normal (ULN). f. Alkaline phosphatase >3 × ULN. g. Serum creatinine >2 × ULN.
- Has received total parenteral nutrition or albumin in the last 30 days prior to randomization.
- Has any unstable or uncontrolled cardiovascular disorder, heart failure moderate to severe (New York Heart Association Class III or IV), any pulmonary, hepatic, renal, gastrointestinal, genitourinary, hematological, coagulation, immunological, endocrine/metabolic, or other medical disorder that, in the opinion of the Investigator, would confound the study results or compromise patient safety.
- Any persons who are: a. An employee of the study site, Investigator, CRO or Sponsor. b. A first-degree relative of an employee of the study site, the Investigator, CRO, or Sponsor. c. Unable to attend all the study visits or comply with study procedures.
- Within 30 days prior to randomization, has received any of the following for the treatment of underlying disease: a. Non-biologic therapies (e.g., cyclosporine, thalidomide) other than those specifically listed in Inclusion Criterion 11. b. A non-biologic investigational therapy. c. An approved non-biologic therapy in an investigational protocol.
- Has received any investigational or approved biologic or biosimilar agent within 60 days or 5 half-lives, prior to randomization (the choice is based on the Investigator’s discretion).
- Has had prior exposure to approved or investigational anti integrin antibodies (e.g., natalizumab, efalizumab, etrolizumab, AMG-181, anti-MAdCAM-1 antibodies) or anti-CD20 antibodies (e.g., rituximab).
- Evidence of abdominal abscess or toxic megacolon at the Screening Visit.
- Extensive colonic resection, subtotal or total colectomy.
- History of ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine.
- History or evidence of colonic mucosal dysplasia.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Bulgaria | Not Recruiting | 13 Jun 2023 | 15 |
 Czechia | Not Recruiting | 13 Jun 2023 | 15 |
 Hungary | Not Recruiting | 13 Jun 2023 | 40 |
 Latvia | Not Recruiting | 13 Jun 2023 | 15 |
 Poland | Not Recruiting | 13 Jun 2023 | 440 |
 Romania | Not Recruiting | 13 Jun 2023 | 15 |
 Slovakia | Not Recruiting | 13 Jun 2023 | 10 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
VEDOLIZUMAB | Test | — | IV INFUSION | 300 | 46 | SUB30452 |
Entyvio 300 mg powder for concentrate for solution for infusion | Comparator | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | IV INFUSION | 300 | 46 | PRD1598541 |