A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Vedolizumab Subcutaneous as Maintenance Therapy in Patients With Moderately to Severely Active Crohn's Disease Who Achieved Clinical Response Following...
Published: 07/18/2017
General Information:
Full Study Title: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Vedolizumab Subcutaneous as Maintenance Therapy in Patients With Moderately to Severely Active Crohn's Disease Who Achieved Clinical Response Following Open-Label Vedolizumab Intravenous Therapy (Study 3031)
The Primary Objective is to assess the effect of vedolizumab SC maintenance treatment on clinical remission at Week 52 in patients with moderately to severely active CD who achieved clinical response at Week 6 following administration of vedolizumab IV at Weeks 0 and 2.
Eligibility:
Key Inclusion Criteria:
- Diagnosis of Crohn's disease (CD) established at least 3 months prior to screening by clinical and endoscopic evidence corroborated by a histopathology report.
- Moderately to severely CD as determined by a Crohn's Disease Activity Index (CDAI) score of 220 to 450 and 1 of the following: -C-reactive protein (CRP) level greater than 2.87 mg/L OR I-ieocolonoscopy with photographic documentation of a minimum of 3 nonanastomotic ulcerations (each greater than 0.5 cm in diameter) or 10 aphthous ulcerations (involving a minimum of 10 contiguous cm of intestine) consistent with CD OR Fecal calprotectin greater than or equal to 250 mcg/g stool during the screening period in conjunction with computed tomography enterography (CTE), magnetic resonance enterography (MRE), contrast-enhanced small bowel radiography, or wireless capsule endoscopy revealing CD ulcerations (aphthae not sufficient),
- CD involvement of the ileum and/or colon, at a minimum
- Inadequate response with, loss of response to, or intolerance to corticosteroids, immunodulators, or Tumor necrosis factor-alpha (TN-a) antagonists
Key Exclusion Criteria
- Evidence of abdominal abscess Extensive colonic resection, subtotal or total colectomy,
- History of greater than 3 small bowel resections or diagnosis of short bowel syndrome,
- IIeostomy, colostomy, or known fixed symptomatic stenosis of the intestine,
- Prior exposure to investigational or approved non-biologic therapies (eg. cyclosporine, tacrolimus, thalidomide, or tofacitnib) for the treatment of underlying disease within 30 days or 5 half-lives of screening (whichever is longer)
- Prior exposure to any investigational or approved biologic or biosimilar agent within 60 days or 5 half-lives of screening (whichever is longer).
- Prior exposure to vedolizumab
- Surgical intervention for CD required at any time during the study.
- History or evidence of adenomatous colonic polyps that have not been removed, or of colonic mucosal dysplasia.
- Suspected or confirmed diagnosis of ulcerative colitis, indeterminate colitis, ischaemic colitis, radiation colitis, diverticular disease associated with colitis, or microscopic colitis.
- Active infections
- Chronic hepatitis B virus (HBV) or C (HCV) infection, TB (active or latent), or congenital or acquired immunodeficiency
- History of any major neurological disorders, including stroke, multiple sclerosis, brain tumor, or neurodegenerative disease.
Study Details:
Study Description
This is a study to evaluate the efficacy and safety of maintenance treatment with vedolizumab subcutaneous in adult patients with moderately to severe active Crohn’s Disease (CD) who achieved a clinical response at Week 6 with open-label therapy with 300 mg vedolizumab intravenous at Week 0 and 2.
Description of Treatment or Intervention (Mechanism of Action)
- Patients that are either tumor necrosis factor-alpha (TNF-α) antagonist naïve or with TNF-α antagonist failure will be included, ensuring no more than 50% of patients with TNF-α antagonist failure are enrolled.
- Participants will enter a 6 week induction Phase where they will be administered open-label vedolizumab IV 300 mg via infusion at Days 1 and 15, and will then be assessed for a clinical response at Week 6. Participants who achieve a clinical response at Week 6 will be randomly assigned to one of the two treatment groups: Vedolizumab SC 108 mg Q2W, Placebo SC Q2W
- Participants who do not achieve a clinical response at Week 6 will not be randomized in to the Maintenance Period, and will receive a third infusion of vedolizumab IV 300 mg at Week 6. If the patients responds to week 6 dose they will be enrolled into the open label MLN0002SC-3030 study. If the patients does not respond they will be discontinued.
- Patients enrolled at select sites will have the option to undergo voluntary ileocolonoscopy examinations prior to the Week 0 dosing and at Week 52 for the evaluation of an alternate definition of clinical remission.
- The overall time to participate in this study is up to 71 weeks. Participants will make multiple visits to the clinic, plus a final visit 18 weeks after last dose of study drug for a follow up assessment. Participants will also participate in a long-term safety follow up, by phone, at 6 months after the last dose of study drug.
- Patients will have routine clinic visits where Physical exams will be completed, and vitals will be assessed. Blood, urine, and stool samples will be collected at select visits. An ECG will be performed. You may be eligible to participate in a sub study and have an Ileocolonoscopy performed. If you participate in this sub study a biopsy tissue sample will taken. As well, quality of life, and various other patient-reported outcome (PRO) measures will be collected at select visits. You will be asked about your health and any changes to your medications routinely.
- Vedolizumab impairs the migration of gut-homing leukocytes into GI mucosa and acts as a gut-selective immunomodulator.
Patient Participation Requirements
- This study includes a 3 week Screening Period, a 6-week open-label vedolizumab IV Induction Period, and a 46-week randomized, double-blind, placebo-controlled Maintenance Period with vedolizumab SC with final visit at Week 52.
- Eligible patients will be enrolled into the Induction Period at Week 0, will receive open-label infusions of vedolizumab IV 300 mg at Weeks 0 and 2, and will be assessed for clinical response by CDAI at Week 6.
- Patients who achieve a clinical response at Week 6 will be randomized at a 2:1 ratio to receive blinded injections of vedolizumab SC 108 mg or placebo SC Q2W, beginning at Week 6 through Week 50.
- At Week 6, patients receiving oral corticosteroids who achieved a clinical response and are randomized into the maintenance period will begin a corticosteroid tapering regimen.
- Prior to patients self injecting study medication they will receive training from a health care provider on the correct injection technique and how to manage potential hypersensitivity reactions associated with the injections. Patient or caregiver will administer SC injections during the scheduled clinic visits at Weeks 14, 22, 30, 38, 46, and 50 under supervision on the Heath Care Professional (HCP).
- For all dosing that occurs outside the clinic, patients will receive a phone call from study staff within 24 hours prior to every (self) injection for these scheduled doses to administer the PML subjective checklist and inquire about general health status and experience with prior injection.
- Patients will also receive a phone call from their HCP within 12 hours after the home injection at Weeks 10 and 12 to inquire about health status and experience with injections.
- Patients who do not participate in the open label trial or discontinue will enter the Follow-Up Period and complete a final assessment at 18 weeks from the last study drug dose. Additionally, subjects who do not participate in the open label trial will be required to participate in a long-term follow up safety survey by telephone, 6 months after the last dose of study medication.
- Ilecolonoscopy assessment will be performed at sites with appropriate capabilities, in patients who volunteer at screening. The ilecolonoscopy will be performed prior to Week 0 dosing and at Week 52 by a local endoscopist.
Possible Risks & Side Effects
Vedolizumab: The most common side effects from controlled clinical trials, reported in 10% - 20% of patients, include:
- worsening of Crohn’s disease in patients with Crohn’s disease
- worsening of Ulcerative Colitis in patients with Ulcerative Colitis
- common cold
- headache
- joint pain
Other side effects, reported in 2-9% of patients, include:
- nausea
- fever
- stomach pain
- upper respiratory tract infection
- tiredness
- vomiting
- low levels of red blood cells (anemia)
- cough
- back pain
- bronchitis (tubes that carry air to the lungs become inflamed and irritated)
- urinary tract infection
- dizziness
- diarrhea
- sinus infection
- flu
- flu-like illness
- rash
- sore throat
- itching
- swollen ankles
- pains in arms or legs
- stomach flu
- an infected cavity filled with pus near the anus or rectum (anal abscess)
- small tunnel which connects an infected gland inside the anus to an opening on the skin around the anus (anal fistula)
Allergic reactions may occur. Risks associated with an ileocolonoscopy/flexible sigmoidoscopy.
Possible discomforts or risks associated with a colonoscopy or sigmoidoscopy:
- Cramping, pain, abdominal bloating (common).
- Nausea, vomiting, bloating, or rectal irritation caused by the bowel cleanse preparation (common).
- Side effects, like drowsiness following sedative or pain medication (less common).
- Peritonitis (inflammation of the lining of the abdominal cavity) (rare).
- Perforation (a hole) of the intestinal wall (rare). Surgery may be needed if a perforation occurs (rare).
Risks associated with infusion site reactions (IV administration)
- Symptoms associated with an infusion site reaction may include redness, tenderness, warmth, itching, or discomfort. Also, medication may leak out from the blood vessel where it was infused which may cause pain, blistering, and possible skin damage.
Risks associated with injection site reactions (SC administration)
- Symptoms associated with an injection site reaction may include redness, tenderness, warmth, itching, discomfort, bleeding, or a nodule or hardening of the skin in the area surrounding where the medication was administered or severe skin or tissue damage.