Efficacy and Safety Study of Ontamalimab as Induction Therapy in Participants With Moderate to Severe Crohn's Disease (CARMEN CD 306)
Condition: Crohn's Disease
MeSH terms: Crohn Disease
Intervention: Ontamalimab; Placebo
Intervention description: Subcutaneous injection of ontamalimab will be administered using a prefilled syringe.; Subcutaneous injection of placebo matched with ontamalimab will be administered using a prefilled syringe.
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 34.0
Sex: All
Minimum age: 16 Years
Maximum age: 80 Years
Healthy volunteers: No

Summary:

      The purpose of this study is to evaluate the efficacy and safety of Ontamalimab in inducing
      clinical remission and endoscopic response in participants with moderate to severe Crohn's
      Disease.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Participants must be between greater than or equal to (> =) 16 and less than or equal
             to (<=) 80 years of age; participants less than (<) 18 years of age must weigh >=40 kg
             and must have body mass index >=16.5 kilogram per meter square (kg/m^2)

          -  Participants must have active moderate to severe ileal (terminal ileum), ileocolic, or
             colonic CD at baseline (Visit 2) as defined by:

               1. CDAI score between 220 and 450 (inclusive) AND

               2. Meeting the following subscores in the 2 item PRO:

             i. Abdominal pain subscore >= 5 (average worst daily pain on the 11 point NRS) and
             abdominal pain subscore >= 2 (average daily pain on the 4-point abdominal pain
             variable of CDAI) over the 7 most recent days out of the 10 days before colonoscopy
             preparation (may or may not be contiguous) AND/OR ii. Average of the daily stool
             frequency subscore >=4 of type 6/7 (very soft stools/liquid stools) as shown in the
             BSFS over the 7 most recent days out of the 10 days before colonoscopy preparation
             (may or may not be contiguous) c. Presence of ulcerations that are characteristic to
             CD, as determined by a colonoscopy performed during screening, and as defined by the
             SES-CD >6 (SES CD >=4 for isolated ileitis) Note that the participant must be
             confirmed as meeting the CDAI score and PRO subscore requirements before a colonoscopy
             is done

          -  Participants must have a documented diagnosis (endoscopic with histology) of CD for
             >=3 months before screening. Documented diagnosis is defined as:

               1. A biopsy report in which the description of the histological findings is
                  consistent with the CD diagnosis AND

               2. A report documenting disease duration based upon prior colonoscopy Note: If a
                  biopsy report is not available in the source document at the time of screening, a
                  biopsy must be performed during the screening colonoscopy and the histology
                  report should be consistent with the CD diagnosis. If the histology description
                  does not support the CD diagnosis at this time point, the participant should not
                  be randomized

          -  Participants must be willing and able to undergo a colonoscopy during screening after
             all other inclusion criteria have been met

          -  Participants must have had an inadequate response to, or lost response to, or had an
             intolerance to at least 1 conventional treatment such as sulfasalazine or mesalamine
             (5-aminosalicylic acid [5-ASA]), glucocorticoids, or immunosuppressants (azathioprine
             [AZA], 6-mercaptopurine [6-MP] or methotrexate [MTX]) or anti-tumor necrosis factor
             (anti-TNF). Participants who have had an inadequate response to sulfasalazine or
             mesalamine should have also failed at least 1 other conventional treatment such as
             glucocorticoids

          -  Participants receiving any treatment(s) for CD are eligible provided they have been,
             and are anticipated to be, on a stable dose for the designated period of time

          -  Participants are males or nonpregnant, nonlactating females who, if sexually active,
             agree to comply with the contraceptive requirements of the protocol, or females of
             nonchildbearing potential. Males and females of reproductive potential who are
             sexually active must agree to use appropriate contraception (ie, highly effective
             methods for female and medically appropriate methods for male study participants, for
             the duration of the study

        Exclusion criteria:

          -  Participants with indeterminate colitis, microscopic colitis, nonsteroidal
             anti-inflammatory drug-induced colitis, ischemic colitis, infectious colitis, or
             clinical/histologic findings suggestive of UC

          -  Participants with colonic dysplasia or neoplasia. (Participants with prior history of
             adenomatous polyps will be eligible if the polyps have been completely removed)

          -  Participants with past medical history or presence of toxic megacolon

          -  Participants with presence of enterovesical (ie, between the bowel and urinary
             bladder) or enterovaginal fistulae

          -  Participants with current symptomatic diverticulitis or diverticulosis

          -  Participants with clinically significant obstructive colonic stricture, or who have a
             history of bowel surgery within 6 months before screening, or who are likely to
             require surgery for CD during the treatment period. Participants who have undergone
             previous colonic resection or ileocolectomy more than 6 months before screening must
             have at least 25 cm of colon remaining

          -  Participants with past medical history of multiple small bowel resections resulting in
             clinically significant short bowel syndrome

          -  Participants requiring total parenteral nutrition

          -  Participants with past medical history of bowel surgery resulting in an existing or
             current stoma. Participants who had a j-pouch are excluded as a j-pouch could result
             in a stoma

          -  Participants have had prior treatment with ontamalimab (formerly PF-00547659; SHP647)

          -  Participants with known or suspected intolerance or hypersensitivity to the
             investigational product(s), closely related compounds, or any of the stated
             ingredients

          -  Participants have received any nonbiologic treatment with immunomodulatory properties
             (other than AZA, 6-MP, or MTX) or continuous antibiotics (>2 weeks) for the treatment
             of CD within 30 days before baseline (Visit 2)

          -  Participants have received anti-TNF treatment within 60 days before baseline (Visit 2)

          -  Participants have received any biologic with immunomodulatory properties (other than
             anti-TNFs) within 90 days before baseline (Visit 2)

          -  Participants have ever received anti-integrin/adhesion molecule treatment (eg,
             natalizumab,vedolizumab, efalizumab, etrolizumab, or any other investigational
             anti-integrin/adhesion molecule)

          -  Participants have received lymphocytes apheresis or selective monocyte granulocytes
             apheresis within 60 days before baseline (Visit 2)

          -  Participants have received enteral nutrition treatment within 30 days before baseline
             (Visit 2)

          -  Participants have received parenteral or rectal glucocorticoids or rectal 5-ASA within
             14 days before screening colonoscopy

          -  Participants have taken >20 milligram per day(mg/day) of prednisone, >9 mg/day of
             budesonide, or equivalent oral systemic corticosteroid dose within 14 days before
             baseline (Visit 2) or have taken >=40 mg/day of prednisone or equivalent oral systemic
             corticosteroid dose within 6 weeks before baseline (Visit 2)

          -  Participants have participated in other investigational studies within either 30 days
             or 5 half-lives of investigational product used in the study (whichever is longer)
             before screening (Visit 1)

          -  Participants have received a live (attenuated) vaccine within 30 days before the
             baseline visit (Visit 2)

          -  Participants with active enteric infections (positive stool culture and sensitivity),
             Clostridium difficile infection or pseudomembranous colitis (subjects with C.
             difficile infection at screening may be allowed retest after treatment), evidence of
             active cytomegalovirus infection or Listeria monocytogenes, known active invasive
             fungal infections such as histoplasmosis or parasitic infections, clinically
             significant underlying disease that could predispose the subjects to infections, or a
             history of serious infection (requiring parenteral antibiotic and/or hospitalization)
             within 4 weeks before the baseline visit (Visit 2)

          -  Participants with abnormal chest x-ray or other imaging findings at screening (Visit
             1), such as presence of active tuberculosis (TB), general infections, heart failure,
             or malignancy (A chest x-ray, computed tomography scan, etc, performed up to 12 weeks
             before study entry [screening, Visit 1] may be used if available; documentation of the
             official reading must be located and available in the source documentation)

          -  Participants with evidence of active or latent infection with Mycobacterium
             tuberculosis (TB) or participants with this history who have not completed a generally
             accepted full course of treatment before baseline (Visit 2) are excluded all other
             participants must have either the Mantoux (purified protein derivative [PPD])
             tuberculin skin test or interferon-gamma release assay (IGRA) performed

        Participants who have no history of previously diagnosed active or latent TB are excluded
        if they have a positive Mantoux (PPD) tuberculin skin test (ie >= 5 millimeter [mm]
        induration) or a positive IGRA (the latter to be tested at the site's local laboratory)
        during screening or within 12 weeks before screening If the IGRA cannot be performed
        locally, a central laboratory may be used, with prior agreement from the sponsor:

          1. An IGRA is strongly recommended for participants with a prior Bacillus Calmette-Guérin
             vaccination but may be used for any participant Documentation of IGRA product used and
             the test result must be in the participant's source documentation if performed locally
             Acceptable IGRA products include QuantiFERON-TB Gold Plus In-Tube Test

          2. If the results of the IGRA are indeterminate, the test may be repeated, and if a
             negative result is obtained, enrollment may proceed In participants with no history of
             treated active or latent TB, a positive test on repeat will exclude the
             participantParticipants with a history of active or latent TB infection must follow
             instructions for "Participants with a prior diagnosis of active or latent TB are
             excluded unless both of the following criteria are met" in this criterion

          3. Participants with repeat indeterminate IGRA results, with no prior TB history, may be
             enrolled after consultation with a pulmonary or infectious disease specialist who
             determines low risk of infection (ie, participant would be acceptable for
             immunosuppressant [eg, anti-TNF] treatment without additional action) This
             consultation must be included in source documentation Results from a chest x-ray,
             taken within the 12 weeks before or during screening (Visit 1)must show no
             abnormalities suggestive of active TB infection as determined by a qualified medical
             specialist

               -  Participants with a pre-existing demyelinating disorder such as multiple
                  sclerosis or new onset seizures, unexplained sensory motor, or cognitive
                  behavioral, neurological deficits, or significant abnormalities noted during
                  screening

               -  Participants with any unexplained symptoms suggestive of PML based on the
                  targeted neurological assessment during the screening period

               -  Participants with a transplanted organ. Skin grafts to treat pyoderma gangrenosum
                  are allowed

               -  Participants with a significant concurrent medical condition at the time of
                  screening (Visit 1) or baseline (Visit 2), including, but not limited to, the
                  following:

        a. Any major illness/condition or evidence of an unstable clinical condition (eg, renal,
        hepatic, hematologic, GI [except disease under study], endocrine, cardiovascular,
        pulmonary, immunologic [eg, Felty's syndrome], or local active infection/infectious
        illness) that, in the investigator's judgment will substantially increase the risk to the
        subject if he or she participates in the study b. Cancer or history of cancer or
        lymphoproliferative disease within the previous 5 years (other than resected cutaneous
        basal cell carcinoma, squamous cell carcinoma, or carcinoma in situ of the uterine cervix
        that has been treated with no evidence of recurrence) c. Presence of acute coronary
        syndrome (eg, acute myocardial infarction, unstable angina pectoris) within 24 weeks before
        screening (Visit 1) d. History of significant cerebrovascular disease within 24 weeks
        before screening (Visit 1)

          -  Participants who have had significant trauma or major surgery within 4 weeks before
             the screening (Visit 1), or with any major elective surgery scheduled to occur during
             the study.

          -  Participant with evidence of cirrhosis with or without decompensation (ie, esophageal
             varices, hepatic encephalopathy, portal hypertension, ascites)

          -  Participant with primary sclerosing cholangitis

          -  Participant with evidence of positive hepatitis B surface antigen (HBsAg) or hepatitis
             B core antibody (HBcAb) Note: if a subject tests negative for HBsAg, but positive for
             HBcAb, the subject would be considered eligible if no presence of hepatitis B virus
             (HBV) DNA is confirmed by HBV DNA polymerase chain reaction (PCR) reflex testing
             performed in the central laboratory

          -  Participant with chronic hepatitis C virus (HCV) (positive HCV antibody [HCVAb] and
             HCV RNA) Note: Participant who are HCVAb positive without evidence of HCV RNA may be
             considered eligible (spontaneous viral clearance or previously treated and cured
             [defined as no evidence of HCV RNA at least 12 weeks prior to baseline])

          -  Participant with any of the following abnormalities in hematology and/or serum
             chemistry profiles during screening (Visit 1) Note: Screening laboratory tests, if the
             results are considered by the investigator to be transient and inconsistent with the
             subject's clinical condition, may be repeated once during the screening period for
             confirmation results must be reviewed for eligibility prior to the screening
             colonoscopy procedure

               1. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels >=3.0
                  × the upper limit of normal (ULN)

               2. Total bilirubin level >=1.5 × ULN or >2.0 × ULN if the subject has a known
                  documented history of Gilbert's syndrome

               3. Hemoglobin level less than or equal to(<=80) gram per liter(g/L) (8.0
                  g/deciliter[dL])

               4. Platelet count <=100× 10^9/L (100,000 cells/mm^3) or >=1000 × 10^9/L (1,000,000
                  cells/mm^3)*

               5. White blood cell count <=3.5 × 10^9/L (3500 cells/mm^3)

               6. Absolute neutrophil count <2 × 10^9/L (2000 cells/mm^3)

               7. Serum creatinine level >1.5 × ULN or estimated glomerular filtration rate <30
                  millilter per minute (mL/min)/173 meter square (m^2) based on the abbreviated
                  Modification of Diet in RenalDisease Study Equation Note: if platelet count is
                  <150,000 cells/mm3, a further evaluation should be performed to rule out
                  cirrhosis, unless another etiology has already been identified

          -  Participant with known human immunodeficiency virus (HIV) infection based on
             documented history with positive serological test, or positive HIV serologic test at
             screening, tested at the site's local laboratory in accordance with country
             requirements or tested at the central laboratory Note: A documented negative HIV test
             within 6 months of screening is acceptable and does not need to be repeated

          -  With known human immunodeficiency virus (HIV) infection based on documented history
             with positive serological test, or positive HIV serologic test at screening, tested at
             the site's local laboratory in accordance with country requirements or tested at the
             central laboratory.

          -  Participants who have, or who have a history of (within 2 years before screening),
             serious psychiatric disease, alcohol dependency, or substance/drug abuse or dependency
             of any kind including abuse of medicinal marijuana (cannabis)

        NOTE: The above Inclusion/Exclusion criteria are NOT exhaustive and other Inclusion/
        Exclusion criteria as defined in the protocol may apply.