The main purpose of this study is to show whether in these individuals, treatment with both mirikizumab and tirzepatide, compared with treatment with mirikizumab and placebo, leads to decrease or disappearance of UC symptoms, and loss of at least one-tenth of the overall body weight.

Participation in this study will last up to 61 weeks, including 52 weeks of treatment.

Inclusion Criteria:

• Have had an established diagnosis of UC for ≥3 months before baseline which includes endoscopic evidence of UC and a histopathology report that supports a diagnosis of UC.

• Have moderately to severely active UC as defined by a modified Mayo score (mMS) of 5 to 9 points and endoscopic subscore (ES) of 2 to 3 (confirmed by central review) within 21 days before baseline.

• Participants with a history of UC for greater than or equal to 8 years who have had a surveillance colonoscopy completed within 1 year prior to baseline must have documented negative results for colorectal dysplasia and cancer.

• Have obesity, [body mass index (BMI) 30 kilograms per meter squared (kg/m2)]

• Have overweight (BMI ≥27 kg/m2 to <30 kg/m2) and in the presence of at least 1 of these weight-related comorbid conditions:

  • hypertension
  • Type 2 Diabetes Mellitus (T2DM)
  • dyslipidemia
  • obstructive sleep apnea, or
  • cardiovascular disease.

• Have an inadequate response to, loss of response to, or intolerance to at least 1 of the conventional medication: oral corticosteroids, oral azathioprine (AZA) or 6-mercaptopurine (6-MP), or oral 5-aminosalicylates (for example, mesalamine, sulfasalazine, olsalazine, and balsalazide) and/or who have an inadequate response to or a loss of response to, or are intolerant to advanced therapy for UC, defined as: a biologic or biosimilar medication such as anti-tumor necrosis factor (TNF) antibodies; anti-integrin antibodies, Janus kinase (JAK) inhibitors such as tofacitinib or upadacitinib, sphingosine 1-phosphate receptor 1inhibitors such as etrasimod or ozanimod, or anti-interleukin(IL)-12p40 antibodies, for example, ustekinumab.

Exclusion Criteria:

• Have a current diagnosis of:

  • Crohn's disease
  • inflammatory bowel disease (IBD) unclassified (formerly known as indeterminate colitis), or
  • primary sclerosing cholangitis.

• Have had or will need bowel resection or intestinal or intra-abdominal surgery.

• Have evidence of toxic megacolon, or stricture or stenosis within the colon that cannot be traversed by a sigmoidoscope or colonoscope.

• Have a diagnosis of Type 1 Diabetes Mellitus (T1DM) or have insulin-treated T2DM.

• Have a history of severe hypoglycemia and/or hypoglycemia unawareness within the 6 months prior to screening.

• Have a self-reported change in body weight greater than 5% (gain or reduction) within 3 months prior to screening.

• Have a current or recent acute, active infection.

Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.

Data are available 6 months after the primary publication and approval of the indication studied in the US and EU, whichever is later. Data will be indefinitely available for requesting.

A research proposal should be approved by an independent review panel and researchers should sign a data sharing agreement.

Mirikizumab will be open label, tirzepatide and placebo to match will be blinded.