Study Evaluating AZD7798 for Treatment in Crohn's Disease Patients With an Ileostomy

A Participant- and Investigator-blind, Randomized, Placebo-controlled Phase II Study to Evaluate Safety, Tolerability, and Mucosal Repair With AZD7798 in Patients With Active Ileal Crohn's Disease and an Ileostomy (CALLISTO)

The purpose of this study is to evaluate safety, tolerability, and effect on mucosal repair of AZD7798 compared with placebo in participants with active ileal Crohn's disease and an ileostomy.

This is a participant-and investigator-blind, randomized, parallel-group, placebo controlled phase II study designed to evaluate safety, tolerability, and mucosal repair with AZD7798 in participants with active ileal Crohn's disease and an ileostomy. This study will include a screening period, an induction period, an open-label maintenance period, and a follow-up period. Approximately 30 participants will be randomized globally to receive either AZD7798 or placebo during 12-week participant- and investigator- blind induction period. At week 12 after induction period, all eligible participants will enter 40-week open label maintenance period. Follow-up visits will take place 8 weeks and 18 weeks after the last dose of study intervention, whether this occurs during the induction period or the open-label maintenance period.

Inclusion Criteria:

• 18 to 80 years of age.
• Diagnosis of Crohn's disease established with clinical AND at least one of imaging, endoscopic, and/or histopathologic evidence.
• Ileostomy (including Kock pouch) for at least 3 months.
• Prior to screening endoscopy, clinical suspicion of active ileal inflammation based on at least one of the following: previous endoscopy, imaging (CT, MRI, IUS), or FCP above upper reference limit.
• Active ileal Crohn's disease as determined by active intestinal mucosal inflammation, as demonstrated on video recorded ileoscopy performed during the screening period and scored by a blinded central reader with agreement on the SES CD ≥ 4 of the ileal segment from 5 to 25 cm (20cm length) proximal to the stoma. Participants with inflammation in additional intestinal segments are not excluded.
• Capable of giving signed informed consent.

Exclusion Criteria:

• Concomitant additional gastrointestinal luminal inflammatory diseases including, but not limited to, infectious enteritis, ischaemic bowel, inflammation and strictures caused by previous radiation therapy

• Strictures/stenoses preventing passage of endoscope throughout the specified segment (up to 25 cm of ileum)

• Short bowel syndrome

• Within 3 months prior to screening:

  1. Diagnosis of peritonitis or need treatment of peritonitis
  2. Bowel perforation or evidence of obstruction

• All intrabdominal, cutaneous and perianal/perirectal abscesses and fistulae are excluded with exception of: cutaneous and perianal/perirectal abscesses and/or fistulae which are adequately drained 4 weeks prior to randomization, and intra-abdominal fistulae between bowel segments only without complications

• Ongoing or expected nutritional dependency on total enteral or parenteral nutrition during study (partial nutrition acceptable).

• In participants with any remaining colon and/or rectum, evidence of an increased risk of colorectal cancer, including:

  1. Adenomatous colonic/rectal polyps that have not been removed
  2. Intestinal dysplasia
  3. Not undertaking appropriate surveillance, if indicated, for colorectal dysplasia/malignancy
  4. Family history of early onset colorectal cancer, established diagnosis of HNPCC pancolitis for >8years duration without up-to-date colorectal cancer surveillance (can be performed during screening endoscopy if considered clinically appropriate by Investigator)

• Reversal of ileostomy or formation of J-pouch planned prior to end of study period.

• High-output stoma (eg, > 2000 mL/24 hours) associated with volume depletion and/or electrolyte disturbance to the extent that, in the opinion of the Investigator, it may put the participant at undue risk because of participation in the study, or impact their ability to participate in the study or interfere with the interpretation of study data.

• Any of the following treatments within the specified time period:

  1. An anti-TNF biologic within 8 weeks prior to randomization, unless therapeutic drug monitoring is performed, and drug concentrations are undetectable.
  2. Any biologic targeting immune response other than an anti-TNF (including vedolizumab and ustekinumab) within 12 weeks prior to randomization unless validated therapeutic drug monitoring is performed, and drug concentrations are indetectable. Biologics not targeting immune response (eg, denosumab) will not be contraindicated.
  3. Other advanced small molecule treatments for Crohn's disease (including JAK inhibitors or S1P modulators) within 4 weeks prior to randomization
  4. Cyclosporine, mycophenolate mofetil, sirolimus (rapamycin), thalidomide, or tacrolimus within 4 weeks prior to randomization
  5. Treatment with apheresis (eg, Adacolumn, Cellsorba) within 4 weeks prior to randomization
  6. Administration of any live vaccine within 4 weeks prior to randomization, or planned administration of any such vaccine during the study
  7. Faecal microbiota transplantation within 4 weeks prior to randomization
  8. Regular intake of NSAIDs within 12 weeks prior to screening ileoscopy and during the study (defined as at least times per week for more than 3 months; not applicable to daily aspirin use up to 325 mg per day)
  9. Lymphocyte-depleting treatment, including, but not limited to rituximab, within 12 months prior to randomization

• Any changes in dosing of the following medications prior to screening ileoscopy as outlined

  1. 5-aminosalicylates within 2 weeks
  2. Oral corticosteroids within 2 weeks. Also excluded if on stable dosing of steroids exceeding the following dose equivalents:

  (i) Systemic steroids > 20 mg/day prednisolone dose or equivalent (ii) Locally targeted steroids exceeding maximum budesonide dose or equivalent [9 mg/day] (c) Immunomodulators (thiopurines or methotrexate) within 4 weeks (d) Antibiotic therapy for the treatment of Crohn's disease, eg, ciprofloxacin or metronidazole within 2 weeks (e) Probiotics within 2 weeks

• Evidence of recent or currently active infection, including use of IV or oral antibiotics for documented infection within 30 days prior to screening. Topical antimicrobials or antimicrobials for the treatment of uncomplicated urinary tract infection may be allowed at the Medical Monitor's discretion.

• Evidence of chronic hepatitis B or C infection defined as:

  1. HBV: HBsAg positive or HBcAb positive
  2. HCV: Positive result for HCV Ab is exclusionary unless HCV RNA is undetectable, and at least 12 weeks post anti-viral treatment of HCV (if treated).

• History of TB (active or latent) unless an appropriate course of treatment has been completed.

• Positive diagnostic TB test at screening (defined as positive QuantiFERON test). In cases where the QuantiFERON test is indeterminate, the patient may have the test repeated once and if their second test is negative, they will be eligible. In the event a second test is also indeterminate, the Investigator has the option to undertake PPD testing. If the PPD reaction is <5mm, then the patient is eligible. If the reaction is ≥ 5 mm, or PPD testing is not undertaken, the patient is not eligible. If there has been a history of completed treatment for TB and, per specialist opinion, a positive QuantiFERON test reflects previous infection only and no current active or latent infection, the participant could be included.

• History of serious opportunistic infection (eg, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, aspergillosis) within 12 months prior to screening

• Symptomatic herpes zoster infection within 3 months prior to screening.

• Positive C. difficile toxin test at screening.

• Any identified immunodeficiency, congenital and/or acquired aetiologies, including, but not limited to:

  1. HIV infection (patients with positive results of HIV testing by the central laboratory will be excluded)
  2. Splenectomy
  3. Previous allogenic bone marrow transplant or history of organ or cell-based transplantation (eg, islet cell transplantation or autologous stem cell transplantation) with the exception of corneal transplant
  4. Primary immune deficiency diseases, excluding selective IgA deficiency.

• Abnormal laboratory results at screening:

  1. Haemoglobin < 8 g/dL
  2. Neutrophil count < 1,500/μL (or < 1.5 × 109/L); a re-test is allowed during screening in cases of mild neutropenia clinically suspected to be transient
  3. Lymphocytes < 500/μL (or < 0.5 × 109/L)
  4. Liver function tests: AST/ALT/ALP > 2 × ULN; or TBL ≥ 1.5 × ULN (isolated bilirubin > 1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%)
  5. eGFR according to CKD-EPI formula < 30 mL/min
  6. Any other abnormal laboratory results at screening, which, in the opinion of the Investigator, will prevent the participant from completing the study or will interfere with the interpretation of the study results

• Prolonged QTcF interval > 450 ms (or > 480 ms for patients with bundle branch block) or congenital long-QT syndrome or family history of long-QT syndrome or sudden cardiac death in age < 40 years. In case of borderline result or concern for artifact, triplicate ECGs should be collected within a 10-minute period, and the averaged value calculated for decision making.

• Clinically significant cardiovascular conditions including:

  1. Acute coronary syndrome (acute myocardial infarction, unstable angina), coronary intervention with percutaneous coronary intervention/coronary artery bypass surgery, stroke, transient ischaemic attack within 6 months prior to screening
  2. Decompensated heart failure requiring hospitalisation, or Class III/IV heart failure, within 6 months prior to screening
  3. Untreated second degree, Mobitz II or third degree atrioventricular-block, significant sinus node dysfunction/pause or therapy-requiring tachyarrhythmia. Patients with atrial fibrillation/flutter and optimally controlled ventricular rate (resting rate < 100 bpm) may be eligible as judged by the Investigator
  4. Hypertrophic cardiomyopathy or clinically significant valvular heart disease which, in the opinion of the Investigator, will prevent the patient from completing the study or will interfere with the interpretation of the study results.

• Reproduction:

  1. Pregnant and breastfeeding participants, or those planning to breastfeed during the study
  2. FOCBP, unless they agree to complete abstinence or to use a highly effective contraceptive method AND barrier method from enrollment until 18 weeks following last drug administration. FONCBP may be included.

• Current malignancy or history of malignancy, except for:

  1. Basal cell carcinoma, localised squamous cell carcinoma of the skin, or in situ carcinoma of the cervix are eligible provided the patient is in remission and curative therapy was completed at least 12 months prior to screening;
  2. Other non-gastrointestinal malignancies are eligible provided that the patient is in remission and curative therapy was completed at least 5 years prior to screening.

• Current significant major or unstable respiratory disease, heart disease, cerebrovascular disease, haematological disease, hepatic disease including large duct primary sclerosing cholangitis with jaundice, recurrent cholangitis or cirrhosis, renal disease, gastrointestinal disease, or other major disease other than active Crohn's disease. Gilbert's syndrome is not exclusionary. Small duct primary sclerosing cholangitis is not exclusionary if liver biomarkers are normal and there is no concern for cirrhosis.

• Current enrolment in another interventional study or treatment with any investigational drug within 4 months (or 5 half-lives, whichever is longer) prior to screening

• Unstable lifestyle factors, such as alcohol use to excess or recreational drug use, to the extent that in the opinion of the Investigator they would interfere with the ability of a patient to complete the study.

• Patients committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.

• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)

• Judgement by the Investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.

• Previous randomization in the present study.

• Investigator concerns regarding patient's willingness and ability to attend all study visits, comply with the study procedures, read in order to complete questionnaires, or to complete the study period.

• Hypersensitivity to the IMP or any of its excipients.