Positron emission tomography (PET) study of changes in [11C]AZ14132516 uptake following administration of AZD7798 to healthy participants and patients with Crohn’s disease

Exclusion Criteria

• HEALTHY PARTICIPANTS:
• 1 Current significant major or unstable respiratory disease, heart disease, cerebrovascular disease, hematological disease, hepatic disease, renal disease, gastrointestinal disease, or other major disease.
• 2 History of cancer with the following exceptions
• (a) Solid malignancy with curative therapy completed at least 5 years prior to screening
• (b) Basal cell carcinoma or localized squamous cell carcinoma of the skin or in-situ carcinoma of the cervix, provided that curative therapy was completed at least 12 months prior to screening
• 3 History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, as judged by the Investigator, or history of hypersensitivity to biologic therapies.
• 4 Participants with unstable hypertension (as judged by the Investigator) or symptomatic hypotension, history of pre-syncope or syncope due to orthostatic hypotension and/or induced by change of posture (orthostatic hypotension defined as 25 mmHg decrease in systolic and/or 15 mmHg).
• 5 Significant abnormalities on clinical examination, including neurological and physical examination, vital signs and electrocardiogram (ECG).
• 6 Chemistry, hematology, or urine analysis results that may interfere with the study or present a safety risk to the participant.
• 7 Leukocyte, lymphocyte, or neutrophil counts below the lower limit of normal. A re-test is allowed during screening in cases of mild leukopenia clinically suspected to be transient.
• 8 Abnormal vital signs, after 10 minutes of supine rest as judged by the investigator. As a guide, any readings outside the following should be considered in the evaluation:
• (a) systolic blood pressure (BP) ≥ 150 mmHg
• (b) diastolic BP ≥ 90 mmHg
• (c) heart rate ≤ 35 beats per minute (bpm) or ≥ 100 bpm
• The inclusion of participants meeting the above criteria may be decided on a case-by case basis by the Principal Investigator (PI).
• 9 Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG that may interfere with the interpretation of QTc interval changes. This may include participants with any of the following:
• (a) PR (PQ) interval prolongation of clinical significance as judged by the Investigator
• (b) Intermittent second or third-degree atrioventricular (AV) block (AV block II Mobitz type 1, Wenchebach, while asleep or in deep rest is not disqualifying)
• (c) Incomplete, full, or intermittent bundle branch block (QRS ≤ 110 ms with normal QRS and T wave morphology is acceptable if there is no evidence of left ventricular hypertrophy)
• (d) Abnormal T wave morphology
• (e) Prolonged QTcF ≥ 470 ms or shortened QTcF ≤ 340 ms or a family history of long QT syndrome
• The inclusion of participants meeting the above criteria may be decided on a case-by case basis by the PI.
• 10 Positive hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) serology as defined by:
• (a) Hepatitis B surface antigen (HBsAg) or anti-hepatitis B core antibodies (anti-HBc Ab) positivity
• (b) Anti-hepatitis C virus antibodies (anti-HCV Ab) positivity
• (c) Anti-HIV antibodies (Ab) positivity
• Prior/Concomitant Therapy
• 11 Participants must abstain from taking prescription or non-prescription drugs (including vitamins, recreational drugs, and dietary or herbal supplements) within 7 days or 5 half-lives (whichever is longer) before the start of study intervention until completion of the follow-up visit, unless, in the opinion of the investigator and sponsor, the medication will not interfere with the study.
• 12 Current drug abuse or dependence or positive screen for drugs of abuse at screening visit.
• 13 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
• 14 Suffers from claustrophobia that limits the ability to undergo the scanning procedure.
• 15 Positive Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapid antigen test at screening.
• 16 Any other reason that, in the study PI opinion, prohibits the inclusion of the participants into the study.
• 17 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.
• 18 Live or attenuated vaccine within 4 weeks of Screening and until the end of the follow-up period and until 12 weeks after the end of the follow-up period (1 year for Bacillus Calmette-Guerin [BCG] vaccination).
• 19 An active infection, or history of serious infection within the preceding 28 days.
• 20 Use of antibiotics within 28 days prior to the first administration of investigational medicinal product (IMP), unless, in the opinion of the investigator, the medication will not interfere with the study.
• 21 History of symptomatic herpes simplex (excluding cold sores) or herpes zoster infection within 3 months prior to screening.
• 22 Positive or indeterminate tuberculosis (TB) QuantiFERON test.
• 23 Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 30 days/5 half-lives, whichever is longer, of the first administration of IMP in this study. The period of exclusion begins 30 days/5 half-lives, whichever is longer, after the final dose.
• 24 Participation in a PET imaging research study within last year.
• PARTICIPANTS WITH CROHN’S DISEASE
• 1 Current diagnosis of ulcerative colitis, indeterminate colitis, inflammatory bowel disease unclassified, infectious colitis, or ischemic colitis.
• 2 History of cytomegalovirus colitis within 12 months prior to screening.
• 3 Complications of Crohn’s Disease including short bowel syndrome, strictures/stenoses with symptomatic obstruction or pre-stenotic dilation, or other conditions where surgery may be anticipated during the study period.
• 4 Planned bowel or perianal surgery for Crohn's disease prior to end of study follow up visit.
• 5 Recent bowel resection surgery within 6 months of screening.
• 6 Participants with undrained fistula or abscess, including active perianal disease.
• 7 Positive Clostridium difficile toxin test during screening.
• 8 Current significant major or unstable respiratory disease, heart disease, cerebrovascular disease, hematological disease, hepatic disease, renal disease, gastrointestinal disease, or other major diseases other than active Crohn's disease.
• 9 History of cancer with the following exceptions
• (a) Solid malignancy with curative therapy completed at least 5 years prior to screening
• (b) Basal cell carcinoma or localized squamous cell carcinoma of the skin or in-situ carcinoma of the cervix, provided that curative therapy was completed at least 12 months prior to screening
• 10 History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, as judged by the Investigator, or history of hypersensitivity to biologic therapies.
• 11 Participants with unstable hypertension (as judged by the Investigator) or symptomatic hypotension, history of pre-syncope or syncope due to orthostatic hypotension and/or induced by change of posture (orthostatic hypotension defined as 25 mmHg decrease in systolic and/or 15 mmHg).
• 12 Significant abnormalities on clinical examination, including neurological and physical examination, vital signs and ECG other than signs of Crohn's disease.
• 13 Chemistry, hematology, or urine analysis results that may interfere with the study or present a safety risk to the participant.
• 14 Abnormal vital signs, after 10 minutes of supine rest as judged by the investigator. As a guide, any readings outside the following should be considered in the evaluation:
• (a) systolic BP ≥ 150 mmHg
• (b) diastolic BP ≥ 90 mmHg
• (c) heart rate ≤ 35 bpm or ≥100 bpm
• The inclusion of participants meeting the above criteria may be decided on a case-by case basis by the PI.
• 15 Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG that may interfere with the interpretation of QTc interval changes. This may include participants with any of the following:
• (a) PR (PQ) interval prolongation of clinical significance as judged by the Investigator
• (b) Intermittent second or third-degree AV block (AV block II Mobitz type 1, Wenchebach, while asleep or in deep rest is not disqualifying)
• (c) Incomplete, full, or intermittent bundle branch block (QRS ≤ 110 ms with normal QRS and T wave morphology is acceptable if there is no evidence of left ventricular hypertrophy)
• (d) Abnormal T wave morphology
• (e) Prolonged QTcF ≥ 470 ms or shortened QTcF ≤ 340 ms or a family history of long QT syndrome.
• The inclusion of participants meeting the above criteria may be decided on a case-by case basis by the PI.
• 16 Positive hepatitis B, hepatitis C or HIV serology as defined by:
• (a) HBsAg or anti-HBc Ab positivity
• (b) Anti-HCV Ab positivity and HCV RNA positivity
• (c) Anti-HIV Ab positivity
• Prior/Concomitant Therapy
• 17 Treatment with an anti-tumor necrosis factor (anti-TNF) biologic within 8 weeks of first dose and throughout the study period, unless therapeutic drug monitoring is performed and drug concentrations are undetectable.
• 18 Treatment with any biologic, other than an anti-TNF (including vedolizumab and ustekinumab) within 12 weeks prior to first dose and throughout the study period, unless therapeutic drug monitoring is performed and drug concentrations are undetectable.
• 19 Treatment with rituximab within 12 months prior to first dose and throughout the study period.
• 20 Treatment with Sphingosine-1-phosphate receptor modulators within 12 weeks prior to first dose and throughout the study period.
• 21 Treatment with Janus Kinase inhibitors within 2 weeks prior to first dose and throughout the study period
• 22 Treatment with apheresis (eg, Adacolumn, Cellsorba) within 2 weeks prior to first dose and throughout the study period.
• 23 Treatment with corticosteroids at a total daily dose of greater than 20 mg prednisone or equivalent.
• 24 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
• 25 Suffers from claustrophobia that limits the ability to undergo the scanning procedure.
• 26 Positive SARS-CoV-2 rapid antigen test at screening.
• 27 Any other reason that, in the study PI opinion, prohibits the inclusion of the participants into the study.
• 28 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.
• 29 Live or attenuated vaccine within 4 weeks of screening and until 12 weeks after the end of the follow-up period (1 year for BCG vaccination).
• 30 An active infection, or history of serious infection within the preceding 28 days.
• 31 History of symptomatic herpes simplex (excluding cold sores) or herpes zoster infection within 3 months prior to screening.
• 32 Positive or indeterminate TB QuantiFERON test performed within 1 year of screening (without known interval exposure to TB) or during screening period unless evidence of completion of full treatment course for latent TB with no clinical symptoms or signs indicative of re-activation.
• 33 Chest x-ray with signs of malignancy or latent or active TB infection performed within 1 year of screening (without known interval exposure to TB) or during screening period.
• 34 Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 30 days/5 half-lives, whichever is longer, of the first administration of IMP in this study. The period of exclusion begins 30 days/5 half-lives, whichever is longer, after the final dose.