Efficacy and Safety Evaluation of AZD7798 in Moderate to Severe Crohn's Disease: A Double-Blind, Placebo-Controlled Phase IIa Clinical Trial

Trial ID: 2023-510487-12-00
Protocol: D9690C00005
Sponsor: AstraZeneca AB

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Diseases & Conditions

Crohn's disease

Objectives

The primary objective of this study is to evaluate the **efficacy** of AZD7798 induction treatment on Crohn's Disease Activity Index (CDAI) remission in patients with moderate to severe Crohn's Disease. This is clinically relevant as achieving remission is a critical goal in the management of Crohn's Disease, potentially improving patient outcomes and quality of life.

Secondary objectives include:

Evaluating the efficacy of AZD7798 induction treatment on endoscopic and additional clinical response measures, which can provide further insights into the treatment's impact on disease activity and progression.
Assessing the **pharmacokinetics** (PK) and immunogenicity of AZD7798, which are essential for understanding the drug's absorption, distribution, metabolism, and potential immune response in the body.
Evaluating the safety and tolerability of repeated doses of AZD7798, ensuring that the treatment is not only effective but also safe for long-term use in patients.

Participants

The clinical trial involves a total of **116 participants** diagnosed with **Crohn's Disease**. The study population includes both male and female subjects, aged between **18 to 80 years**. Participants were selected based on their ability to provide informed consent and a confirmed diagnosis of Crohn's Disease through clinical, imaging, endoscopic, or histopathologic evidence. The trial includes individuals with moderate to severe active Crohn's Disease, as indicated by specific Crohn’s Disease Activity Index (CDAI) scores and active intestinal mucosal inflammation. Participants may have a history of intolerance or inadequate response to conventional treatments or corticosteroid dependency. The trial population encompasses individuals with ileal/ileocecal, colonic, or ileocolonic disease. The study does not specify particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, ensuring comprehensive representation of the disease's impact across different demographics.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy and safety of **AZD7798** in patients with moderate to severe **Crohn's Disease**. This is a randomized, double-blind, placebo-controlled Phase IIa study. The trial aims to assess the induction treatment's impact on achieving Crohn’s Disease Activity Index (CDAI) remission. The study is expected to commence recruitment on June 17, 2024, and conclude by May 21, 2027, with a maximum treatment period of 48 weeks for participants.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and disease severity. The screening will involve clinical, imaging, endoscopic, and histopathologic evaluations. Following successful screening, participants will be randomized to receive either AZD7798 or a placebo, administered as a **lyophilisate for solution for injection** via the subcutaneous route. The primary endpoint is achieving CDAI remission, defined as a CDAI score of less than 150. Secondary endpoints include endoscopic response, endoscopic remission, and changes in CDAI and endoscopic scores from baseline.

Study visits will include regular follow-up assessments to monitor efficacy and safety, including evaluations of serum AZD7798 concentration and anti-drug antibody response. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination. Participants may be withdrawn from the study if they experience significant adverse events, fail to adhere to the protocol, or withdraw consent. The expected length of participant involvement is up to 48 weeks, contingent upon individual response and adherence to the study protocol.

Treatment

The clinical trial involves the administration of **AZD7798**, an experimental medication developed by AstraZeneca AB. AZD7798 is formulated as a **lyophilisate for solution for injection**. The active substance, also named AZD7798, is classified as a protein of other origin. The medication is administered via the **subcutaneous route**. The dosing schedule and specific dosage amounts are not explicitly detailed in the provided data, but the maximum treatment period is specified as 48 weeks. Participant compliance with the administration schedule will be monitored throughout the trial to ensure adherence to the protocol.

In addition to the experimental treatment, a **placebo** is utilized as a comparator in this double-blind, placebo-controlled study. The placebo is referred to as "AZD7798 Placebo" in the trial documentation. However, specific details regarding the pharmaceutical form, active substance, and route of administration for the placebo are not provided in the available data. The use of a placebo is integral to the study design, allowing for the assessment of the efficacy and safety of AZD7798 in patients with moderate to severe **Crohn's Disease**. The trial aims to evaluate the induction treatment's impact on the Crohn’s Disease Activity Index (CDAI) remission.

Efficacy

The efficacy of AZD7798 in the treatment of moderate to severe **Crohn's Disease** will be assessed through a double-blind, placebo-controlled Phase IIa clinical trial. The primary endpoint for evaluating efficacy is the achievement of Crohn's Disease Activity Index (CDAI) remission, defined as a CDAI score of less than 150. Secondary endpoints include endoscopic response, characterized by a 50% or greater decrease from baseline in the Simple Endoscopic Score for Crohn's Disease (SES-CD) total score, and endoscopic remission, defined by specific SES-CD score criteria. Additional secondary endpoints involve changes in CDAI scores, symptomatic remission, and serum AZD7798 concentration along with the incidence and titre of anti-drug antibody (ADA) response.

Data collection will involve the use of validated scales such as the CDAI and SES-CD to measure disease activity and endoscopic outcomes. The trial will monitor changes from baseline in these scores to assess the treatment's impact. The schedule for measuring these parameters will be aligned with the trial's protocol, ensuring consistent and reliable data collection throughout the study duration. The trial aims to provide comprehensive insights into the efficacy of AZD7798 in inducing remission and improving clinical outcomes in patients with Crohn's Disease.

Inclusion and Exclusion Criteria

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Inclusion Criteria

18 to 80 years of age inclusive, at the time of signing the ICF.
Diagnosis of Crohn’s disease established with verifiable clinical, AND at least one of imaging, endoscopic, and/or histopathologic evidence.
Capable of giving signed informed consent
A history of at least one of (a) Intolerance or inadequate response to conventional treatment (oral corticosteroid, azathioprine, 6-mercaptopurine, or methotrexate), biologics, or other approved advanced therapy OR (b) Corticosteroid dependency.
Moderate to severe active Crohn’s disease as determined by: (a) CDAI score of 220-450 during screening OR CDAI score of 200-450 during screening for ileal/ileocecal disease AND (b) Active intestinal mucosal inflammation, as demonstrated on centrally-read video-recorded ileocolonoscopy performed during the screening period with the following findings: (I) SES-CD ≥ 6 OR (II) SES-CD ≥ 4 for ileal/ileocecal disease.
Ileal/ileocecal (L1), colonic (L2), or ileocolonic (L3) disease, as classified based on the localisation of active inflammation.

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Exclusion Criteria

Evidence, or clinical suspicion, of other forms of IBD (ulcerative colitis, indeterminate colitis) or concomitant additional active gastrointestinal luminal inflammatory diseases including, but not limited to, infectious colitis, ischaemic colitis, radiation colitis, microscopic colitis, and uncontrolled coeliac disease.
Known symptomatic strictures or bowel stenoses or strictures preventing passage of endoscope throughout the colon.
Any complications of Crohn’s disease where surgery is anticipated or planned prior to end of study treatment.
Evidence of extensive prior gastrointestinal surgical interventions, including: (a) > 2 small bowel resection surgeries (b) Extensive colonic resection: hemicolectomy, subtotal or total colectomy (c) Any intra-abdominal surgery, bowel resection, diversion, placement of ostomy or stoma within 3 months prior to screening. Patients with a current stoma are excluded irrespective of the time from surgery (d) Short bowel syndrome.
Within 3 months prior to screening endoscopy visit: (a) History of toxic megacolon (b) Diagnosis of peritonitis or need for treatment of peritonitis (c) Bowel perforation or evidence of obstruction.
Undrained cutaneous and perianal or perirectal abscesses and fistula, and all intrabdominal abscesses.
Ongoing or expected nutritional dependency on total enteral or parenteral nutrition during study.
Evidence of an increased risk of colorectal cancer, including: (a) Adenomatous colonic polyps that have not been removed (b) Colonic mucosal dysplasia (c) Family history of early onset colorectal cancer, established diagnosis of HNPCC, pancolitis for > 8 years duration without up-to-date colorectal cancer surveillance (can be performed during screening endoscopy if clinically appropriate per Investigator).
Symptomatic oral Crohn’s disease within one year is excluded with the exception of aphthous ulcers not requiring oral specialist intervention.
Any of the following treatments within the specified time period prior to screening endoscopy visit: (a) An anti-TNF biologic within 8 weeks prior to screening endoscopy visit, unless therapeutic drug monitoring is performed, and drug concentrations are undetectable (b) Any biologic targeting immune response (including vedolizumab and ustekinumab) other than an anti-TNF within 12 weeks prior to screening endoscopy visit unless validated therapeutic drug monitoring is performed, and drug concentrations are undetectable. (c) Other advanced small molecule treatments for Crohn’s disease (including JAK inhibitors or S1P modulators) within 4 weeks prior to screening endoscopy visit (d) Cyclosporine, mycophenolate mofetil, sirolimus (rapamycin), thalidomide, or tacrolimus (FK-506) within 4 weeks prior to screening endoscopy visit (e) Treatment with apheresis within 4 weeks prior to screening endoscopy visit (f) Administration of any live vaccine within 4 weeks prior to screening endoscopy visit, or planned administration of any such vaccine over the course of the study (g) Faecal microbiota transplantation within 4 weeks prior to screening endoscopy visit (h) Lymphocyte-depleting treatment, within 12 months prior to screening endoscopy visit (i) Any previous exposure to AZD7798.
Any changes in dosing of the following medications prior to screening endoscopy visit as outlined: (a) 5-aminosalicylates within 2 weeks (b) Oral corticosteroids within 2 weeks or stable doses of steroids exceeding the following dose equivalents: (i) Systemic steroids > 20 mg/day prednisolone equivalent (see Appendix N) (ii) Locally targeted steroids exceeding maximum budesonide dose 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.
Known or suspected history of chronic use of nonsteroidal anti-inflammatory drugs (defined as at least 3 times per week for more than 3 months; not applicable to daily aspirin use up to 325 mg per day).
Evidence of recent or currently active infection, including use of IV or oral antibiotics for documented infection within 30 days prior to screening endoscopy visit. Topical antimicrobials or antimicrobials for the treatment of uncomplicated urinary tract infection may be allowed at the Medical Monitor’s discretion.
Evidence of chronic HBV or HCV infection defined as: (a) HBV: HBsAg positive or HBcAb positive (b) HCV: Positive result for HCV IgM Ab is exclusionary. Positive result for HCV IgG is acceptable only if RNA is undetectable, and at least 12 weeks post-antiviral 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 suggestive of current TB infection.
History of serious opportunistic infection within 12 months prior to screening endoscopy visit
CMV colitis within previous 12 months prior to screening endoscopy visit.
Positive C. difficile toxin stool test at screening.
Symptomatic herpes zoster infection within 3 months prior to screening endoscopy visit.
Any identified immunodeficiency, congenital and/or acquired aetiologies, including, but not limited to: (a) HIV infection (patients with positive results of HIV testing by the central laboratory will be excluded) (b) Splenectomy (c) 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 (d) Primary immune deficiency diseases, excluding selective IgA deficiency.
Abnormal laboratory results at screening: (a) Haemoglobin < 8 g/dL (b) Neutrophil count < 1,500/μL (or < 1.5 × 109/L); a re-test is allowed during screening in cases of mild leukopenia clinically suspected to be transient (c) Lymphocytes < 500/μL (or < 0.5 × 109/L) (d) Liver tests: AST/ALT/ALP > 2 × ULN; or TBL ≥ 1.5 × ULN (isolated bilirubin > 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%) (e) eGFR according to CKD-EPI formula < 30 mL/min (f) Any other abnormal laboratory results at screening, 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: (a) Pregnant and breastfeeding patients, or those planning to breastfeed during the study (b) FOCBP, unless they agree to complete abstinence or to use a highly effective contraceptive method AND barrier method from enrolment until 18 weeks following last drug administration. FONCBP may be included
Prolonged QTcF interval (QTc > 450 ms, or QTc > 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 a 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: (a) 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 endoscopy visit (b) Decompensated heart failure requiring hospitalisation, or Class III/IV heart failure, within 6 months prior to screening endoscopy visit (c) 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 (d) 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.
Current malignancy or history of malignancy, except for: (a) Basal cell carcinoma, localised squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible provided that the patient is in remission and curative therapy was completed at least 12 months prior to screening endoscopy visit. (b) 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 endoscopy visit.
Current significant major or unstable respiratory disease, heart disease, cerebrovascular disease, haematological disease, hepatic disease including large duct primary sclerosing cholangitis, renal disease, gastrointestinal disease, or other major disease other than active Crohn’s disease.
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 endoscopy visit.
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.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Austria	Not Recruiting	17 Jun 2024	4
Belgium	Not Recruiting	17 Jun 2024	4
Bulgaria	Not Recruiting	17 Jun 2024	5
Croatia	Not Recruiting	17 Jun 2024	4
France	Not Recruiting	17 Jun 2024	5
Germany	Not Recruiting	17 Jun 2024	5
Hungary	Not Recruiting	17 Jun 2024	6
Italy	Not Recruiting	17 Jun 2024	4
The Netherlands	Not Recruiting	17 Jun 2024	—
Poland	Not Recruiting	17 Jun 2024	20