2023-510487-12-00招募中2 期
A Double-blind, Placebo-controlled Phase IIa Study to Evaluate the Efficacy and Safety of AZD7798 in Patients with Moderate to Severe Crohn’s Disease (AMALTHEA)
适应症
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 77
- 试验地点
- 68
- 主要终点
- CDAI remission (CDAI score < 150)
研究概览
简要总结
To evaluate the efficacy of AZD7798 induction treatment on Crohn’s Disease Activity Index (CDAI) remission
研究设计
- 分配方式
- Not Applicable
- 主要目的
- Open label
- 盲法
- None
入排标准
- 年龄范围
- 18 years 至 65+ years（65+ Years, 18-64 Years）
- 接受健康志愿者
- 是
入选标准
- •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.
排除标准
- •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.
- •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 AZD
- •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.
- •Known symptomatic strictures or bowel stenoses or strictures preventing passage of endoscope throughout the colon.
- •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.
- •Any complications of Crohn’s disease where surgery is anticipated or planned prior to end of study treatment.
- •Patients committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
- •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.
结局指标
主要结局
CDAI remission (CDAI score < 150)
CDAI remission (CDAI score < 150)
次要结局
- Endoscopic response (> 50% decrease from baseline in Simple Endoscopic Score for Crohn’s Disease (SES-CD) total score). Participants who meet definition of endoscopic remission will be considered to also have met endoscopic response.
- Endoscopic remission *SES-CD total score ≤ 2 OR *SES-CD total score ≤ 4 (≤ 2 with ileal/ileocecal disease) and at least 2-point decrease from baseline with no individual subscore > 1
- Endoscopic score change from baseline
- CDAI response (≥ 100 points decrease from the baseline CDAI or CDAI score < 150 points)
- CDAI score change from baseline
- Symptomatic remission (average daily stool frequency ≤ 2.8 AND average daily abdominal pain ≤ 1, and neither worse than baseline)
- Serum AZD7798 concentration and incidence and titre of anti-drug antibody (ADA) response
研究者
AstraZeneca Clinical Study Information Center
Scientific
AstraZeneca AB
研究点 (68)
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