Ensayos clínicos

Inclusion Criteria:

• Signed Informed Consent Form).
• Age 18–70 years at time of signing Informed Consent Form.
• Body mass index (BMI) of 18 to 35 (kg/m2 ) at screening.
• Ability to comply with the study protocol, in the investigator’s judgment.
• History of medically diagnosed celiac disease that meets at least one of the following three criteria: ­
  • Any change in duodenal villous architecture consistent with celiac disease (e.g., atrophy, blunting, flattening or effacing of villi) and positive celiac serology (must have both);
  • Increased intraepithelial lymphocytes (IEL), positive celiac serology and symptoms or signs responsive to GFD (must have all three). In the context of positive celiac serology, symptoms or signs responsive to GFD, and a positive HLA-DQ2.5 genotype, a duodenal biopsy that shows IELs alone (without change in villous architecture) is sufficient histologic support of the diagnosis of celiac disease;
  • tTG-IgA > 10x ULN, have had a positive celiac serology (i.e., DGP-IgG, DGP-IgA or EMA (endomysial antibody)-IgA) on a separate blood sample, and symptoms or signs responsive to GFD (must have all three).
• Be on a GFD for at least 12 months prior to screening.
• Willing and able to use the electronic patient-reported outcome (ePRO) device.
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use two effective methods of contraception, including at least one method with a failure rate of < 1% per year during the treatment period and for at least 5 half-lives of DONQ52 after the last dose of study drug, and agreement to refrain from donating eggs for the same period. ­ A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). ­ Examples of highly effective contraceptive methods with a failure rate of < 1% per year include; bilateral tubal ligation, male partner sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. ­ A barrier method may be used as the second contraceptive method.  The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post ovulation methods) and withdrawal are not acceptable methods of contraception.
• Valid results from either central testing or previous testing of blood documenting positive for the HLA-DQ2.5 genotype (HLA-DQA1*05 and HLA-DQB1*02) (homozygous or heterozygous) ­ Previous testing of blood must be performed at a Clinical Laboratory Improvement Amendments (CLIA) or equivalently certified laboratory. The details of the genotype assay methods must be recorded in the CRF. ­ Patients without available previous test results for HLA genotyping must submit a blood sample to determine whether an eligible HLA-DQ2.5 genotype is present by the central testing.
• Experienced at most mild symptoms of celiac disease within the month before screening. At screening patients are required to have either no symptoms or less than 2 mild symptoms on the CDSD scale in the 14 days recording period. ­
  • If the investigator determines that symptoms reported on the CDSD scale at screening are not due to celiac disease, the symptoms can be excluded from the judgment of patient eligibility.;
  • CDSD record reported in the original screening period can be used for eligibility judgement of sponsor-approved selective extension of the screening or rescreening when patient report the CDSD scale for the 14 days within 28 days prior to Day 1 and those frequency and severity of symptoms reported on CDSD during that time meet the criteria.

Exclusion Criteria:

• Refractory celiac disease according to “The Oslo definitions for coeliac disease and related terms” (i.e., persistent or recurrent malabsorptive symptoms and signs with villous atrophy despite a strict GFD for more than 12 months).
• Positive for any of the 3 serology tests within the month before screening or during screening period ­ Tissue transglutaminase-2 [tTG2-IgA] (≥10 U/mL; normal range: 0–3.99 U/mL), but weak positive (4–10 U/mL) is acceptable. ­ Deamidated gliadin peptide-IgA [DGP-IgA] (≥30 U; normal range: 0–20 U), but weak positive (20–30 U) is acceptable. ­ Deamidated gliadin peptide-IgG [DGP-IgG] (≥30 U; normal range: 0–20 U), but weak positive (20–30 U) is acceptable.
• History of hypersensitivity reactions including anaphylaxis to a biologic medical product or any of the excipients.
• Any medical condition that, in the opinion of the investigator, would impact the immune response (other than celiac disease), confound interpretation of study results, or pose an increased risk to the patient.
• Previous participation in this study.
• Participation in an investigational study involving non-biologic therapy within 30 days or 5 half-lives of the investigational product (whichever is greater) prior to screening.
• Participation in an investigational study involving biologic therapy (including vaccines) within 90 days or 5 half-lives of the investigational product (whichever is greater) prior to screening unless they are known to have only received placebo.
• Participation in immune tolerance study where they received an immune-tolerogenic agent for celiac disease within 12 months prior to screening.
• Helicobacter pylori tests that indicate current infection.
• Any known active infection (with the exception of fungal nail infections or oral herpes).
• Any diseases known to increase the risk of developing serious complications from infectious disease (e.g., severe asthma, uncontrolled type 1 and type 2 diabetes).
• Any major episode of infection requiring hospitalization or treatment with intravenous (IV) anti-microbials within 8 weeks prior to and during screening or treatment with oral anti-microbials within 2 weeks prior to and during screening. ­ Antimicrobials include antifungal, antibacterial, and antiviral agents.
• History of invasive fungal infections such as Candida or Aspergillus (excluding thrush or other superficial fungal infections) within 6 months prior to screening.
• History of any other opportunistic infections within 12 weeks prior to screening.
• History of organ transplant.
• History of or currently active primary or secondary immunodeficiency.
• Positive human immunodeficiency virus (HIV) antibody test at screening.
• Positive hepatitis B surface antigen (HBsAg) test or positive both total hepatitis B core antibody test and hepatitis B virus deoxyribonucleic acid (DNA) test at screening.
• Positive hepatitis C virus (HCV) antibody test at screening, except in patients who have negative results for HCV ribonucleic acid (RNA) test at screening.
• Positive for tuberculosis (TB) during screening or within 3 months prior to screening, as a positive QuantiFERON®-TB Gold test (QFT) or (if QFT is not available) a positive purified protein derivative (PPD) skin test according to Centers for Disease Control and Prevention guidelines, with the following exceptions: ­ Patients with a history of Bacillus Calmette-Guérin (BCG) vaccination who have a positive PPD skin test will not be excluded if they have a negative QFT at screening ­ Patients who have a positive or indeterminate QFT and patients with no history of BCG vaccination who have a positive PPD skin test will not be excluded if they meet all of the following criteria
  • No symptoms consistent with TB;
  • Documented history of a completed course of adequate prophylaxis (completed treatment for latent TB) per local standard of care prior to screening;
  • No known exposure to a case of active TB after most recent prophylaxis;
  • No evidence of active TB on chest X-ray performed during screening or within 3 months prior to screening.
• History or presence of an abnormal ECGs that is clinically significant in the investigator’s opinion (for example, bundle-branch blocks, Mobitz type II second- or third-degree atrioventricular block, symptomatic or intervention-required Mobitz type I- or first degree- atrioventricular block or evidence of prior myocardial infarction).
• Clinically significant ECG abnormalities at screening such as the following: ­ The average QT interval with Fridericia’s correction of triplicate-measurements in supine position at 10-minute rest > 450 msec for male and > 470 msec for female ­ Bradycardia at rest (average heart rate 100 bpm).
• History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as structural heart disease (e.g., severe left ventricular systolic dysfunction, left ventricular hypertrophy), coronary heart disease (symptomatic or with ischemia demonstrated by diagnostic testing), clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of long QT syndrome.
• Current treatment with medications that are known to cause QT interval prolongation.
• Pregnant or breastfeeding, or intending to become pregnant during the study or for at least 5 half-lives of DONQ52 after the final dose. ­ Women of childbearing potential must have a negative serum pregnancy test result within 30 days prior to initiation of DONQ52/placebo administration.
• History of hyposplenism. ­ Patients with encapsulated bacteria vaccine (e.g., haemophilus influenza type b vaccine, pneumococcal conjugate vaccine) will be permitted.
• History of recurrent bacterial, viral, mycobacterial or fungal infections (defined as > 2 similar episodes requiring anti-microbial treatment within the previous 12 months), with the exception of recurrent oral or genital herpes (HSV1/HSV2) or uncomplicated urinary tract infection (excluding pyelonephritis or urosepsis).
• Patients who have ongoing clinically significant manifestations which are dependent on nutrient deficiencies. (e.g. iron, vitamin D, calcium, vitamin B12/B6, folic acid, magnesium, zinc, vitamin K). 29). Any uncontrolled complications of celiac disease (e.g., enteropathy associated T-cell lymphoma, ulcerative jejunitis, intestinal perforation).
• Any uncontrolled other autoimmune disease. ­ Autoimmune thyroid disease that is euthyroid or stable on thyroid replacement therapy is acceptable.
• Any other chronic, active gastrointestinal disease (e.g., inflammatory bowel disease, microscopic colitis, peptic ulcer, gastroesophageal reflux disease, functional dyspepsia, or irritable bowel syndrome).
• Evidence of clinically significant cardiac, neurologic, psychiatric, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled type 1 and type 2 diabetes mellitus), metabolic, or gastrointestinal disease that, in the investigator’s opinion, would preclude patient participation.
• History of cancer, including hematologic malignancy and solid tumors, within 5 years prior to screening. ­ Basal or squamous cell carcinoma of the skin that has been excised and is considered cured and in situ carcinoma of the cervix treated with apparent success by curative therapy > 1 year prior to screening are not exclusionary.
• History of a live attenuated vaccine within 6 weeks prior to screening or requirement to receive these vaccinations at any time during study drug treatment or for at least 5 half-lives of DONQ52 after the final dose of study drug treatment. ­ For Seasonal influenza, H1N1, if the inactivated vaccine formulation is administered, history of vaccination 7 days prior to initiation of DONQ52/placebo dosing or requirement to receive these vaccinations prior to the timing of judgment on cohort / part transition. For COVID-19 vaccination, history of vaccination 14 days prior to screening/ rescreening or requirement to receive these vaccinations prior to the timing of judgment on cohort/part transition.
• Planned surgery during the study (including tooth extraction).
• Illicit drug, recreational drug (including medical use of marijuana / cannabis) or alcohol abuse within 12 months prior to screening, in the investigator’s judgment.
• Blood donation within 6 weeks prior to screening and plasma donation within 2 weeks prior to screening.
• Blood transfusion within 8 weeks prior to screening.
• Poor peripheral venous access.
• The following exclusion criteria are based on screening laboratory tests. Laboratory tests may be repeated once during the screening period unless otherwise indicated: ­ eGFR 1.5 × upper limit of normal (ULN). chronic hepatitis that may progress to cirrhosis, liver cirrhosis or portal hypertension. ­ Total bilirubin >1.5 × ULN (may be repeated if 1.5–3 × ULN). Total bilirubin >2 × ULN, in case that gilbert’s syndrome can be confidently diagnosed, which is unconjugated hyperbilirubinaemia, accompanied by:
  • Conjugated bilirubin is within the normal range and/or < 20% of total bilirubin;
  • Other liver enzymes and albumin are within the normal range;
  • No additional symptoms or signs which suggest hepatobiliary disease;
  • A negative hemolysis screen (normal hemoglobin and reticulocyte count, and no fragmented or abnormal red cells on blood film);
  • Hemoglobin < 10 g/dL (may be repeated if < 10 g/dL);
  • Absolute Neutrophil count (ANC) < 1.5 × 10^9 /L (may be repeated if 1.0–1.5 × 10^9 /L);
  • Platelet count < 150 × 10^9 /L (may be repeated if 80–150 × 10^9 /L) ­ IgG < 500 mg/dL (should not be repeated);
  • Serum IgA below detectable range;
  • Abnormalities in hepatic synthetic function tests (e.g., prothrombin time [PT], international normalized ratio [INR], partial thromboplastin time [PTT], albumin) judged by the investigator to be clinically significant.
• Use of immune checkpoint inhibitors (e.g., ipilimumab) within 60 months prior to screening.
• Use of agents that deplete B or T cells (e.g., rituximab, alemtuzumab or visilizumab) within 60 months prior to screening.
• Use of immunomodulatory or immune-suppressing medical treatment during the 6 months prior to screening (e.g., azathioprine, methotrexate, Jak inhibitors or biologics).
• Use of oral or parenteral corticosteroids within the 4 weeks prior to screening. ­ Topical or inhaled corticosteroids are acceptable.
• Use of intravenous (or subcutaneous) immunoglobulin G (IVIG) or plasmapheresis within 4 weeks prior to screening.
• History of myeloablative chemotherapy or bone marrow of stem cell transplantation.
• Chronic nonsteroidal anti-inflammatory drugs (NSAIDs) use ­ Occasional use (< 3 times per week) of NSAIDs or acetaminophen (e.g., for headache, arthritis, myalgias, or menstrual cramps) and aspirin up to 325 mg/day is permitted.
• Planning to initiate to take any new oral probiotic supplements (not including probiotics contained in commercially available food preparations) or to terminate any probiotic supplements which have been taken at screening timing during treatment period
• A patient is eligible if his/her oral probiotic regimen is stable for at least 2 weeks prior to randomization.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 11/16/23. Questions regarding updates should be directed to the study team contact.