Dapansutrile in Diabetes and Diabetes-Related Complications - Dapan-Dia Trial

Prior treatment

• Woman of childbearing potential, or man whose sexual partner(s) is a woman of childbearing potential, who: a. Is or intends to become pregnant (including use of fertility drugs) while participating in the study (i.e., through the Week 30 follow-up call) b. Is lactating/breastfeeding or plans to breastfeed while participating in the study (female subjects only) c. Is not willing to use an acceptable, highly effective method of contraception until all follow-up procedures are complete (see Section 4.11.2 for more details on acceptable forms of contraceptives and required duration of use).
• Any other concomitant medical or psychiatric conditions, diseases, or prior surgeries that, in the opinion of the Investigator, would impair the subject from safely participating in the trial and/or completing protocol requirements.
• History of alcohol or substance abuse within 12 months prior to the Screening Visit or an Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) score ≥ 5 at the Screening Visit.
• Enrolment in any trial investigating a medicinal product within 3 months prior to the Screening Visit.
• Active malignancy or recent malignancy with any systemic anti-cancer treatment (e.g., immunotherapy or chemotherapy) within 6 months prior to the Screening Visit.
• Has a serious illness that resulted in hospitalisation within 30 days prior to the Screening Visit.
• Significant weight loss (> 5 kg) in the 12 weeks prior to the Screening Visit
• Previous myocardial infarction, any cardiac surgery (including percutaneous transluminal coronary angioplasty), coronary artery bypass graft, a documented history of unstable angina, or a cerebrovascular accident within 6 months prior to the Screening Visit.

Other illness

• Diagnosis of type 1 diabetes mellitus.
• Evidence/suspicion of an active infection including cellulitis.
• History of, or known positive for, human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or antibodies to hepatitis C virus (HCV) with a positive polymerase chain reaction (PCR) result for HCV
• Positive test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, if tested, within 4 weeks of the Screening Visit
• Current use of any of the following medications or any other prohibited medications per Table 4-2: a. Oral or injectable corticosteroids (topical hydrocortisone and inhaled corticosteroids are permitted; replacement dosing [15 mg or less hydrocortisone] for primary or secondary adrenal insufficiency is permitted). b. Any drugs specifically targeting the immune system (e.g., tumour necrosis factor [TNF]- blockers, canakinumab, anakinra, rituximab, abatacept, tocilizumab) or oral immune-suppressants (e.g., Janus kinase [JAK] inhibitors, tyrosine kinase 2 [TYK2] inhibitors, methotrexate, hydroxychloroquine). c. Colchicine or sulfasalazine. Low-dose aspirin for cardiovascular disease or anti-thrombotic prophylaxis is allowed. d. Bile acid sequestrants (e.g., cholestyramine or colestipol).
• Has a hypersensitivity or allergy to dapansutrile or other drugs in its class and/or the components of the IMP (dapansutrile tablets or placebo tablets).
• Systolic blood pressure (BP) ≥ 160 mmHg, diastolic BP ≥ 100 mmHg, or resting heart rate (HR) ≥ 100 beats/minute at the Screening Visit. Note: Subjects not meeting BP criteria may be re-screened once within 4 weeks of the initial assessment.
• Clinical symptoms compatible with New York Heart Association (NYHA) class III or IV heart failure.

Lab values

• Clinically significant hepatic disease or alanine aminotransferase (ALT)/aspartate aminotransferase (AST) > 3.5 × the upper limit of the normal (ULN) reference range or total bilirubin > 1.5 × ULN (other than Gilbert’s syndrome) at the Screening Visit.
• Clinically significant anaemia (i.e., haemoglobin concentration < 12.0 g/dL for males or < 11.0 g/dL for females) at the Screening Visit or known diagnosis of haemoglobinopathies (e.g., sickle cell anaemia or thalassaemia).
• Any concurrent conditions or any clinically significant abnormalities identified on the screening physical examination, laboratory tests, or electrocardiogram (ECG) that, in the opinion of the Investigator, may affect the interpretation of the study results, or would otherwise contraindicate participation in a clinical study with a new chemical entity.
• HbA1c value of ≤ 7.5% or ≥ 10.5% at the Baseline Visit/Day 1, as determined at point of care (local laboratory).
• Use of thiazolidinediones (glitazones), pramlintide, or short-acting insulin/insulin analogues (as bolus or premixed insulin) within 12 weeks prior to the Screening Visit. Note: Basal (long-acting) insulin, glucagon-like peptide 1 (GLP-1) receptor agonists, dual glucose-dependent insulinotropic polypeptide (GIP)-GLP-1 receptor agonists, sodium-glucose cotransporter-2 (SGLT2) inhibitors, dipeptidyl peptidase (DPP)-IV inhibitors, metformin, and sulfonylureas are permitted.
• Less than 80% compliance in taking IMP (placebo tablets) by pill count during the Single-Blind Run-In Period, as assessed at the Baseline Visit/Day 1. Note: If compliance is < 80% over the 4-week run-in interval due to a significant life event, the run-in interval may be extended by 2 weeks at the discretion of the Investigator, but then the subject must have ≥ 90% compliance during the final 2 weeks of the Single-Blind Run-In Period to be considered eligible.
• Known diagnosis of advanced chronic kidney disease or known history of renal impairment (e.g., estimated glomerular filtration rate [eGFR] < 45 mL/min/1.73 m2, according to Modification of Diet in Renal Disease [MDRD] equation).

Other

• Thyroid stimulating hormone (TSH) outside of the normal range at the Screening Visit.
• Is an employee, family member, or student of the Investigator or study site.
• For substudy participants only: Has a contraindication to undergoing magnetic resonance [MR]-based assessments. Note: The substudy will only be conducted at select study sites.

• Male and female adults age ≥ 18 and ≤ 75 years at the Screening Visit.
• Diagnosis of T2DM as defined by the criteria of the American Diabetes Association (ADA) Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (see Appendix 1) and recognized by the World Health Organization (WHO, 2019), for at least 3 months prior to the Baseline Visit/Day 1.
• HbA1c value of ≥ 7.7% to ≤ 11.0% at the Screening Visit. Note: Refer to Exclusion Criterion #2) for further HbA1c criteria (assessed at the Baseline Visit/Day 1).
• High-sensitivity C-reactive protein (hsCRP) ≥ 1.5 mg/L at the Screening Visit.
• Body mass index (BMI) between 25 to 40 kg/m2 at the Screening Visit.
• Acceptable overall medical condition to safely participate in the study and complete all study procedures (particularly with regard to cardiovascular, renal, and hepatic conditions), in the opinion of the Investigator.
• Able and willing to provide written informed consent prior to initiation of any study-related procedures.
• Ability, in the opinion of the Investigator, to understand and comply with all the requirements of the study, which includes the ability to use CGM and to complete the 2 hour mixed-meal tolerance test (MMT). Note: The MMT at the Week 8 Visit is optional. Thus, subjects who are willing to perform an MMT only at the Baseline Visit/Day 1 and Week 26 Visit may be enrolled.
• Fasting Glucose levels at run-in and baseline < 11 mmol/l (200 mg/dl)