Randomized, Double-Blind, Placebo-Controlled Study of Dapansutrile for Glycemic Control in Type 2 Diabetes Mellitus Patients on Standard Therapy
- Trial ID
- 2024-511828-14-00
- Protocol
- OLT1177-12
- Sponsor
- Kantonsspital Baden AG
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of dapansutrile as an add-on therapy compared to placebo in reducing HbA1c levels after 26 weeks of treatment in subjects with Type 2 Diabetes Mellitus (T2DM) that is inadequately controlled on standard-of-care anti-diabetic therapy. This is clinically relevant as achieving optimal glycemic control is crucial in managing T2DM and preventing complications associated with the disease.
Secondary objectives include assessing the effect of dapansutrile compared to placebo on **β-cell secretory function**, insulin resistance, and glycemic parameters. Additionally, the study aims to evaluate the safety and tolerability of dapansutrile relative to placebo. These objectives are important for understanding the broader metabolic effects of dapansutrile and ensuring its safety profile in the target population.
Participants
The clinical trial involves a total of **70 participants** diagnosed with **Type II diabetes mellitus**. The study population comprises both male and female adults aged between 18 and 75 years. Participants were selected based on specific inclusion criteria, including a diagnosis of Type II diabetes mellitus for at least three months prior to the baseline visit, an HbA1c value ranging from 7.7% to 11.0%, and a body mass index (BMI) between 18 to 40 kg/m². Additionally, participants were required to have a high-sensitivity C-reactive protein (hsCRP) level of at least 1.5 mg/L. The trial excludes vulnerable populations and focuses on individuals with an acceptable overall medical condition, particularly concerning cardiovascular, renal, and hepatic health, as assessed by the investigator. Participants are expected to comply with study requirements, including the ability to use continuous glucose monitoring (CGM) and complete a mixed-meal tolerance test. The trial does not impose specific lifestyle considerations such as diet or physical activity, but participants must have fasting glucose levels below 9 mmol/L (162 mg/dL) at run-in and baseline.
Plans and Procedures
The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the safety and efficacy of the oral NLRP3 inhibitor **dapansutrile** in subjects with **Type 2 diabetes mellitus**. The primary objective is to assess the efficacy of dapansutrile as an add-on therapy in lowering HbA1c levels after 26 weeks of treatment in subjects whose diabetes is inadequately controlled on standard anti-diabetic therapy. The trial is expected to commence recruitment on October 1, 2024, and conclude by June 30, 2026.
Participants will be involved in the study for a maximum of 26 weeks. The trial will include several key visits: an initial **screening visit** to determine eligibility based on criteria such as age, HbA1c levels, and overall medical condition; a **baseline visit** (Day 1) where eligible participants will be randomized to receive either dapansutrile or placebo; and subsequent **follow-up visits** at Weeks 4, 8, 12, 16, 20, and 26 to monitor changes in HbA1c, fasting plasma glucose, and other metabolic parameters. The **end-of-study visit** will occur at Week 26, marking the completion of the participant's involvement in the trial.
Participants may be withdrawn from the study early if they experience adverse events that compromise their safety, fail to comply with study procedures, or if the investigator deems it necessary for any other reason. The study will employ a placebo that is visually identical to the active drug product but contains no active substance, ensuring the integrity of the double-blind design. The placebo and dapansutrile tablets will be administered orally, with a maximum daily dose of 2000 mg for dapansutrile. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results.
Treatment
The clinical trial involves the administration of **Dapansutrile**, an oral NLRP3 inhibitor, in tablet form. Dapansutrile is chemically synthesized and is identified by the synonym OLT-1177. The pharmaceutical form of Dapansutrile is a tablet, and it is administered orally. The maximum daily dose is 2000 mg, with a total treatment period of 26 weeks. The primary objective of the trial is to evaluate the efficacy of Dapansutrile as an add-on therapy in lowering HbA1c levels in subjects with Type 2 Diabetes Mellitus (T2DM) that is inadequately controlled on standard-of-care anti-diabetic therapy.
The trial also includes a **placebo** group for comparison. The placebo tablets are visually identical to the Dapansutrile tablets but contain no active drug substance. The qualitative composition of the placebo tablets includes microcrystalline cellulose (Avicel PH112) as a diluent, crospovidone (Polyplasdone XL) as a disintegrant, colloidal silicon dioxide (Cab-O-Sil M-5P) as a glidant, and magnesium stearate (HyQual 2257) as a lubricant, with a total weight of 600 mg per unit. The placebo tablets are contained in a white, HDPE, round wide-mouth bottle that is induction sealed and closed with a white polypropylene child-resistant plastic cap with a polyethylene liner. A polyester coil and an appropriately sized desiccant are added to each container to maintain tablet integrity.
Efficacy
The efficacy of dapansutrile in subjects with Type 2 Diabetes Mellitus (T2DM) will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change from baseline in **HbA1c** levels at Week 26, comparing dapansutrile to placebo. Secondary endpoints include changes from baseline in HbA1c at Weeks 4, 8, 12, 16, and 20, as well as changes in fasting plasma glucose at Weeks 4, 8, 12, 16, 20, and 26. Additionally, the study will evaluate changes in β-cell secretory function and insulin sensitivity, derived from mathematical modeling of glucose, insulin, and C peptide after a 2-hour standardized mixed-meal tolerance test (MMT) at Weeks 8 and 26. Other secondary endpoints include changes in fasting proinsulin to insulin ratio at Weeks 8 and 26, and changes in glycaemic control, measured as the percentage of time spent in target glycaemic range, below target range, and above target range, as assessed by continuous glucose monitoring (CGM) at Week 26.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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)
Exclusion Criteria
- Diagnosis of type 1 diabetes mellitus.
- 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.
- Significant weight loss (> 5 kg) in the 12 weeks prior to the Screening Visit
- 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.
- 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.
- Clinical symptoms compatible with New York Heart Association (NYHA) class III or IV heart failure.
- 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).
- 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).
- Thyroid stimulating hormone (TSH) outside of the normal range at the Screening Visit.
- 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
- 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.
- 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).
- 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.
- 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).
- 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Recruiting | 01 Oct 2024 | 45 |
 France | Recruiting | 01 Oct 2024 | 110 |
 Germany | Recruiting | 01 Oct 2024 | 75 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Dapansutrile | Test | TABLET | ORAL | 2000 | 26 | PRD11313910 |
The placebo product is visibly identical to the drug product but contains no drug substance.
The qualitative composition of Placebo Tablets is listed in Table 32. Placebo Tablets are free
from TSE and BSE.
The placebo product is contained in a white, HDPE, round wide-mouth bottle that is induction
sealed and closed with a white polypropylene child-resistant plastic cap with polyethylene
liner. A polyester coil and appropriately sized desiccant are added to each container.
Qualitative Composition of Placebo Tablets:
Microcrystalline cellulose (Avicel PH112) Diluent 563.70 mg/unit
Crospovidone(Polyplasdone XL) Disintegrant 24.00 mg/unit
Colloidal silicon dioxide (Cab-O-Sil M-5P) Glidant 9.30 mg/unit
Magnesium stearate (HyQual 2257) Lubricant 3.00 mg/unit
Total 600 mg/unit
An 800-mg tablet weight could not be achieved with the placebo tableting blend; however, the 600-mg placebo
tablet was compressed to the thickness range of the active product and is visually identical to the active drug
product. | Placebo | N/A | — | — | — | N/A |