Endothelial Dysfunction, Type2diabetes
Conditions
Brief summary
This trial is a single-centre, randomized, double-blind, placebo-controlled, 2-way cross-over phase 1b trial evaluating the pharmacodynamic effect of C21 on endothelial dysfunction and safety in subjects with type 2 diabetes mellitus (T2DM).
Interventions
DRUGC21
C21 is an angiotensin II type 2 receptor agonist (ATRAG)
Sponsors
Vicore Pharma AB
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female patient aged ≥ 40 years at the time of the screening visit (Visit 1). * Documented diagnosed with T2DM prior to the screening visit (Visit 1). * An RHI score ≤ 2 as assessed by EndoPAT at the time of the screening visit (Visit 1).
Exclusion criteria
* Known, active hepatitis B, C, or human immunodeficiency virus (HIV) infection (i.e., HIV with a CD4 (cluster of differentiation 4) count \<500 cells/mm³). * Impaired hepatic function or clinically significant liver disease, which in the investigator's opinion makes the subject inappropriate for this trial. * Severe renal impairment (i.e., estimated glomerular filtration rate (eGFR) ≤30 mL/min/1.73 m2). * Prolonged QTcF (QT interval with Fridericia's correction) (\>450 ms), atrial fibrillation, clinically significant arrhythmia or other clinically significant abnormality in the resting ECG (electrocardiogram) at screening (Visit 1), as judged by the investigator. * Unstable or deteriorating cardiac condition. * Malignancy within the past 5 years with the exception of in situ removal of basal cell carcinoma and cervical intraepithelial neoplasia grade I.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacodynamic Effect | Maximum 15 days after first Investigational Medical Product (IMP) intake. | Reactive hyperemia index (RHI) score as measured by EndoPAT (Endothelial pulse amplitude tonometry (PAT)). The EndoPAT software, provided with the device, is calculating the RHI using a computerised, automated algorithm. Reactive Hyperemia Index (RHI) score is a post-to-pre occlusion pulse amplitude tonometry signal ratio in the occluded arm relative to the same ratio in the control arm, and corrected for baseline vascular tone. RHI is a measure of endothelial function. Normal value: RHI \> 1.67. Abnormal value: RHI ≤ 1.67. There is no theoretical minimum and/or maximum values for the RHI score. A lower RHI score following C21 compared to placebo is the desired outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Augmentation Index (AI) Score as Measured by EndoPAT (Endothelial Pulse Amplitude Tonometry (PAT)). The AI Score Reported is Change Between Baseline Value and Value at the Visit Where Either C21 or Placebo is Taken. | Maximum 15 days after first Investigational Medical Product (IMP) intake. | The EndoPAT software, provided with the device is calculating the the Augmentation index (AI) using a computerised, automated algorithm. Augmentation index is a measurement of vascular stiffness. Augmentation index is calculated from PAT pulses based on the following formula AIx = 100 × (Augmentation pressure)/(Pulse Pressure). Ideally the augmentation index is somewhere between 20-80, but can be both negative and positive depending on the value of the augmentation pressure. A higher value is indicative of vascular stiffness. |
Countries
Sweden
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Experimental: C21 First, Then Placebo Participants first received a single oral dose of C21. After a washout period of 3 to 14 days, they then received a single oral dose of placebo (matching the C21 tablet). | 6 |
| Experimental: Placebo First, Then C21 Participants first received a single oral dose of placebo (matching the C21 tablet). After a washout period of 3 to 14 days, they then received a single oral dose of C21. | 5 |
| Total | 11 |
Baseline characteristics
| Characteristic | Experimental: Placebo First, Then C21 | Total | Experimental: C21 First, Then Placebo |
|---|---|---|---|
| Age, Continuous | 64.4 years STANDARD_DEVIATION 8.5 | 64.5 years STANDARD_DEVIATION 7.6 | 64.5 years STANDARD_DEVIATION 7.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 11 Participants | 6 Participants |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 5 Participants | 9 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 11 |
| other Total, other adverse events | 2 / 11 | 1 / 11 |
| serious Total, serious adverse events | 0 / 11 | 0 / 11 |
Outcome results
Primary
Pharmacodynamic Effect
Reactive hyperemia index (RHI) score as measured by EndoPAT (Endothelial pulse amplitude tonometry (PAT)). The EndoPAT software, provided with the device, is calculating the RHI using a computerised, automated algorithm. Reactive Hyperemia Index (RHI) score is a post-to-pre occlusion pulse amplitude tonometry signal ratio in the occluded arm relative to the same ratio in the control arm, and corrected for baseline vascular tone. RHI is a measure of endothelial function. Normal value: RHI \> 1.67. Abnormal value: RHI ≤ 1.67. There is no theoretical minimum and/or maximum values for the RHI score. A lower RHI score following C21 compared to placebo is the desired outcome.
Time frame: Maximum 15 days after first Investigational Medical Product (IMP) intake.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| C21 Treatment | Pharmacodynamic Effect | 1.787 score on a scale | Standard Error 0.062 |
| Placebo Treatment | Pharmacodynamic Effect | 1.911 score on a scale | Standard Error 0.062 |
Comparison: The primary endpoint (RHI score) was compared between treatments using an analysis of variance model (ANOVA) with treatment and period as fixed effects and subjects as random effect.p-value: 0.192590% CI: [-0.285, 0.037]ANOVA
Secondary
Augmentation Index (AI) Score as Measured by EndoPAT (Endothelial Pulse Amplitude Tonometry (PAT)). The AI Score Reported is Change Between Baseline Value and Value at the Visit Where Either C21 or Placebo is Taken.
The EndoPAT software, provided with the device is calculating the the Augmentation index (AI) using a computerised, automated algorithm. Augmentation index is a measurement of vascular stiffness. Augmentation index is calculated from PAT pulses based on the following formula AIx = 100 × (Augmentation pressure)/(Pulse Pressure). Ideally the augmentation index is somewhere between 20-80, but can be both negative and positive depending on the value of the augmentation pressure. A higher value is indicative of vascular stiffness.
Time frame: Maximum 15 days after first Investigational Medical Product (IMP) intake.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| C21 Treatment | Augmentation Index (AI) Score as Measured by EndoPAT (Endothelial Pulse Amplitude Tonometry (PAT)). The AI Score Reported is Change Between Baseline Value and Value at the Visit Where Either C21 or Placebo is Taken. | 15.937 score on a scale | Standard Error 2.484 |
| Placebo Treatment | Augmentation Index (AI) Score as Measured by EndoPAT (Endothelial Pulse Amplitude Tonometry (PAT)). The AI Score Reported is Change Between Baseline Value and Value at the Visit Where Either C21 or Placebo is Taken. | 20.877 score on a scale | Standard Error 2.484 |
Comparison: The secondary pharmacodynamic endpoint (AI) was analysed using a similar ANOVA model as for the primary endpoint.p-value: 0.194190% CI: [-11.392, 1.513]ANOVA