A Study to Evaluate the Safety, Tolerability, PK and PD of AP303 in DKD Patients
- Conditions
- Diabetic Kidney Disease
- Interventions
- Drug: AP303 150μgDrug: Placebo 150μgDrug: AP303 300μgDrug: Placebo 300μg
- Registration Number
- NCT06666283
- Lead Sponsor
- Alebund Pharmaceuticals
- Brief Summary
The study will be a single center, double-blind, randomized, placebo-controlled, multiple-ascending-dose study to evaluate the safety, tolerability, PK and PD of AP303 following 2-week oral administration to Diabetic Kidney Disease patients.
- Detailed Description
Eligible patients will be enrolled into one of the two dose cohorts, each cohort will include 9 participants randomized to AP303 and placebo at 2:1 ratio (6 on AP303 and 3 on placebo).
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 18
- Male and female participants, ≥30 years of age at the time of signing the informed consent form.
- BMI (body mass index) 18-30 kg/m².
- Patient has a clinical diagnosis of Type 2 Diabetes Mellitus and is taking at least one type of hypoglycemic drugs.
- Patient must be on a stable dose of angiotensin converting anzyme inhibitior (ACEI) or Angiotensin II receptor blockers (ARB) for at least 4 weeks prior to screening.
- Hemoglobin A1c ≥6.5% but ≤10.5% at the screening visit.
- Estimated GFR ≥30 mL/min/1.73m² but < 60 mL/min/1.73m² at the screening visit.
- Urinary albumin to creatinine ratio ≥ 30 mg/g at the screening visit.
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Chronic kidney disease other than type 2 diabetic kidney disease.
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Patient receiving corticosteroid immunotherapy or other immunosuppressants (such as calcineurin inhibitors ciclosporin, cyclophosphamide, or mycophenolate mofetil) in the past 3 months before screening.
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Recently having acute kidney injury or received renal surgery within the last 6 months before screening visit, or have received renal transplantation.
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Congestive heart failure classified New York Heart Association (NYHA) class II to IV within the last 3 months before the screening visit.
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Peripheral edema above the ankle level at the screening or randomization visit.
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Confirmed (based on the average of 2 separate resting blood pressure measurements in a sitting position, after at least 5 minutes rest) systolic BP greater than 160 or less than 90 mmHg, and diastolic BP greater than 100 or less than 50 mmHg at screening.
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Myocardial infarction, acute coronary syndrome, stroke or transient ischemic attack, cardiovascular surgery within 6 months prior to the screening visit.
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Abnormalities of ECG parameters and abnormal shape of ECG wave on screening ECG: e.g.
- QTc interval (QTcF > 450 ms for male and QTcF > 470 ms for female) based on the average interval on triplicate ECGs obtained after 5 minute's rest in a supine position
- Notable resting bradycardia (mean HR < 40 bpm)
- Notable resting tachycardia (mean HR > 100 bpm)
- ECG with QRS and/or T wave judged to be unfavorable for a consistently accurate QT measurement (e.g., neuromuscular artifact that cannot be readily eliminated, indistinct QRS onset, low amplitude T wave, merged T- and U-waves, prominent U waves)
- Any other significant abnormality
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Implantation of cardiac pacemaker or clinically significant arrhythmia, e.g. atrial fibrillation, atrial flutter, right or left bundle branch block, Wolf-Parkinson-White Syndrome.
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Current or previous treatment with insulin within the last 3 months before the screening visit (except injected continuously for less than 7 days in the emergency room).
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Current or previous treatment with a thiazolidinedione (e.g., medications containing pioglitazone or rosiglitazone, like Actos, Avandia, ActoplusMet, Avandamet, Avandaryl), PPARa agonist (like fenofibrate) or any dual/multiple PPARa/g agonist (e.g., Chiglitazar Sodium) in the 3 months preceding screening visit.
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Previous treatment with CYP2C8 inducer or strong/moderate inhibitor (refer to the list in Appendix 4) in the 1 month preceding screening visit.
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Chronic therapy with non-steroidal anti-inflammatory drugs (NSAIDs) (except prophylactic stable low dose aspirin, defined as its dose not higher than 100 mg daily; paracetamol/acetaminophen was allowed) in the last month before screening.
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ALT or AST >1.5 × ULN, or laboratory tests revealed other clinically significant abnormalities in liver function at screening.
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Creatine phosphokinase (CPK) elevated > 3 x ULN at screening visit or history of drug-induced myopathy.
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History of malignancy within 5 years before screening (exceptions: squamous and basal cell carcinomas of the skin and carcinoma of the cervix in situ, or a malignancy that in the opinion of the investigator, with concurrence with the sponsor's medical monitor, is considered cured with minimal risk of recurrence).
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Participants who have had significant acute infection, e.g., COVID-19, influenza, local infection, acute gastrointestinal symptoms or any other clinically significant illness within two weeks before study drug administration.
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Positive test at screening of any of the following: Hepatitis B (HBsAg), Hepatitis C (HCVAb), human immunodeficiency virus (HIV Ab) or syphilis AB.
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Dosed with a small-molecule investigational drug within 3 months, or biologic investigational drug within 3 months or 5 half-lives (whichever is the longer) prior to first dose of this study.
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History of drug and/or alcohol abuse or addiction. History (within 3 months of screening) of alcohol consumption exceeding 3 and 2 standard drinks per day on average (1 standard drink = 10 grams of alcohol) for male and female, respectively.
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Use of >5 cigarettes or equivalent nicotine-containing product per day.
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Medical or social conditions that would potentially interfere with the participant's ability to comply with the study visit schedule or the study assessments.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description AP303 AP303 150μg - AP303 AP303 300μg - Placebo Placebo 150μg - Placebo Placebo 300μg -
- Primary Outcome Measures
Name Time Method Cmax Day 1, Day 14 Maximum observed plasma concentration
Tmax Day 1, Day 14 Time to maximum observed plasma concentration
AUC0-24h Day 1 Area under the plasma concentration versus time curve up to 24 hours
AUC0-last Day 1 Area under the plasma concentration versus time curve up to the last measurable concentration
AUC0-inf Day 1 Area under the plasma concentration versus time curve extrapolated to infinity
AUC0-t Day 14 Area under the plasma concentration-time curve for a dosing interval
t1/2 Day 1, Day 14 Apparent terminal half-life, computed as ln(2)/λz
CL/F Day 1 Apparent oral clearance calculated from Dose/ AUC0-inf
V/F Day 1, Day 14 Apparent volume of distribution of oral drug
Cav Day 14 Average plasma concentration
Ctrough Day 3-14 Trough plasma concentration
Rac Day 3-14 Ratio of accumulation
Incidence and severity of adverse events Day 1-28 Incidence and severity of adverse events
Incidence of laboratory abnormalities, based on hematology, clinical chemistry, coagulation and urinalysis test results Day 1-28 Incidence of laboratory abnormalities, based on hematology, clinical chemistry, coagulation and urinalysis test results
Effect of AP303 on ECG parameters Day 1-28 Number of participants with abnormal heart rate
Vital signs（Systolic blood pressure） Day 1-28 Change of systolic blood pressure
Effect of AP303 on physical examination result Day 1-28 Number of pariticipants with abnormal physical examination findings by nature and severity
Body weight Day 1-28 Change of body weight
Vital signs (Diastolic blood pressure) Day1-28 Change of diastolic blood pressure
Vitlal signs (Body temperature) Day 1-28 Change of body temperature
- Secondary Outcome Measures
Name Time Method Fasting lipid profile Baseline, Days 6, 10, 14 and 28 Change of Triglyceride, HDL-C, LDL-C, Total cholesterol
Serum creatinine Baseline, Days 6, 10, 14 and 28 Change of serum creatinine
eGFR Baseline, Days 6, 10, 14 and 28 Change of estimated glomerular filtration rate
Fasting glucose Baseline, Days 6, 10, 14 and 28 Change of fasting glucose