A Phase 2a Trial to Investigate Safety, Tolerability and Exploratory Clinical Efficacy of AGP100 in Patients With Catecholaminergic Polymorphic Ventricular Tachycardia (PACE-CPVT)
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- Incidence of adverse events (AEs)
研究概览
简要总结
This trial is conducted in patients with an inherited heart rhythm disorder called catecholaminergic polymorphic ventricular tachycardia (CPVT). This condition causes the heart to beat dangerously fast during situations of physical or emotional stress. CPVT is a serious condition that can limit the length and quality of patients' lives. Current treatment does not always prevent the abnormal heart rhythms that can occur as part of CPVT during strenuous exercise or stress, so new and improved medications are needed.
The main questions that the trial will answer are:
- How safe and tolerable is the drug AGP100; i.e, what medical problems do patients experience when taking the drug?
- Does the drug help CPVT patients to maintain a normal heart rhythm while they are exercising?
- How does the drug affect the levels of key heart cell signalling molecules?
Patients with a diagnosis of CPVT who are aged between 18 and 75 and experience abnormal heart rhythms during exercise, despite taking a stable dose of the medication(s) prescribed by their doctor for their CPVT can take part in this trial. Participants should have normal kidney and liver function and not have high blood pressure or a diagnosis of structural heart disease. Women who are pregnant or breastfeeding cannot take part in the study. Participants who may become pregnant (and their partners) need to use highly effective methods of contraception during the study and for 90 days after the study ends.
Participants will take part in the study for ten weeks. During this time, participants will be asked to take three different doses of the the drug (AGP100), as well as their normal heart medication. The drug is an oral capsule and each different dose will be taken once a day for 13 days. The study starts with participants taking a low dose for 2 weeks, then a medium dose and then a high dose. At each dose, participants will undergo a clinical examination, report any potential side effects and the treating doctor will investigate the safety, tolerability and side effects of AGP100. In total, participants will take AGP100 once a day for about six weeks. The last four weeks of the study will be a follow-up period where participants will not take AGP100.
During the study, participants will need to visit the hospital six times. The visits will be three outpatient appointments and three overnight stays.
详细描述
The investigational medicinal product (IMP) used in this study is AGP100, a selective small molecule inhibitor of phosphodiesterase 2 (PDE2) under development by Agiana Pharmaceuticals (the Sponsor) for the treatment of catecholaminergic polymorphic ventricular tachycardia (CPVT) and cardiac arrhythmias (abnormal heart rhythms) that occur in other cardiovascular diseases.
The clinical data generated to date support the continued development of AGP100, and non-clinical data held by the Sponsor provide evidence that inhibition of PDE2 can attenuate cardiac calcium overload arrhythmias. Together, this supports the development of AGP100, a specific PDE2 inhibitor, as the first member of a new class of antiarrhythmic therapies. AGP100 was well tolerated, with no safety signals observed during administration to 95 individuals at single doses up to 125 mg and multiple doses up to 75 mg. The formulation of AGP100 planned to be used in this study (oral capsules containing either 5 or 25 mg AGP100), has been previously administered, as has a similar dosing regimen.
This phase IIa study will evaluate safety, tolerability, and preliminary clinical efficacy of multiple ascending doses of AGP100 in participants with confirmed CPVT - i.e., a trial population within the proposed indication for AGP100, and will be the first study in which AGP100 has been administered to patients (rather than healthy volunteers).
Current first-line prophylactic treatment for CPVT is full-dose non-selective β-blockers, with the addition of flecainide as a second-line treatment in some patients. However, despite currently available therapies, significant unmet medical need exists due to adverse effects, drug interactions, and/or limited efficacy in maintaining normal heart rhythm on current standard of care therapy when the patients undergoes surges of adrenergic stimulation. Therefore, the objective of this phase IIa clinical study is to assess the safety and tolerability of increasing doses of AGP100 in CPVT patients and to obtain preliminary efficacy data to support the development of AGP100 as the first member of a new class of antiarrhythmic therapies for the treatment of CPVT and other cardiac arrhythmias.
AGP100 will be given together with current standard of care. As discussed above, non-clinical data suggests that positive synergy between β-blockers and AGP100 may be expected as they function through distinct, complimentary modes of action.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
盲法说明
There is no masking as the study is a single-arm, open-label study. It is an intra-patient dose escalation study where patients first receive a low dose of the drug, then an medium dose, and then a high dose.
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Signed informed consent prior to any study-related procedures
- •Male or female, aged between 18 and 75 years (inclusive)
- •Clinical diagnosis of CPVT based on proven RYR2 mutation AND reproducible premature ventricular contraction with exercise or polymorphic or bidirectional ventricular tachycardia with exercise
- •Able and willing to undergo exercise testing (bicycle test) AND exhibits exercise-induced ventricular ectopic beats at Screening (at least 1 point on the VA scale)
- •On stable, maximum tolerated, dose of non-selective β-blocker for at least 4 weeks before Visit
- •The dosage and choice of β-blocker are to be determined by the patients' physician(s) before entry into the study and must remain unchanged throughout the conduct of the study. Participants taking a stable dose of flecainide for at least 4 weeks, in addition to β-blocker, are also eligible.
- •Clinical laboratory evaluations including clinical chemistry, haematology, urinalysis, thyroid function (including thyroid stimulating hormone, triiodothyronine, thyroxine, and free T4) and coagulation testing (activated partial thromboplastin time, and international normalized ratio) within the reference range, unless deemed not clinically significant by the Investigator
- •Willing to refrain from strenuous or new exercise for 24 hours before each study visit
- •Women of childbearing potential (WOCBP) agree to implement accepted and highly effective means of contraception from study entry until at least 33 days after study drug discontinuation (as per the Clinical Trials Facilitation and Coordination Group guidelines).
- •The main exclusion criteria are:
- •Diagnosis of structural heart disease, including coronary artery disease or heart failure with reduced ejection fraction (left ventricular ejection fraction <45%)
- •Participants who have had arrhythmias causing hemodynamic instability at previous exercise tests (performed while on the current standard of care treatment)
- •Participants having a sustained VT (VA score of 5) during the exercise tests performed as part of the screening activities
- •Participation in another clinical study with an investigational product or device within 60 days of 5 half-lives prior to Baseline (whichever is longer)
- •Medical history of severe anaphylactic reactions to any component(s) of the IMP
- •Sensitivity to any of the study treatments, or components thereof, or any drug or other allergy that, in the opinion of the Investigator precludes participation in the study
- •Hypersensitivity or contraindication to PDE2 inhibitor drugs
- •Use of PDE3, PDE4, or PDE5 inhibitor drugs.
- •Participants taking any antiarrhythmic drug(s) except flecainide and non-selective β-blockers
- •Significant hypertension (defined as systolic blood pressure of >160 mmHg and/or diastolic blood pressure of >95 mmHg). If the blood pressure results are out of range at Screening, the measurements can be repeated on the same day more than once, or at another convenient visit
- •Prolonged PR and/or QTc interval at Screening, defined as PR >240 ms or QTc >480 ms
排除标准
- 未提供
研究组 & 干预措施
AGP100
Within this single arm, three doses levels are planned in an intra-patient dose-escalation design. These will be administered in sequential treatment periods:
- Daily dose of 5 mg (1 x 5 mg capsule), oral route, for a planned duration of 13 days (starting dose)
- Daily dose of 25 mg (1 x 25 mg capsule), oral route, for a planned duration of 13 days
- Daily dose of 50 mg (2 x 25 mg capsules), oral route, for a planned duration of 13 days
干预措施: AGP100 (Drug)
结局指标
主要结局
Incidence of adverse events (AEs)
时间窗: From Day 1 (start of treatment) through Day 68 [EoS])
Changes in heart rate (HR)
时间窗: Day 1, Day 2, Day 14, Day 15, Day 27, Day 28, Day 39 (End of Treatment), and Day 68 (EoS)
Unit: beats per minute (bpm)
Changes in 12-lead electrocardiogram parameters: estimated ventricular frequency
时间窗: Day 1, Day 2, Day 14, Day 15, Day 27, Day 28, Day 39 (End of Treatment), and Day 68 (EoS)
Unit: bpm
Changes in 12-lead electrocardiogram parameters: PR
时间窗: Day 1, Day 2, Day 14, Day 15, Day 27, Day 28, Day 39 (End of Treatment), and Day 68 (EoS)
Unit: milliseconds (ms)
Changes in 12-lead electrocardiogram parameters: QRS
时间窗: Day 1, Day 2, Day 14, Day 15, Day 27, Day 28, Day 39 (End of Treatment), and Day 68 (EoS)
Unit: milliseconds (ms)
Changes in 12-lead electrocardiogram parameters: QTc
时间窗: Day 1, Day 2, Day 14, Day 15, Day 27, Day 28, Day 39 (End of Treatment), and Day 68 (EoS)
Unit: milliseconds (ms)
Tolerability of the IMP
时间窗: From Day 1 (start of treatment) through Day 68 [EoS])
This will be assessed as a binary parameter (tolerable Yes or No): If any of following changes in IMP dosing is deemed necessary, the participant will be classified as 'No': * Dose adjustments prescribed by the Investigator * Dose interruptions prescribed by the Investigator * Discontinuation of treatment
次要结局
- Change from baseline in urine cyclic adenosine monophosphate (cAMP) levels(Day 1 (post-dose), Day 14, Day 27, Day 39, and Day 68)
- Change from baseline in the amount and complexity of exercise-induced ventricular ectopic beats as assessed using the ventricular arrythmia (VA) score(Day 1 (post-dose), Day 14, Day 27, Day 39, and Day 68)
- Change from baseline in plasma cGMP levels(Day 1 (post-dose), Day 14, Day 27, Day 39, and Day 68)
- Change from baseline in plasma cAMP levels(Day 1 (post-dose), Day 14, Day 27, Day 39, and Day 68)
- Change from baseline in urine cyclic guanosine monophosphate (cGMP) levels(Day 1 (post-dose), Day 14, Day 27, Day 39, and Day 68)