A Phase I, Partially Blind, Placebo-Controlled, Ascending Single and Multiple Oral Dose, Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Study in Healthy Subjects and Osteoarthritis Patients Administered APPA-1
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 40
- 试验地点
- 2
- 主要终点
- Safety of APPA-1 - Adverse Events will be collected and classified into standard terminology using MedDRA coding.
研究概览
简要总结
To determine the safety and tolerability of ascending single and multiple oral doses of APPA-1 in healthy subjects and osteoarthritis patients.
To determine the single and multiple oral dose pharmacokinetics of APPA-1 constituents (paeonol/apocynin) in healthy subjects and osteoarthritis patients.
To determine the effect of food on the single oral dose pharmacokinetics of APPA-1 constituents (paeonol/apocynin) in healthy subjects.
To determine the effect of gender on the single oral dose pharmacokinetics of APPA-1 constituents (paeonol/apocynin) in healthy subjects.
To determine the multiple oral dose pharmacodynamics of APPA-1 in osteoarthritis patients.
详细描述
APPA is being developed for the treatment of osteoarthritis (OA) and other pain-related and inflammatory conditions.
APPA is an acronym for the combination of apocynin (AP) and its isomer, paeonol (PA). It is an orally administered synthetic combination of two compounds:
The intention is that the two actives will be available as a fixed combination product. The proposed ratio is 7:2 (paeonol:apocynin).
Apocynin is a naturally occurring plant compound, derived primarily from Picrorhiza kurroa, although it also occurs in other plant genera and species. Paeonol is one of several bioactive compounds derived from plants of the Paeonia genus, principally Paeonia suffruticosa. Paeonia is one of the most commonly used plants in Traditional Chinese Medicine. There is a long history of traditional use of these two plants for the treatment of a range of ailments, including inflammatory conditions.
Significant body of evidence has accrued from use of the individual components of APPA (which includes registration in the UK under the Traditional Herbal Medicinal Products Scheme THMPS) over the centuries, together with consistent preclinical and animal model data suggesting that APPA has the potential to represent an effective drug for the relief of pain in osteoarthritis and that the risk of toxicity will be potentially lower than existing drugs, which currently comprise simple analgesics or non-steroidal anti-inflammatory agents.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
The randomisation code list will be generated by the LCTU trial statistician with the software package STATA. The trial is partially-blinded. Study participants will be allocated to treatment via block randomisation. The block size used in the randomisation will be kept blinded during the conduct of the study. An independent randomisation expert at the University of Liverpool will execute the randomisation program.
Part A, group A1 will be partially blind and placebo controlled. Part A, groups A2, A3, A4 and A5 and Part B will be double-blind and placebo-controlled to avoid bias in the collection and evaluation of data during their conduct.
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
- 是
入选标准
- •Written informed consent
- •Between 18 and 75 years of age, inclusive
- •Of any ethnic origin
- •Healthy male subjects (groups A1 to A4)
- •Healthy female subjects (group A5)
- •BMI between 18.0 to 35.0 kg/m2
- •In good health as defined by medical history (including confirmation from GP), physical examination, vital signs assessment, 12 lead ECG and clinical laboratory evaluation.
- •Written informed consent
- •Between 18 and 75 years of age inclusive
- •Of any ethnic origin
- •Male or female subjects with a diagnosis of osteoarthritis fulfilling the American College of Rheumatology (ACR) criteria for diagnosis
- •BMI between 18.0 to 35.0 kg/m2
排除标准
- •Male subjects who do not agree, or whose partners of childbearing potential do not agree, to use appropriate contraception or to refrain from donating sperm from the time of dosing until 3 months after the last dose of study drug.
- •Female subjects of childbearing potential not in agreement to use two highly effective methods of contraception, or to refrain from donating ova, from the time of screening until 28 days after the Follow Up Visit.
- •Female subjects who are pregnant or currently lactating
- •Donated blood in the 3 months prior to screening, plasma in the 7 days prior to screening, platelets in the 6 weeks prior to screening
- •Consume more than 28 units of alcohol per week if male, or 21 units of alcohol per week if female or any significant history of alcohol / substance misuse as determined by the investigator
- •Unwilling to abstain from vigorous exercise for 48 hours prior to any study visit
- •Unwilling to abstain from alcohol for 48 hours prior to any study visit
- •Tobacco smoking within 30 days of first dose, including use of e-cigarettes and not willing to abstain from smoking until after study involvement.
- •Received any medication, including St John's Wort, known to chronically alter drug absorption or elimination within 30 days prior to first dose administration unless in the opinion of the investigator it will not interfere with study procedures or compromise safety.
- •Received any prescribed systemic or topical medication within 14 days prior to the first dose administration (with the exception of the OCP)
- •Received any non-prescribed systemic or topical medication, herbal remedy or vitamin / mineral supplementation within 14 days prior to the first dose administration (with the exception of paracetamol).
- •Subjects who have any abnormality of vital signs prior to the first dose administration that, in the opinion of the investigator, would increase the risk of participating in the study
- •Subjects who have any clinically significant abnormal physical examination finding
- •Subjects who have any clinically significant 12 lead ECG abnormality that, in the opinion of the investigator, would increase the risk of participating in the study
- •Subjects who have, or have any history of, any clinically significant cardiovascular, respiratory, gastrointestinal, neurological, psychiatric, metabolic, endocrine, renal, hepatic, haematological or other major disorder as determined by the investigator
- •Subjects with International Normalised Ratio (INR) > 1.3
- •Subjects who have any clinically significant allergy or allergic condition as determined by the investigator (with the exception of non-active hay fever)
- •Subjects who have any clinically significant abnormal laboratory safety results as determined by the investigator with specific exclusions of any AST or ALT greater than or equal to 1.5 times ULN at screening or day -1; total bilirubin > ULN (Gilbert's syndrome is acceptable)
- •Subjects who have hepatitis B or C or are carriers of HBsAg or are carriers of HCV Ab or are positive for HIV 1/2 antibodies.
- •Subjects who have a positive alcohol breath test or a positive urine drug screen ( a repeat assessment is acceptable)
- •Subjects who are still participating in another clinical study or who have participated in a clinical study involving administration of an investigational product in the 3 months (or 5 half-lives, whichever is longer) prior to first dose administration
- •Subjects who have previously received APPA-1 or its constituent parts within 3 months of receiving first dose
- •Subjects who, in the opinion of the investigator, should not participate in this study.
- •Male subjects who do not agree, or whose partners of childbearing potential do not agree, to use appropriate contraception or to refrain from donating sperm from the time of dosing until 3 months after the last dose of study drug.
- •Female subjects of childbearing potential not in agreement to use two highly effective methods of contraception, or to refrain from donating ova, from the time of screening until 28 days after the Follow Up Visit.
- •Female subjects who are pregnant or currently lactating
- •Donated blood in the 3 months prior to screening, plasma in the 7 days prior to screening, platelets in the 6 weeks prior to screening
- •Consume more than 28 units of alcohol per week if male, or 21 units of alcohol per week if female or any significant history of alcohol / substance misuse as determined by the investigator
- •Unwilling to abstain from vigorous exercise for 48 hours prior to any study visit
- •Unwilling to abstain from alcohol for 48 hours prior to any study visit
- •Tobacco smoking within 30 days of first dose, including use of e-cigarettes and not willing to abstain from smoking until after study involvement
- •Received any medication, including St John's Wort, known to chronically alter drug absorption or elimination within 30 days prior to first dose administration unless in the opinion of the investigator it will not interfere with study procedures or compromise safety.
- •Received and prescribed systemic or topical medication within 14 days prior to the first dose administration unless in the opinion of the investigator it will not interfere with study procedures or compromise safety and has been at stable dose for at least two weeks prior to screening.
- •Received any non-prescribed systemic or topical medication, herbal remedy or vitamin / mineral supplementation within 14 days prior to the first dose administration unless in the opinion of the investigator it will not interfere with study procedures or compromise safety.
- •Subjects who have any abnormality of vital signs prior to the first dose administration that, in the opinion of the investigator, would increase the risk of participating in the study
- •Subjects who have any clinically significant abnormal physical examination finding
- •Subjects who have any clinically significant 12 lead ECG abnormality that, in the opinion of the investigator, would increase the risk of participating in the study
- •Subjects who have any clinically significant medical history in the opinion of the investigator: stable, well controlled conditions such as hypertension, dyslipidaemia, type 2 diabetes (controlled by diet, exercise and/or oral medications), asthma (controlled by inhaled corticosteroids and or beta-2 agonists) etc. are acceptable
- •Subjects who have had recent (<3 months) surgery or are scheduled to have any surgical procedure in the study period
- •Subjects who have any clinically significant allergy or allergic condition as determined by the investigator (with the exception of non-active hay fever)
- •Subjects who have any clinically significant abnormal laboratory safety results as determined by the investigator with specific exclusions of any AST or ALT greater than or equal to 1.5 times ULN at screening or day -1; total bilirubin > ULN (Gilbert's syndrome is acceptable)
- •Subjects who have hepatitis B or C or are carriers of HBsAg or are carriers of HCV Ab or are positive for HIV 1/2 antibodies.
- •Subjects who have a positive alcohol breath test or a positive urine drug screen ( a repeat assessment is acceptable)
- •Subjects who are still participating in another clinical study or who have participated in a clinical study involving administration of an investigational product in the 3 months (or 5 half-lives, whichever is longer) prior to first dose administration
- •Subjects who have previously received APPA-1 or its constituent parts within 3 months of receiving first dose.
- •Subjects who, in the opinion of the investigator, should not participate in this study.
研究组 & 干预措施
APPA-1
PART A: 16 healthy volunteers, oral capsule(s). One dose, except for group A3 (two treatment periods) Group A1: 400 mg, APPA-1 capsule A2 - 800 mg, 2 capsules A3 - 1600 mg, capsules A4 - 3200 mg, 8 capsules A5 - TBC - females Dose levels may change following review of safety and PK data from previous dose levels.
PART B: 9 osteoarthritis, one dose to be determined following Part A.
干预措施: APPA-1 (Drug)
Placebo
PART A: 4 healthy volunteers, oral capsule(s). One dose, except for group A3 (two treatment periods) Group A1: 400 mg, APPA-1 capsule A2 - 800 mg, 2 capsules A3 - 1600 mg, capsules A4 - 3200 mg, 8 capsules A5 - TBC - females Dose levels may change following review of safety and PK data from previous dose levels.
PART B: 3 osteoarthritis, one dose to be determined following Part A.
干预措施: Placebo Oral Tablet (Drug)
结局指标
主要结局
Safety of APPA-1 - Adverse Events will be collected and classified into standard terminology using MedDRA coding.
时间窗: Part A: 67 days (groups A1,2,4 and 5) and 75 days group A3. Part B: 77 days
Adverse events will be collected from consent until 28 days after treatment ends.
次要结局
- Effect of food on pharmacokinetics of APPA-1 constituents(14 days.)
- Effect of gender on pharmacokinetics of APPA-1 constituents (paeonol/apocynin) in healthy subjects(14 days.)
- Pharmacokinetics of APPA-1 constituents - plasma concentrations of apocynin and paeonol(14 days)
- Pharmacokinetics of APPA-1 constituents - plasma concentrations of apocynin and paeonol(14 days.)