NCT07429565

Testing APPA-1 in Healthy Subjects and Osteoarthritis Patients

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

• Status: Completed
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 40 (actual)
• Sponsor: University of Liverpool · Academic / Other
• Sex: All
• Age: 18 Years – 75 Years
• Healthy volunteers: Accepted

Summary

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.

Detailed description

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. Part A will comprise a single dose, sequential group study, incorporating a single group, fixed sequence, two-period crossover arm to investigate the effect of food. 20 subjects will be studied in 5 groups (Group A1 to A5), each group consisting of 4 subjects. Groups A1 to A4 will be male subjects only, Group A5 will consist of female subjects only to assess potential gender effects. Duration: Each subject will participate in 1 treatment period only, residing in the CRU from Day -1 (the day before dosing) to Day 2 (24 hours post dose), except for group A3, where each subject will participate in 2 treatment periods separated by a minimum of 7 days. All subjects will return for a post-study visit 7-10 days after their last dose. Based on the ongoing review of safety, tolerability and pharmacokinetic results, additional non-residential visits may be required. The number of additional non-residential visits will not exceed three per treatment period and will not extend beyond 28 days after each final dosing occasion. Dose Regimen: In each of groups A1 to A5, 3 subjects will receive APPA-1 and 1 will receive placebo. All doses will be administered in accordance with a randomisation schedule in the fasted state in the morning of Day 1. Additionally in Group A3 Treatment Period 2, APPA-1 or placebo will be given 30 minutes after a high fat breakfast to assess potential food effect. A high-fat (approximately 50 percent of total caloric content of the meal) and high-calorie (approximately 800 to 1000 calories) meal is recommended as a test meal for food-effect BA and fed BE studies. This test meal should derive approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively. The caloric breakdown of the test meal will be provided in the study report. Each subject in Groups A1, A2, A4 and A5 will receive only a single dose of APPA-1 or placebo during the study. In Group A3, subjects will have the same treatment in both periods such that each subject will receive two single doses of APPA-1 or placebo during the study. Dosing in Group A3 Treatment Period 2 will not occur until safety data are available from Group A4 in case food increases bioavailability. Group A5 (Females) will be commenced once a dose level for that group has been determined and is contingent on review of the safety and PK data in the next highest dose escalation group. For example, a dose of 1600mg could only be administered in Group A5 if safety data and PK data were available for male subjects receiving 3200mg. In Group A1, dosing will occur such that two subjects (one active and one placebo), will be dosed at least 24 hours before the remaining subjects, where continuation to dose the remaining subjects will be at the Investigator's discretion following review of the safety data up to 24 hours post dose. Escalation to higher doses will be completed after reviewing the 24h post dose safety information and pharmacokinetic data of previous groups. There will be a minimum of 10 days between drug administrations in each group; where escalations to higher doses will be decided by a Dose Escalation Committee. Dose levels may be changed following review of safety and PK data from the previous dose levels. The dose level for Group A5 will be determined following review of safety and PK data from previous cohorts. Part B will comprise a multiple dose, sequential group study. Twelve osteoarthritis patients will be studied in 3 groups (Group B1, B2 and B3), each group consisting of 4 patients. Additional dose groups may be added dependent upon the results from Part A. Osteoarthritis patients will be assessed in this part to determine the potential for pain relief. Duration: Each subject will participate in one treatment period only, residing at the CRU from the evening of Day -1 (day before dosing) until the morning of Day 2, outpatient visits on Day 7 and then residing at the CRU from Day 13 to Day 15. All patients will return for a post study visit on Day 21. Dose regimen: For Part B of the study, in each of Groups B1, B2 and B3, three patients will receive APPA-1 and one patient will receive placebo. The dietary state for dosing in Part B will be subject to review of PK data from the fed/fasted comparison in Part A. For all patients, up to two times daily dosing will occur on Days 1 to 13 inclusive and a final single dose administration will occur in the morning of Day 14. Dosing in Part B may commence following review of data from Part A, group A3 (fed) and group A5 (females). . There will be a minimum of 10 days between dose escalations. Dose levels: To be confirmed following completion of Part A, group A3 (fed) and group A5 (female). Doses will not exceed the likely exposure limits of the GLP toxicology studies. Doses will be administered as the appropriate number of 400 mg capsules.

Conditions

• Osteoarthritis

Interventions

Type	Name	Description
DRUG	APPA-1	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: * 4'-hydroxy-3'-methoxy-acteophenone (apocynin\[acetovanillone\]); * 2'-hydroxy -4'-methoxy acetophenone (paeonol). The intention is that the two actives will be available as a fixed combination product. The proposed ratio is 7:2 (paeonol:apocynin).
DRUG	Placebo Oral Tablet	Identical to IMP apart from active substance.

Timeline

• Start date: 2018-04-09
• Primary completion: 2018-12-31
• Completion: 2018-12-31
• First posted: 2026-02-24
• Last updated: 2026-02-24

Locations

2 sites across 1 country: United Kingdom