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

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.

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.

Inclusion Criteria:

PART A:

1. Written informed consent
2. Between 18 and 75 years of age, inclusive
3. Of any ethnic origin
4. Healthy male subjects (groups A1 to A4)
5. Healthy female subjects (group A5)
6. BMI between 18.0 to 35.0 kg/m2
7. In good health as defined by medical history (including confirmation from GP), physical examination, vital signs assessment, 12 lead ECG and clinical laboratory evaluation.

PART B:

1. Written informed consent
2. Between 18 and 75 years of age inclusive
3. Of any ethnic origin
4. Male or female subjects with a diagnosis of osteoarthritis fulfilling the American College of Rheumatology (ACR) criteria for diagnosis
5. BMI between 18.0 to 35.0 kg/m2

Exclusion Criteria:

PART A:

1. 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.
2. 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.
3. Female subjects who are pregnant or currently lactating
4. 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
5. 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
6. Unwilling to abstain from vigorous exercise for 48 hours prior to any study visit
7. Unwilling to abstain from alcohol for 48 hours prior to any study visit
8. Tobacco smoking within 30 days of first dose, including use of e-cigarettes and not willing to abstain from smoking until after study involvement.
9. 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.
10. Received any prescribed systemic or topical medication within 14 days prior to the first dose administration (with the exception of the OCP)
11. 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).
12. 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
13. Subjects who have any clinically significant abnormal physical examination finding
14. 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
15. 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
16. Subjects with International Normalised Ratio (INR) > 1.3
17. Subjects who have any clinically significant allergy or allergic condition as determined by the investigator (with the exception of non-active hay fever)
18. 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)
19. 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.
20. Subjects who have a positive alcohol breath test or a positive urine drug screen ( a repeat assessment is acceptable)
21. 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
22. Subjects who have previously received APPA-1 or its constituent parts within 3 months of receiving first dose
23. Subjects who, in the opinion of the investigator, should not participate in this study.

PART B:

1. 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.
2. 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.
3. Female subjects who are pregnant or currently lactating
4. 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
5. 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
6. Unwilling to abstain from vigorous exercise for 48 hours prior to any study visit
7. Unwilling to abstain from alcohol for 48 hours prior to any study visit
8. Tobacco smoking within 30 days of first dose, including use of e-cigarettes and not willing to abstain from smoking until after study involvement
9. 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.
10. 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.
11. 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.
12. 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
13. Subjects who have any clinically significant abnormal physical examination finding
14. 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
15. 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
16. Subjects who have had recent (<3 months) surgery or are scheduled to have any surgical procedure in the study period
17. Subjects who have any clinically significant allergy or allergic condition as determined by the investigator (with the exception of non-active hay fever)
18. 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)
19. 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.
20. Subjects who have a positive alcohol breath test or a positive urine drug screen ( a repeat assessment is acceptable)
21. 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
22. Subjects who have previously received APPA-1 or its constituent parts within 3 months of receiving first dose.
23. Subjects who, in the opinion of the investigator, should not participate in this study.