A placebo-controlled, double-blinded, randomized, dose-finding trial using a combination of apocynin and paeonol (APPA) for the treatment of knee osteoarthritis

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Akl Research & Development Limited

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

Trial duration

8 Jul 2024 → 24 Jun 2025

Decision date (initial)

2024-04-30

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To evaluate the change in pain of the target knee

Secondary objectives 4

1. To evaluate safety and tolerability of APPA
2. To evaluate changes in symptoms of OA
3. To evaluate changes in physical functioning
4. To evaluate changes in quality of life

Conditions and MedDRA coding

Knee osteoarthritis

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. The participant is able to read and understand the language and content of the study material, understand and comply with the requirements of the study, and is willing to provide information at the scheduled evaluations and appropriate written informed consent has been obtained.
2. Age between 40 years and 85 years at the time of screening (inclusive) of either sex.
3. Femorotibial osteoarthritis of the knee, according to the American College of Rheumatology (ACR) clinical and radiographic criteria (Appendix I).
4. Radiological OA grade 2 or 3 of the target knee, using the Kellgren-Lawrence method (Kellgren & Lawrence 1957) as graded by central, independent reading of a Fixed-Flexion X-ray obtained during screening, or on a recent (within 6 months) X-ray image which fulfills the protocol specifications for reading.
5. Screening and baseline target knee WOMAC pain sub-score (5 questions) ≥ 25 and < 45 out of 50.
6. PainDETECT ≥ 13out of 38 at screening
7. Failure in response or intolerance of at least one OA therapy (e.g. physiotherapy, paracetamol, local or systemic NSAID, short term opioid use, injections of hyaluronic acid, or corticosteroids) in the opinion of the investigator.

Exclusion criteria 19

1. Known or suspected hypersensitivity to or previous hypersensitivity reactions to APPA, or any of the excipients in the investigational product.
2. For women of childbearing potential: a. Pregnancy (i.e. positive serum pregnancy test at screening) or breastfeeding b. Failure to agree to practice a highly effective method of contraception (see Appendix II), from enrolment up to at least 3 months after the study end.
3. For sexually active men with a female partner of childbearing potential: a. Failure to agree to ensure that their female partners use a highly effective method of contraception (see Appendix II) from enrolment up to at least 3 months after the study end. b. Failure to agree not to donate sperm throughout the study and at least 3 months after the study end.
4. Intra-articular injection of corticosteroids within 3 months or hyaluronic acid within 6 months of screening in the target knee or into any other major joint within 30 days prior to screening (for extended-release corticosteroid injections: within 6 months in target knee and 3 months into any other major joint).
5. Systemic corticosteroid treatment for the treatment of musculoskeletal conditions of more than 14 days during the past 6 months prior to screening.
6. Target knee major surgery or arthroscopy within the year prior to screening.
7. Planned surgery on either knee within the next 6 months.
8. Use of a currently unapproved investigational drug, device, or biologic within 3 months prior to randomization.
9. Presence of inflammatory arthritis, such as rheumatoid arthritis, psoriatic arthritis, polymyalgia rheumatica, gout or pseudogout with significant history of clinical attacks (in the opinion of the investigator), or presence of connective tissue disease.
10. Current malignancy or treatment for malignancy within the past five years, apart from resected basal cell carcinoma, squamous skin cell carcinoma, or resected cervical atypia or carcinoma in situ, unless affecting the target knee area.
11. Any other abnormal laboratory results or significant medical conditions that the Investigator believes should preclude participation in the trial.
12. Prior septic arthritis of the target knee.
13. Known OA of the hip(s) if pain in either or both hip(s) exceeds that of the target knee on the WOMAC Hip Pain sub-score at the time of screening.
14. Active comorbid condition other than OA (e.g radicular back pain, bursitis, tendinitis) significantly affecting target knee pain reporting in the opinion of the investigator.
15. Body Mass Index ≥ 40 kg/m2
16. Estimated glomerular filtration rate < 30 mL/min using the Modification of Diet in Renal Disease (MDRD) method.
17. Substantial use of moderate or higher strength opioid medication within 6 weeks before the screening visit, as evaluated by the investigator.
18. Use of serotonin–norepinephrine reuptake inhibitors (i.e duloxetine), pregabalin, or gabapentin within 4 weeks before the screening visit.
19. History of alcohol or drug abuse within the 5 years prior to randomization, in the opinion of the investigator.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint of this trial is the change from baseline in WOMAC pain sub-score (sum of questions 1 to 5) of the target knee as evaluated at week 12.

Secondary endpoints 12

1. Changes from baseline in WOMAC total score and the WOMAC function and stiffness scores at week 12
2. Changes from baseline in constant, intermittent and total OA pain assessed by ICOAP scores at week 12
3. Changes from baseline in WOMAC pain weight-bearing score (questions 1, 2, and 5) and non-weight bearing score (questions 3 and 4) at week 12
4. Change from baseline in the weekly mean of the average daily NRS pain intensity at Week 12
5. Area-under-effect curves of the weekly mean of the average daily NRS pain intensity at Week 12
6. OMERACT-OARSI responder rate at week 12
7. Total number of days where rescue medication was reported used for treatment of target knee pain
8. Total dose of rescue medication calculated as the sum of tablets used, based on pill counts
9. Changes from baseline in the Patient Global Assessment (PGA) score at week 12
10. Changes from baseline in quality of life assessed by the EQ5D at week 12
11. Nature, incidence and severity of AEs
12. Changes in laboratory safety parameters, vital signs, ECG parameters, and weight

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Akl Research & Development Limited

Sponsor organisation

Akl Research & Development Limited

Address

Gunnels Wood Road

City

Stevenage

Postcode

SG1 2FX

Country

United Kingdom

Scientific contact point

Organisation

Akl Research & Development Limited

Contact name

Chief Scientific Officer

Public contact point

Organisation

Akl Research & Development Limited

Contact name

Chief Executive

Third parties 6

Locations

1 EU/EEA country · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 10 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications