E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Moderate to severe osteoarthritis pain in the index knee |
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E.1.1.1 | Medical condition in easily understood language |
Moderate to severe osteoarthritis pain in the knee with most pain |
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E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10023476 |
E.1.2 | Term | Knee osteoarthritis |
E.1.2 | System Organ Class | 100000004859 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the efficacy of AKR 202 for the treatment of patients with moderate to severe osteoarthritis (OA) pain in the index knee |
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E.2.2 | Secondary objectives of the trial |
To ssess the safety and tolerability of AKR 202 in patients with moderate to severe OA pain in the index knee.
To assess further aspects of efficacy of AKR 202 (such as Patient Global Assessment, Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC] pain subscale, stiffness, physical function scores) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Willing and able to provide informed consent
2. Patient is between 40 and 75 years of age
3. Clinical diagnosis of OA of the knee for more than 6 months prior to Visit 1 based on clinical and radiographic criteria
4. Patient is of American Rheumatism Association (ARA) functional Class I, II, or III
5. Patients should have an average pain level of between 4 and 8 on a Numeric Rating Scale (NRS) for at least 5 of 7 days before the randomisation, when answering the question: Please, rate the average pain in your index knee during the last 24 hours
6. Patients should use pharmacological treatments, such as Non-Steroidal Anti-Inflammatory Drug (NSAIDs), acetaminophen or weak opiods for their OA pain on a regular basis (defined as having used NSAIDs, acetaminophen or weak opiods at least 10 days out of 30 days during the last month prior to the screening visit)
7. Female patients of childbearing potential must have a negative pregnancy test prior to study enrolment
8. Patient is using adequate contraceptive measures from Visit 1 until 3 months after the last dose of IMP
Female patients who have been post-menopausal for more than one year or female patients of childbearing potential using a highly efficient method of contraception (i.e. a method with less than 1% failure rate [e.g. sterilisation, hormone implants, hormone injections, some intrauterine devices, or vasectomised partner])
Male patients agreeing to use condoms during the study and for 3 months after the last dose of the IMP, or patients having a partner who is using a highly efficient method of contraception as described above
9. Patient is willing to avoid unaccustomed physical activity for the duration of the study and follow-up period
10. With the exception of OA, the patient is judged, by the Investigator, to be in good general health based on medical history, physical exam, and routine laboratory tests
11. Patient is able to read, hear, understand, and complete study questionnaires, including questions requiring a NRS
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E.4 | Principal exclusion criteria |
1. Patient has a concurrent medical/arthritic disease that could confound or interfere with evaluation of efficacy
2. Patient is legally incompetent (e.g., a minor or mentally incapacitated), or has active psychosis, or significant emotional problems at the time of the study which in the view of the Investigator are sufficient to interfere with the conduct of the study
3. Patient has a history of gastric or biliary surgery (including gastric bypass surgery), or small intestine surgery, either of which causes clinical malabsorption
4. Patient has a history of Hepatitis B, Hepatitis C or Human Immunodeficiency Virus (HIV), or positive viral test result for Hepatitis B or C or HIV 1 or 2
5. Patient is allergic to, or has a history of a significant clinical or laboratory adverse experience associated with AKR 202 or any of its constituents
6. Patient has an estimated creatinine clearance less than or equal to 50 ml/min, or patients taking medications that might impaire renal function
7. Patient has New York Heart Association (NYHA) Class III-IV congestive heart failure
8. The patient has a history of uncontrolled hypertension or a current blood pressure that in the opinion of the Investigator makes the patient unsuitable for the study
9. Patient has moderate or severe hepatic insufficiency defined as Child Pugh score >6, or serum transaminase levels (Alanine Aminotransferase [ALT] or Aspartate Aminotransferase [AST]) of >1.5 X upper reference level for normal
10. Patient has a history of neoplastic disease within the last 5 years, or a current neoplastic disease, with the exception of basal carcinoma
11. Patient has a history of any illness, which in the opinion of the Investigator, might confound the results of the study or pose additional risk to the patient
12. Patient has a history of alcohol or substance abuse
Patient is, at the time of screening, a user of recreational or illicit drugs or has had a recent history (within the last 2 years) of drug or alcohol abuse or dependence. Or the patient has a currently weekly alcohol consumption of >14 units for females and >21 units for males
13. Patients considered morbidly obese with a Body Mass Index (BMI) ≥40 kg/m2
14. Patient has (within 4 weeks of the screening visit ,Visit 1) started or changed the following non medical treatment: physical medicine modalities involving the study joint, including but not limited to: physical therapy, chiropractic interventions, acupuncture, herbal medication administered for OA, Transcutaneous Electrical Nerve Stimulator (TENS), and ultrasound
15. Patients with a trauma or surgery at the index knee within 3 month prior to screening (Visit 1)
16. Patient is expected to undergo in-patient hospitalisation or any planned surgery during the course of the study
17. Patients using oral or injectable steroids or other immunosuppressant medication within 2 months prior to screening (Visit 1)
18. Patients using corticosteroid, hyaluronic acid or Autologous Conditioned Plasma (ACP) injections to any joint within 2 months prior to screening (Visit 1)
19. Patients using topical or systemic analgesic medications not allowed in the study protocol at any time during the study, with the exception of low-dose aspirin (≤325 mg/day) used for prophylaxis of cardiovascular events
20. Patients with clinically significant abnormalities, as judged by the Investigator, on Visit 1 clinical examination or laboratory safety tests
21. Patients currently participating in or has participated in a study with an investigational drug or device within 4 weeks prior to screening (Visit 1)
22. Female patients: currently pregnant or breast-feeding or intending to become pregnant within 3 months after last dose of IMP or intending to donate ova during such time period
23. Use of strong opioids or other central acting drugs for analgesic purposes within the 3 months prior to screening (Visit 1)
24. Previous or current prescribed use of strong opioids for the treatment of pain due to OA
25. Previous or current use of Nerve Growth Factors (NGF)
26. Donation of blood or plasma 12 weeks prior to or planned during the study period, including the 4 week follow-up period.
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline in WOMAC pain subscale at Week 8 or at the final visit at the time of patient discontinuation |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary endpoint: Week 8 or at the final visit at the time of patient discontinuation |
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E.5.2 | Secondary end point(s) |
• Change from baseline in the Patient Global Assessment at Week 4 and Week 8 or at the final visit at the time of patient discontinuation
• Change from baseline in WOMAC pain subscale at Week 4 or at the final visit at the time of patient discontinuation
• Change from baseline in the WOMAC OA function subscale score at Week 4 and Week 8 or at the final visit at the time of patient discontinuation
• Change from baseline in the WOMAC OA Index stiffness subscale score at Week 4 and Week 8 or at the final visit at the time of patient discontinuation
• Change from baseline in the total WOMAC OA Index pain, stiffness and physical function subscale score at Week 4 and Week 8 or at the final visit at the time of patient discontinuation
• Change from baseline for each of the WOMAC OA questions at Week 4 and Week 8 or at final visit at the time of patient discontinuation
• Proportion of patients with a reduction of 50% and more and an absolute decrease of 2 points or more in WOMAC pain or physical function sub scales, or two of the following three findings:
o A decrease in WOMAC pain subscale by 20% or more and an absolute reduction by 1 point or more
o A decrease in WOMAC physical function subscale by 20% or more and an absolute reduction by 1 point or more
o A decrease in patients global assessment by 20% or more and an absolute reduction by 1 point or more
• Pain rating captured on a NRS by daily questions through the IVRS during 7 days before the baseline visit and during 7 days before the Week 8 visit by answering the following questions: 1) Please, rate the average pain in your index knee during the last 24 hours; 2) Please, rate the worst pain in your index knee during the last 24 hours
• Pain rating captured on a NRS at the baseline visit, the Week 4 visit and the Week 8 visit by answering the following questions: 1) Please, rate the average pain in your index knee during the last 24 hours; 2) Please, rate the worst pain in your index knee during the last 24 hours.
• Use and amount of rescue medication: Compliance/accountability check at the clinic visits Week 4 and Week 8
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoint: Week 4 and/or week 8 and/or at the final visit at the time of patient discontinuation |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 22 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of study is defined as the date of the last patient’s last follow up call |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |