E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 10019115 |
E.1.2 | Term | Hand osteoarthritis |
E.1.2 | System Organ Class | 100000004859 |
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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 AMAP102 in patients with pain secondary to osteoarthritis (OA) over 28 days of dosing |
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E.2.2 | Secondary objectives of the trial |
• To assess the efficacy of AMAP102 in OA patients. • To assess the safety and tolerability of AMAP102 in OA patients. • To measure the plasma concentrations of AMAP102 in OA patients. • To explore the effects of AMAP102 on interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF α), cartilage oligomeric matrix protein (COMP), and serotonin (5-HT) in OA patients
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female outpatients aged ≥ 50 years. 2. Male or female outpatients with a body mass index of 18 to 30 kg/m2 and a minimum weight of 50 kg. 3. Patients with a clinical diagnosis of unilateral or bilateral knee OA based on clinical and radiographic criteria. Patients should fulfill the validated criteria for the classification of primary OA, published by the American College of Rheumatology (ACR): • The ACR Classification Criteria (1986) for clinical and radiographic OA of the knee are: - Knee pain. - Osteophytes - And one of the following: o Age ≥ 50 years. o Stiffness of < 30 minutes upon rising in the morning. o Crepitus. 4. Patients taking non-steroidal anti-inflammatory drugs (NSAIDs) or paracetamol at a dose suggested by the European Medicines Agency-approved over-the-counter/prescription labelling on a regular basis (approximately 20 of the past 30 days) prior to the screening visit and with a history of knee pain treatment response with NSAID or paracetamol use. 5. Patients with mild to moderate OA of the knee at the screening visit (Visit 1). Mild to moderate OA of the knee is defined using the following criteria: • Mild: mild symptoms (no limitations of normal activities). • Moderate: moderate symptoms (limitation of some normal activities). • Severe: severe symptoms (inability to carry out most normal activities). • Extreme: very severe symptoms (inability to carry out all normal activities). 6. Patients with arthritis ‘flare’ in the target knee within 12 days of withdrawing from NSAID or paracetamol. Flare, by definition, must meet the criteria described below and the patient should be randomised as soon as these criteria are met: • Minimum score of 5 or greater on the 11-item NRS for the patient’s overall pain intensity during activity in the target knee for the last 24 hours on 2 consecutive days, taken from patient’s diary and a score of 5 or greater in the target knee at Visit 2 (baseline). • Increase of at least 2 on the NRS for the patient’s overall pain intensity during activity in the target knee within the last 24 hours when compared with the value obtained at the screening visit (Visit 1). 7. Ability to provide written, personally signed, and dated informed consent to participate in the study, in accordance with the ICH GCP Guideline E6 and applicable regulations, before completing any study related procedures. 8. An understanding, ability, and willingness to fully comply with study procedures and restrictions. 9. The ability to swallow and retain all of the investigational medicinal product. |
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E.4 | Principal exclusion criteria |
1.The patient has primary inflammatory diseases of the joint (e.g.rheumatoid arthritis,psoriatic arthritis,Reiter’s syndrome,arthritis of inflammatory spondyloarthropathy or inflammatory bowel disease, or infectious arthritis). 2.The patient has unstable knees including a history of the knee catching or giving way and/or physical examination evidence of instability (e.g.positive posterior drawer sign,positive Lachman,positive anterior drawer sign,medial or lateral collateral ligament instability,etc). 3.The patient has arthropathies that occur in conjunction with systemic diseases such as chondrocalcinosis,chondromatosis,gout,pseudo gout,haemophilia,or collagen vascular disease. 4.The patient has a chronic pain condition (e.g.somatisation disorders,chronic headache,fibromyalgia,etc).The patient has chronic lower back pain (individual cases should be discussed with the Medical Monitor) that could confound the analgesic response of the study medication. 5.The patient has a history of knee surgery within the past 12 months,arthroscopy within the past 6 months,or is anticipated to undergo knee surgery in next 3 months or general surgery during the time of participation in the study. 6.The patient has advanced joint damage (Kellgren-Lawrence grade 4); or,in the opinion of the investigator,the patient has advanced joint damage assessed without an X-ray. 7.The patient has a history of osteotomies. 8.The patient is using any of the prohibited medications that are listed in Table 3 of the protocol. 9.The patient used opioids (e.g.codeine,propoxyphene,or combinations of these drugs with NSAIDs or paracetamol) for OA pain within 1 month or 5 half-lives of the drug (whichever is longer) prior to the screening visit (Visit 1). 10.The patient received intra-articular injections of sodium hyaluronate agents within 6 months or 5 half lives of the drug (whichever is longer) before the screening visit (Visit 1) or steroids in joints other than the knee or intravenous or intramuscular steroids within 2 months or 5 half-lives of the drug (whichever is longer) before the screening visit (Visit 1). 11.The patient used oral steroids,intra-articular steroids in the knee, or other immunosuppressant medications within 2 months or 5 half-lives of the drug (whichever is longer) before the screening visit (Visit 1). 12.The patient received methotrexate within 30 days before the screening visit (Visit 1). 13.The patient must agree not to take rescue medication (paracetamol) between the screening visit and baseline, and for 24 hours before any clinic visit. 14.The patient has significant renal impairment (defined as a serum creatinine > 2 x upper limit of normal [ULN] or creatinine clearance < 30 mL/min), liver enzymes elevated > 3 x ULN, positive class III/IV angina or uncontrolled congestive heart failure in the opinion of the investigator, significant active hepatic disease, history of malignant neoplastic disease (other than basal cell carcinoma of the skin) within the past 5 years, or a current severe infectious disease with or without fever. 15.The patient is a woman of childbearing potential who has a positive serum pregnancy test or is a nursing mother. The patient is not surgically sterile (by tubal ligation or hysterectomy) or at least 2 years postmenopausal and has not practiced an acceptable form of birth control (defined as the use of an intrauterine device with spermicide, a barrier method with spermicide, condoms with spermicide, subdermal implant, oral contraceptives, or abstinence) for at least 2 months before the screening visit (Visit 1). 16.The patient has a clinically significant psychiatric condition or history of substance abuse or dependence as defined by the Diagnostic and Statistical Manual of Mental Disorders-IV within 1 year before the screening visit (Visit 1), which in the opinion of the investigator may interfere with participation in the study. 17.The patient has a score of 14 or higher on the Beck II Depression Inventory at the screening visit (Visit 1). 18.The patient received another investigational drug or device or participated in any other clinical study within 1 month or 5 half-lives of the drug (whichever is longer) before the screening visit (Visit 1). 19.The patient has a heavy alcohol consumption rate (i.e., more than 35 units per week or 8 units per day for men, or more than 24 units per week or 6 units per day for women; 1 unit is defined as 35 cL beer, 6 cL hard alcohol, or 18 cL wine). 20.The patient is an employee, or family member of an employee, of the study centre, the CRO (PRA), or the Sponsor (AnaMar AB) involved in this study. 21.The patient is unsuitable to participate in the study in the opinion of the investigator. 22.The patient answers yes to either question 4 or 5 of the screening visit version of the C-SSRS. 23.The patient has a history of dysrhythmias (e.g., bradycardia or tachycardia) or any clinical significant cardiac disease. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint: WOMAC Pain subscale for the target knee.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary Efficacy Endpoint: at Visit 2 (Day 1) Visit 3 (Day 7), Visit 4 (Day 14) and Visit 5 (Day 28) |
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E.5.2 | Secondary end point(s) |
• Daily 24-hour average pain during activity score in the target knee measured with the NRS from the patient’s daily diary. • Daily 24-hour average pain score in the target knee measured with the NRS from the patient’s daily diary. • Daily 24-hour average worst pain score in the target knee measured with the NRS from the patient’s daily diary. • Daily cumulative proportion of responders from baseline to on average 24-hour pain during activity scores in the target knee assessed with the NRS from the patient’s daily diaries. A responder is defined as a patient who achieves and maintains a 30% improvement in the average 24-hour pain during activity scores over baseline until the end of the study. • Number of responders, defined as patients who achieve and maintain a 30% improvement in the average 24-hour pain during activity scores in the target knee over baseline until the end of the study. • Average daily and weekly use and total use of rescue medication (paracetamol). • Daily quality of sleep rating assessed by the Modified Pittsburgh Sleep Quality Index. • WOMAC Stiffness subscale for the target knee. • WOMAC Physical Functioning subscale for the target knee. • WOMAC total score for the target knee. • Patient global assessment of study drug satisfaction. • Investigator global assessment of study drug satisfaction. • EQ-5D-5L™. • Serum hsCRP levels.
Safety Endpoints: Safety will be assessed using incidence of all adverse events, serious adverse events and those leading to withdrawal of study medication, review of clinical laboratory assessments (haematology, clinical chemistry and urinalysis), concomitant medications, ECG monitoring, physical examinations, vital signs, body weight and C-SSRS.
Pharmacokinetic Endpoints: • Plasma AMAP102 concentrations at Visit 3 (Day 7), Visit 4 (Day 14), Visit 5 (Day 28) and Visit 6 (Day 35) after b.i.d. dosing in each treatment group. • The proportion of patients in each treatment group showing measurable amounts of AMAP102 at Visit 3 (Day 7), Visit 4 (Day 14), Visit 5 (Day 28) and Visit 6 (Day 35).
Exploratory Endpoints: • Serum IL-6, TNF-α and COMP and serum and plasma 5-HT levels at Visit 2 (Day 1), Visit 3 (Day 7), Visit 4 (Day 14), Visit 5 (Day 28) and Visit 6 (Day 35). • AUSCAN Pain subscale for the target hand. • Daily 24-hour average pain during activity score in the target hand measured with the NRS from the patient’s daily diary. •Daily 24-hour average pain score in the target hand measured with the NRS from the patient’s daily diary. • Daily 24-hour average worst pain score in the target hand measured with the NRS from the patient’s daily diary. • Daily cumulative proportion of responders from baseline on average 24 hour pain during activity scores in the target hand assessed with the NRS from the patient’s daily diaries. A responder is defined as a patient who achieves and maintains a 30% improvement in the average 24-hour during activity pain scores over baseline until the end of the study. • Number of responders, defined as patients who achieve and maintain a 30% improvement in the average 24-hour pain during activity scores in the target hand over baseline until the end of the study. • AUSCAN Stiffness subscale for the target hand. • AUSCAN Physical Functioning subscale for the target hand. • AUSCAN total score for the target hand. Note: the AUSCAN and NRS endpoints for the target hand will only be assessed on the sub population of patients with arthritis ‘flare’ in the target hand (Appendix 2: Definition of the Target Joint) at the baseline visit. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
AUSCAN Pain subscale-at Visits 2, 3, 4 & 5 Average pain in target knee, at rest & during activity-Daily Average pain in target hand at rest & during activity-Daily Worst pain in target knee & hand-Daily Rescue medication use-Daily Quality of sleep-Daily AUSCAN Stiffness & Physical Functioning subscales & total score for target hand-at Visits 2, 3, 4 & 5. WOMAC Physical Functioning subscale & total score for the target knee at Visits 2, 3, 4 & 5 Patient & Investigator global assessment of study drug satisfaction - at Visits 3, 4 & 5 EQ-5D-5L™ - at Visits 2, 3, 4 & 5 Serum hsCRP levels - at Visits 2, 3, 4, 5 & 6 Safety Endpoints: ongoing Pharmacokinetic Endpoints: at Visits 3, 4, 5 & 6 Explorative Laboratory Endpoints: at Visits 2, 3, 4, 5 & 6
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
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
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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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 13 |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 19 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 19 |
E.8.9.2 | In all countries concerned by the trial days | 0 |