| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Symptomatic osteoarthritis (OA) of the knee. |
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| E.1.1.1 | Medical condition in easily understood language |
| Degeneration of the cartilage of the knee joint |
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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 | 17.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10028395 |
| E.1.2 | Term | Musculoskeletal and connective tissue disorders |
| E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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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 evaluate fasitibant, given as single IA injection at three different doses versus placebo, as an efficacious symptom modifying treatment of knee OA. |
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| E.2.2 | Secondary objectives of the trial |
1.To assess the dose-effect relationship of fasitibant to support the choice of the dose to be studied in a subsequent clinical phase III study.
2.To evaluate the safety and tolerability of single IA fasitibant doses of 1 mg, 2.5 mg and 5 mg as 1 mL solution to patients with symptomatic knee OA.
3.To evaluate fasitibant population pharmacokinetics (pop-PK) in patients with symptomatic OA of the knee and the exposure-response relationship (PK/PD).
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Properly executed written informed consent.
2.Male or female patients 40-80 years old and with a BMI < 30 kg/m².
3.Mentally competent and compliant to undergo all visits and procedures scheduled in the study, including questionnaires/symptoms reporting.
4.Women of childbearing potential [i.e. not postmenopausal (postmenopausal defined as 52 years or older and amenorrhoeic for at least 2 years at Screening); not surgically sterile (i.e. have had a hysterectomy or bilateral oophorectomy tubal ligation), or otherwise be incapable of pregnancy], and sexually active are eligible, if they use a double-barrier method of contraception supplemented with the use of a spermicide for at least 30 days after treatment administration. Since a potential interaction between IMP metabolism and hormonal contraceptives cannot be fully excluded, the use of hormonal contraception (oral, injections or implants) is not regarded as highly effective method and it is not a sufficient method for contraception in this study. True sexual abstinence is considered an acceptable method ofcontraception.
5.Symptomatic primary osteoarthritis at the index knee (American College of Rheumatology [ACR] criteria) since ≥ 3 months prior to screening, with documented Kellgren Lawrence Grade 2 to 3 radiological severity, based on X-rays not older than 6 months prior to screening, for which an IA treatment is indicated.
NOTE: The radiographic technique used for the X-ray must be standardized and the full extension view (patient standing, central alignment of medial-tibial plateau, anterior-posterior-view) has to be used for grading of radiological severity in all eligible patients.
6.WOMAC VA 3.1 A subscore (total pain) at the target knee >= 200 mm and < 400 mm out of the 500 mm total score on visual analogue scale (VAS).
7.WOMAC VA 3.1 A1 subscore (pain while walking on a flat surface) at the target knee >= 40 mm and < 80 mm on a 100 mm visual analogue scale (VAS).
8.WOMAC VA 3.1 A subscore (total pain) at the contralateral knee < 150 mm out of the 500 mm total score on visual analogue scale (VAS).
9.Pain of moderate to severe intensity along the previous 4 weeks, even if treated with chronic doses of non steroidal antinflammatory drugs.
10.Minimum flexion of 90 degrees in both knees.
11.Ability to perform the 15-meter walk test without the support of crutches or other assistive devices.
12.Willingness to discontinue all analgesics or other OA medications (e.g. non-steroidal anti-inflammatory drugs [NSAIDs], cyclooxygenase-2 [COX-2] inhibitors, antidepressive agents) prior to randomisation and for the entire course of the study, with a minimum wash-out period corresponding to five half-lives of drug.
NOTE: This does not include paracetamol (acetaminophen), up to 4000 mg/24 hours, which may be used as rescue medication up to 48 hours prior to each visit, and low dose aspirin for cardioprotection, up to 100 mg/24 hours, or other salicilates at equivalent doses.
13.Willingness to refrain from paracetamol use 48 hours prior to each study visit.
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| E.4 | Principal exclusion criteria |
1.Inability to personally provide written informed consent (e.g. patients with psychiatric illness).
2.Inability to understand or collaborate with study procedures and requirements, including answering to the study questionnaire/symptoms reporting.
3.Patients who participated in another clinical trial within 30 days (90 days in case of OA trial) prior to screening.
4.Patients with Kellgren Lawrence Grade 1 or Grade 4 OA of the knee.
5.Knee condition representing on Investigator’s judgment an indication for surgery (e.g. significant axial deviation, severe medio-lateral and/or anterior-posterior instability, severe bone/joint deformity).
6.OA secondary to inflammatory/autoimmune forms of arthritis, septic arthritis, or genetic diseases, which have a distinct impact on the outcome.
7.Patients with acute fractures, severe loss of bone density, history of aseptic necrosis, isolated patella-femoral syndrome (i.e. chondromalacia), or joint replacement in the affected knee.
8.Patients with OA predominant in the lateral compartment, or any significant valgus deformity.
9.Patients who -as per Investigator’s judgment- have any clinically significant or unstable disease or condition interfering with the evaluation of the safety and efficacy of study treatment along the study period (e.g. clinically significant and unstable cardiovascular or respiratory diseases, congenital defects, spinal OA).
10.History of symptomatic severe hip OA and painful hip prosthesis.
11.Major injury (including ligament sprains or muscle/tendon strains > grade 2 and meniscal tears > grade 2) or major surgery to the index knee.
12.Any pain > 30 mm on a 100 mm visual analogue scale (VAS) that could interfere with the assessment of the index knee pain (e.g. local or radiating pain in any part of the lower extremities).
13.Clinically significant venous or lymphatic stasis in the relevant limb.
14.Acupuncture and physiotherapy in the last 4 weeks prior to randomisation, or likely to start during the course of the study.
15.Any pharmacological treatment of concomitant disease(s) started or changed during 4 weeks prior to randomisation, or likely to be changed during the course of the study.
16.Use of systemic or topical corticosteroids > 10 mg prednisolone equivalent per day, or immunosuppressant drugs during 30 days prior to randomisation, or likely to be used during the course of the study.
17.Use of any pain or OA medication (e.g. NSAIDs, COX-2 inhibitors, analgesics, antidepressive agents), including topical treatments, within a minimum of 5 times their half life prior to randomisation and during the course of the study.
18.Viscosupplementation (intra-articular injection of hyaluronic acid) to the target knee administered < 4 months prior to randomisation and/or scheduled during the course of the study.
Safety-related exclusion criteria
19.History of hypersensitivity/allergy to drugs including paracetamol and to disinfectants (antimicrobial soaps and /or povidone-iodine solution).
20. Use of any medications that are substrate of CYP3A4 and/or moderate or strong CYP3A4 inhibitors during the 4 weeks prior to Randomisation and the overall study duration.
21.Patients with any of the following:
a)clinically relevant cardiovascular, pulmonary, gastro-intestinal, haematological, neurologic, psychiatric or infectious diseases, or unstable metabolic diseases, or malignant neoplasms that, in the opinion of the Investigator, may pose the patient at risk, or confound the efficacy and safety results of the study;
b)clinically relevant (according to the investigator judgment) abnormal safety laboratory test results, and/or abnormalities in vital signs, and/or ECG parameters at screening, and/or prior to treatment administration.
22.Patients with liver disease (i.e. alkaline phosphatase, alanine aminotransferase [ALT], aspartate aminotransferase [AST] and/or conjugated bilirubin > 2x upper limit of normal [ULN]).
23.Patients with moderate or severe renal insufficiency (Creatinine Clearance [CrCl] according to Cockgroft-Gault formula < 60 mL/min).
24.Pregnant or breastfeeding women.
25.Any sign of significant immunodeficiency, systemic infection (fever, increased C-reactive protein [CRP], leukocytosis), knee infection (severe knee pain associated with fever, chills and inability to move the knee, tense effusion, with or without reddening or heating of the knee) or knee bursitis.
26.Any skin disorder or infection overlying the index knee.
27.Any IA or local peri-articular puncture, or injection to the index knee during the 3 months preceding screening.
28.Patients with bleeding diathesis or on therapy with anticoagulants (low-dose aspirin not exceeding 100 mg/24 hours, or other salicilates at equivalent doses are permitted).
29.Significant peri-articular calcification.
30.Previous infection to the index knee.
31.Previous ligament reconstruction of the index knee
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The Primary Efficacy Endpoint is the change of the WOMAC VA 3.1 A (total pain) subscore from baseline (Visit 2) over 2 weeks after randomisation. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| from randomization (T0) over 2 weeks after randomization |
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| E.5.2 | Secondary end point(s) |
Clinical Efficacy of study treatments (until 6 weeks):
Assessment of OA symptoms (pain, walking pain, stiffness, function) using validated standard questionnaires (WOMAC 3.1 VAS).
Assessment of pain at rest and after 15 meters walk.
Patients' global assessment of efficacy.
Patient’ evaluation of quality of life.
Use of Rescue Medication.
Exploratory efficacy endpoints
The changes from baseline (visit 2) over 12 weeks after randomisation and at 12 week of:
Assessment of OA symptoms (pain, walking pain, stiffness, function) using validated standard questionnaires (WOMAC 3.1 VAS).
Assessment of pain at rest and after 15 meters walk.
Patients' global assessment of efficacy.
Patient’ evaluation of quality of life.
Safety and tolerability of study treatments:
Changes in vital signs (blood pressure, pulse rate, respiratory rate,
body temperature; 12-lead electrocardiogram (ECG) parameters;
laboratory safety battery tests, and physical examination.
Incidence and severity of adverse events.
Local tolerability of study medication.
Pharmacokinetics of the study treatments in terms of absorption,
distribution, metabolism and elimination of the study treatments,
including analysis of dose proportionality.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Clinical Efficacy:
Between time of dosing (T0), 1 week (+/-1 days), 2 weeks (+/-1 days), 4 weeks (+/-1 days) and 6 weeks (+/-2 days) after treatment administration.
Exploratory efficacy:
Between time of dosing (T0) over 12 weeks and at 12 week.
Pharmacokinetics:
Between time of dosing (T0) and defined time points until 4 weeks (+/-21 days) after treatment administration
Safety and tolerability of study treatments:
Between time of dosing (T0), over 6 weeks (+/-2 days) after treatment administration.
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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 | Yes |
| 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 | 4 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| 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 | |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 15 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 15 |
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