| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Osteoarthritis of the knee |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10031165 |
| E.1.2 | Term | Osteoarthritis knee |
|
| 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 |
Part A
• To investigate the safety and tolerability of ESBA105 administered by intraarticular injection into the osteoarthritic knee joint
• To determine the systemic exposure to ESBA105 upon intra-articular injection into the osteoarthritic knee joint
• To determine the appropriate doses of ESBA105 for Part B of the study
Part B
• To investigate the safety and tolerability of ESBA105 administered by intraarticular injection into the osteoarthritic knee joint
• To determine the systemic exposure to ESBA105 upon intra-articular injection into the osteoarthritic knee joint
• To evaluate the extent and explore the duration of effect on signs and symptoms of osteoarthritis of the knee of two different doses of ESBA105
|
|
| E.2.2 | Secondary objectives of the trial | |
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| In part B of the study regular MRI assessments will be conducted on a sub-population of patients, who agree to undergo such assessments. MRIs will be read centrally. MRI changes (in subset of patients in Part B only) from baseline to Day 7 and Week 12 will be evaluated and summarised descriptively. |
|
| E.3 | Principal inclusion criteria |
• Signed and dated Informed Consent.
• Male or female.
• >= 40 years of age.
• Body mass index < 30.
• Negative pregnancy test for females of child bearing potential (pre-menopausal, < 2 years post-menopausal, not surgically sterile).
Female patients of childbearing potential and their partners must to use 2 forms of contraception (including 1 barrier method), from screening until 2 months after the injection with ESBA105.
Primary forms of contraception include intrauterine devices, oral contraceptive agents that the patient has already been using for at least 90 days before screening, and injectable/implantable/insertable hormonal birth control products. Secondary forms of contraception include diaphragms, latex condoms, and cervical caps.
• Patients with diagnosed OA of the knee (unilateral or bilateral) according to the American College of Rheumatology (ACR) Criteria for classification of idiopathic OA (clinical and radiological criteria) of the knee at Screening (for ACR criteria, see Appendix 16.1).
• Radiographic evidence of tibiofemoral OA within the last 6 months before Screening, consisting of Grade II or Grade III changes, according to Kellgren Lawrence grading system.
• Presence of pain in the index knee (in case of bilateral OA, “index knee” is the more painful knee) defined by a level of >= 60 mm on a 100 mm (linear) VAS at Screening.
• Paracetamol and NSAIDs (apart from acetyl salicylic acid ≤ 100 mg/day) must be withdrawn at least 24 hours prior to Screening (Day -7 [-3 days]).
• Paracetamol, which is allowed to be re-initiated after completion of Screening assessments (Day -7 [-3 days]), must be withdrawn again as of Day -3.
• Doses of “chondroprotective” agents containing glucosamine and/or chondroitin sulphate must be stable for at least 3 months prior to Screening.
• Doses of any non-prescription medication claiming effects on signs or symptoms of OA (e.g., Rosa canina (lithocin), Perna canaliculus (“Grünlippenmuschelextrakt”), Harpagophytum procumbens (“Teufelskralle”)) must be stable for at least 3 months prior to Screening.
• Use of non-pharmacological treatment modalities (e.g., physical therapy, biomechanical devices, magnetic therapy, ointments, and heating pads) must be stable for at least 3 months prior to Screening.
• Negative QuantiFERON-TB Gold test.
• Ability to comply with the study requirements
|
|
| E.4 | Principal exclusion criteria |
• Radiographic evidence of tibiofemoral OA within the last 6 months before Screening, consisting of Grade IV, according to Kellgren-Lawrence grading system.
• Instability of the index knee joint of > 10° as assessed by goniometer at Screening.
• Arthroscopic or open surgery to the index knee joint within 6 months prior to Screening.
• Post-traumatic or any other secondary OA of the knee (e.g., hemochromatosis, severe chondrocalcinosis characterised by linear calcification of the hyaline cartilage, major knee trauma (e.g., rupture of cruciate ligaments, joint fractures)).
• Relevant complex, radial or vertical meniscal tears if documented by pre-existing MRI scans.
• Isolated OA of the patello-femoral joint.
• Pain in the hip as assessed upon internal and external rotation of the hip joint that would confound measurement of the knee pain.
• Co-morbidity that would confound measurement of knee pain (i.e., myopathy, spinal canal stenosis, radiculopathy) at Screening, if documented by pre-existing imaging.
• More significant pain from the back than the knee that would confound measurement of knee pain.
• Evidence of any inflammatory arthritis.
• History of Reiter’s Syndrome, RA, psoriatic arthritis, ankylosing spondylitis, lymphoma, arthritis associated with inflammatory bowel disease, sarcoidosis, amyloidosis, or any other inflammatory disease (immune mediated inflammatory disease) that may affect the knee.
• Clinical signs or symptoms of active knee infection at Screening or Baseline.
• Planned knee replacement during the course of the study.
• Local or systemic contraindication for an i.a. injection at Screening or Baseline.
• Treatment within 3 months prior to the injection with anticoagulant therapy.
• Treatment within 3 months prior to Screening or concomitant treatment with neuroleptic agents, monoamine oxidase inhibitors, serotonin/norepinephrine re uptake inhibitor, tricyclic antidepressants, anticonvulsants, or anti-parkinsonian drugs, potent analgesic agents (i.e., opiates).
• Treatment within 3 months prior to Screening or concomitant treatment with systemic corticosteroids.
• Skin barrier breakdown (e.g., psoriasis) at the knee where the injection would take place at Screening or Baseline.
• Any known sensitivity to E. coli derived products.
• Any i.a. injection (corticosteroids, hyaluronic acid, etc.) within the 3 months prior to Screening.
• History of high risk exposure to Mycobacterium tuberculosis.
• Positive urine opiate test.
• History of, or known current problems with drug or alcohol abuse at Screening.
• History or suspicion of unreliability, poor cooperation or non-compliance with medical treatment at Screening.
• HIV, hepatitis B or C infection.
• Uncontrolled diabetes mellitus or cardiovascular disease (NYHA criteria III + IV), incl. uncontrolled hypertension (> 160/100 mmHg).
• Active infectious episodes, or history of recurrent or chronic systemic infections.
• Malignancy within 5 years prior to Screening, except for surgically-cured non melanoma skin cancer or cervical carcinoma in situ.
• Significant haematological disease including leukopenia (total white blood cell count <2.0 x 109/L) or thrombocytopenia (<150,000 / mm3) within 1 month prior to or at Screening.
• Moderately to severely impaired hepatic function, or laboratory values reflecting inadequate hepatic function (> 3 x upper limit of normal in ALT and AST at Screening).
• Received any live vaccine within 3 months prior to Screening.
• Receiving investigational drug within 3 months before screening.
• Taking or planning to take any investigational drugs during the course of the study.
• Presence of chronic renal failure defined by a calculated creatinine clearance (CrCl) of < 40 mL/min, using the Cockcroft-Gault estimate for GFR as follows: CrCl=(140-age (years)) x weight (kg))/(serum creatinine (mg/dL) x 72), with female gender adjustment (CrCl female = CrCl x 0.85).
• Use of cyclosporine, mycophenolate or tacrolimus within 3 months of screening and during the study.
• Previous or current use of etanercept, adalimumab, rituximab or infliximab.
• Patients with a pending disability claim or OA related litigation.
• Have previously been randomised to ESBA105CRD02.
• Are nursing mothers at Screening or are planning to nurse a baby during the study.
• Have any concurrent disease or condition that, in the opinion of the Investigator, would make the patient unsuitable for participation in the study.
Additional criteria for the sub-population of patients undergoing MRI (Part B only):
• Contraindications to MRI.
• Known allergy to gadolinium contrast material.
• Presence of chronic renal failure defined by a calculated creatinine clearance (CrCl) of < 60 mL/min, using the Cockcroft-Gault estimate for GFR as follows: CrCl=(140-age (years)) x weight (kg))/(serum creatinine (mg/dL) x 72), with female gender adjustment (CrCl female = CrCl x 0.85). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Primary efficacy endpoint is the change from Baseline (Day 0) to Day 7 in Visual Analogue Scale (VAS) to assess the intensity of knee pain. The VAS pain intensity score will be determined by measuring the change in millimetres on a 100 mm scale, as indicated by the patient marks. |
|
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| 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.8.3 |
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 | 10 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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
|
| The overall end of this study will be reached when the last patient has completed the final Follow-up visit of part B. |
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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