Clinical Trial to Assess Efficacy, Tolerability of Rising Doses of Clodronate in Painful Knee Osteoarthritis Patients

The goal of this clinical trial is to to clarify which is the best dose of administration, to select a dose and to confirm the therapeutic efficacy of clodronate in patients with painful knee osteoarthritis (OA). The clinical trial will be divided in two parts.

The main questions it aims to answer are:

* in Phase II, to assess the safety and tolerability of different escalating doses of intra articular (IA) clodronate
* in Phase II, to set a defined therapeutic dose (DTD) to be used in Phase III
* in Phase III, to assess the safety and tolerability of different escalating doses of IA clodronate to confirm and extensively evaluate the therapeutic efficacy and safety of the clodronate DTD in patients with knee OA

The phase II will be a multicenter, double-blind, randomized, placebo-controlled, parallel group four-arm study, according to the treatment dose (dose finding).

Briefly, 4 groups of 74 patients (in order to have 64 fully evaluated patients taking into consideration 10 patients dropped out), i.e. a total of 296 patients, with knee OA each will be randomly allocated to the following treatments:

1. IA clodronate 2 mg/2 ml once a week for 4 weeks (total clodronate dose = 8 mg).
2. IA clodronate 5 mg/2 ml once a week for 4 weeks (total clodronate dose = 20 mg).
3. IA clodronate 10 mg/2 ml once a week for 4 weeks (total clodronate dose = 40 mg).
4. Placebo 2 ml once a week for 4 weeks (total clodronate dose = 0 mg).

At the end of phase II, the minimum effective clodronate dose will be selected as DTD for the Phase III.

The phase III will be a multicenter, double-blind, randomized, placebo-controlled, two parallel groups (DTD vs. placebo) study.

Briefly, patients with knee OA will be randomly assigned to two experimental groups:

1. the DTD defined during the Phase II.
2. Matching placebo. The sample size of Phase III will be definitively calculated according to the extent of pain Visual Analogue Scale (VAS) reduction observed in the Phase II.

Eligibility Criteria:
Inclusion Criteria:

* Female and male patients aged 50 up to 75 years at ICF signature.
* Diagnosis of knee OA according to the American College of Rheumatology, confirmed by Rx during the screening (a Rx performed in the last 3 months before Baseline is accepted).
* Kellgren-Lawrence radiographic score between 2 and 3 degrees in the tibiofemoral joint.
* Symptomatic knee OA (pain) since at least 6 months with a knee pain (VAS) ranging between 40 and 80 mm at Screening visit (the figure should be confirmed at Baseline).
* Female patients of childbearing potential must have a negative pregnancy test before each treat-ment and during the Visit 5 - Week 4 and they must use adequate methods of contraception throughout the course of the study.
* A signed ICF by the patient after exhaustive study discussion with the investigators.

Exclusion Criteria:

* BMI \> 35 kg/m² (Class II obesity).
* Joint instability due to other reasons than knee OA, such as f.i. algo dystrophic syndrome, either partial or complete rupture of internal / externals ligaments, kneecap instability, etc.
* Otherwise located lower limb pain, such as hip pain.
* Other musculoskeletal disorders related to the target knee.
* Any treatment with IA drugs in the last 3 months before Day 0 - Baseline (including any formulation of corticosteroids or hyaluronic acid injections).
* Corticosteroid use by any systemic route, and hyaluronic acid injection or intraarticular corticosteroids for any other joint in the previous month will not be permitted.
* Any treatment with systemic non-steroidal anti-inflammatory drugs (NSAIDs) in the week before enrolment, or any steroid anti-inflammatory drugs and chondroprotective drugs in the thirty (30) days before month before Baseline.
* Any treatment with systemic bisphosphonates in the last twelve (12) months before Baseline.
* Any treatment with Glucosamine or Chondroitin sulfate, Diacerein and Matrix metalloproteinase (MMP) inhibitors in the 4 weeks before Baseline.
* Any treatment with Denosumab in the twelve (12) months before Baseline.
* Any treatment with Paracetamol in the twelve (12) hours before Baseline.
* Any knee surgery in the past or knee arthroplasty.
* Any diagnostic or surgical arthroscopy of the knee in the six (6) months before Baseline.
* Any jaw osteonecrosis in the last twenty-four (24) months before Baseline or at a risk of jaw osteonecrosis.
* Any known hypersensitivity to the drug in the study to its excipients or other bisphosphonates, and any hypersensitivity to Paracetamol (rescue drug).
* Any participation in a clinical study in which the last administration of the investigational medicinal product was within two (2) weeks before consenting to study participation (i.e.signing ICF).
* Inadequate organ function defined by the following laboratory parameters:

  1. Absolute Neutrophil Count (ANC) \< 1500/μl.
  2. Hemoglobin (Hb) \< 9 g/dl (\< Hb 5.6 mmol/L)
  3. Platelet Count \< 100.000/μl
  4. Serum Creatinine \> 1.5 x Upper limit normal (ULN) or estimated Glomerular Filtration Rate (eGFR) \< 60 mL/min (as per Cockroft-Gault formula).
  5. Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST)\> 1.5 x Upper limit normal(ULN).
  6. Serum Total Bilirubin \> 1.5 x Upper limit normal (ULN).
* Pregnant or breastfeeding women, or women planning to become pregnant during the study.
* Any positive or suspected history of alcoholism or drug use.
* Clinically significant (i.e.) gastrointestinal, renal, hepatic, pulmonary, cardiovascular or neurological disease that could interfere with the outcome of the study or the patient's ability to comply with study requirements.
* Patients unwilling or unable to comply with the protocol.