Evaluation of Intra-Articular Clodronate Disodium for Efficacy and Tolerability in Patients with Knee Osteoarthritis: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this clinical trial is to evaluate the **safety** and **tolerability** of different escalating doses of intra-articular clodronate in patients with painful knee osteoarthritis. This will be assessed in terms of serious adverse events (SAEs), adverse events (AEs), and any abnormal laboratory or clinical signs of intolerance. Additionally, the trial aims to determine the dose to be used in Phase III, defined as the lowest clodronate dose that results in a ≥ 10-mm reduction in the Visual Analogue Scale (VAS) of knee pain at Week 7 compared to placebo. In Phase III, the objective is to confirm the therapeutic efficacy of the determined dose in patients with knee osteoarthritis, again based on the VAS score of knee pain at Week 7 versus placebo, while also assessing safety and tolerability.

Secondary objectives include: assessing VAS knee pain at each visit; describing the effects of different escalating doses of intra-articular clodronate on knee function using the Lequesne Algofunctional Index and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC); evaluating knee range of motion through knee extension and flexion; and measuring the consumption of rescue medication (paracetamol) in patients treated with different doses of intra-articular clodronate. In Phase III, the effects of the determined dose on knee function will be assessed using the Lequesne Algofunctional Index and WOMAC index, and the use of rescue medication in patients with knee osteoarthritis treated with the determined dose will be measured.

The clinical trial focuses on evaluating the safety, tolerability, and therapeutic efficacy of clodronate in patients with **knee osteoarthritis**. The study population comprises both female and male participants aged between 50 and 75 years, as per the inclusion criteria. Participants are required to have a confirmed diagnosis of knee osteoarthritis according to the American College of Rheumatology, with a Kellgren-Lawrence radiographic score between 2 and 3 degrees in the tibiofemoral joint. The trial includes individuals who have experienced symptomatic knee osteoarthritis for at least six months, with a knee pain visual analog scale (VAS) score ranging from 40 to 80 mm at the screening visit. Female participants of childbearing potential must have a negative pregnancy test and use adequate contraception throughout the study. The trial population selection criteria ensure a representative sample of the target demographic, although the total number of participants is not disclosed by the sponsor. Participants' general health status and lifestyle considerations, such as diet and physical activity, are not specified in the available data.

The clinical trial is designed as an **adaptive, multicenter, randomized, double-blind, parallel-group, placebo-controlled** study to evaluate the efficacy and tolerability of escalating doses of intra-articular **clodronate disodium** in patients with painful knee osteoarthritis. The trial is structured in two phases: Phase II focuses on assessing the safety and tolerability of different doses, while Phase III aims to confirm the therapeutic efficacy of the determined therapeutic dose (DTD). The primary endpoint is a reduction of ≥10 mm in the Visual Analog Scale (VAS) of knee pain at Week 7 compared to placebo. Secondary endpoints include mean changes in VAS scores, Lequesne Algo-functional Index, WOMAC Index, range of motion, and rescue drug consumption across visits.

The trial is expected to commence recruitment on March 1, 2023, and conclude by October 1, 2025. Participants will be involved for a maximum treatment period of 4 weeks, with the study comprising several key visits. The inclusion visit, or screening, will confirm eligibility based on criteria such as age, diagnosis of knee osteoarthritis, and radiographic evidence. Baseline assessments will be conducted prior to the first dose. Follow-up visits will occur weekly to monitor safety, efficacy, and any adverse events. The end-of-study visit will finalize data collection and assess the overall outcomes.

Participants are expected to remain in the study for the full duration unless conditions arise that necessitate early termination, such as significant adverse events or withdrawal of consent. The trial will adhere to rigorous ethical standards, ensuring that all participants provide informed consent and that their safety is continuously monitored throughout the study. The investigational product, **disodium clodronate**, will be administered via intra-articular injection, with doses ranging from 2 mg to 10 mg, depending on the study arm. A placebo group will receive an identical composition without the active substance to maintain blinding and control for placebo effects.

The clinical trial involves the administration of **disodium clodronate**, a chemical compound used in the treatment of painful knee osteoarthritis. The investigational medicinal product is provided in the form of a **solution for injection**. The administration route is **intraarticular**, directly into the joint space. The trial evaluates three escalating doses of disodium clodronate: 10 mg, 5 mg, and 2 mg per day. The maximum total dose for each respective group is 40 mg, 20 mg, and 8 mg over a treatment period of 4 weeks. The pharmaceutical form and administration method are consistent across all doses, ensuring uniformity in delivery. The product is manufactured by SPA-SOCIETA PRODOTTI ANTIBIOTICI S.P.A., and the sponsor product code is SPA-S-899.

The trial also includes a **placebo** group to serve as a comparator. The placebo is identical in composition to the investigational medicinal product, except for the absence of the active substance, clodronate disodium. This ensures that any observed effects can be attributed to the active treatment rather than other components of the injection solution. The placebo is administered via the same intraarticular route and follows the same dosing schedule as the active treatment groups.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol. The trial is designed to assess both the safety and efficacy of the investigational product, with a focus on determining the optimal dose that achieves a significant reduction in knee pain as measured by the Visual Analog Scale (VAS) at Week 7, compared to the placebo group.

The efficacy of the clinical trial will be assessed primarily through the measurement of knee pain reduction using the Visual Analogue Scale (VAS). A dose of **clodronate** will be considered effective if it results in a reduction of 10 mm or more in the VAS score of knee pain at Week 7 compared to placebo. Secondary efficacy endpoints include mean changes in the VAS of knee pain at various visits compared to both placebo and baseline, as well as mean changes in the Lequesne Algo-functional Index, WOMAC Index, and Range of Motion at each visit. Additionally, the use of rescue medication, specifically paracetamol, will be monitored across patient visits.

Efficacy parameters will be collected and analyzed at multiple timepoints, including baseline, Weeks 1, 2, 3, and 7. The VAS score will also be assessed 120 minutes post-intra-articular injection at baseline and during the first three weeks. These assessments will be conducted using validated scales and patient-reported outcomes to ensure accuracy and reliability. The trial aims to confirm the therapeutic efficacy of the determined therapeutic dose (DTD) of clodronate in patients with knee osteoarthritis, as well as to evaluate its safety and tolerability.