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

NCT ID: NCT06263517

Last Updated: 2024-02-16

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 296 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-10-12
• Study Completion Date: 2025-10-31

Brief Summary

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

Detailed Description

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.

Conditions

Osteoarthritis of Knee

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Arm 1

Intra articular clodronate 2 mg/2 ml once a week for 4 weeks (total clodronate dose = 8 mg)

Group Type: EXPERIMENTAL

Clodronate

Intervention Type: DRUG

For Arm 1, patients will be treated with intra articular clodronate 2 mg/2 ml from Baseline to Week 3

Arm 2

Intra articular clodronate 5 mg/2 ml once a week for 4 weeks (total clodronate dose = 20 mg).

Group Type: EXPERIMENTAL

Clodronate

Intervention Type: DRUG

For Arm 2, patients will be treated with intra articular clodronate 5 mg/2 ml from Baseline to Week 3

Arm 3

Intra articular clodronate 10 mg/2 ml once a week for 4 weeks (total clodronate dose = 40 mg)

Group Type: EXPERIMENTAL

Clodronate

Intervention Type: DRUG

For Arm 3, patients will be treated with intra articular clodronate 10 mg/2 ml from Baseline to Week 3

Arm 4

Placebo 2 ml once a week for 4 weeks (total clodronate dose = 0 mg).

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

For Arm 4, patients will be treated with Placebo 2 ml from Baseline to Week 3

Interventions

Clodronate

For Arm 1, patients will be treated with intra articular clodronate 2 mg/2 ml from Baseline to Week 3

Intervention Type: DRUG

Clodronate

For Arm 2, patients will be treated with intra articular clodronate 5 mg/2 ml from Baseline to Week 3

Intervention Type: DRUG

Clodronate

For Arm 3, patients will be treated with intra articular clodronate 10 mg/2 ml from Baseline to Week 3

Intervention Type: DRUG

Placebo

For Arm 4, patients will be treated with Placebo 2 ml from Baseline to Week 3

Intervention Type: DRUG

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.

• Minimum Eligible Age: 50 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Pharmaceutical Development and Services

UNKNOWN

Sponsor Role: collaborator

SPA Società Prodotti Antibiotici S.p.A.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

IRCCS Istituti Clinici Maugeri

Castel Goffredo, Mantova, Italy

Site Status: RECRUITING

Ospedale San Pellegrino

Castiglione delle Stiviere, Mantova, Italy

Site Status: RECRUITING

Ospedale Civile Servizio di Riabilitazione Funzionale

Volta Mantovana, Mantova, Italy

Site Status: RECRUITING

Azienda Ospedaliera Universitaria San Luigi Gonzaga

Orbassano, Torino, Italy

Site Status: NOT_YET_RECRUITING

Centro Riabilitativo Polifunzionale Teresio Borsalino

Alessandria, , Italy

Site Status: RECRUITING

IRCCS Ospedale Policlinico San Martino

Genova, , Italy

Site Status: RECRUITING

Ospedale Israelitico

Roma, , Italy

Site Status: RECRUITING

Ospedale San Pietro

Rome, , Italy

Site Status: RECRUITING

Ospedale San Paolo

Savona, , Italy

Site Status: NOT_YET_RECRUITING

Azienda Ospedaliero Universitaria Senese

Siena, , Italy

Site Status: RECRUITING

Ospedale Policlinico "G.B. Rossi" Borgo Roma

Verona, , Italy

Site Status: RECRUITING

Countries

Italy

Central Contacts

Maria Rosa Galmozzi

Role: CONTACT

mariarosa.galmozzi@spafarma.com

0289139429 ext. +39

Facility Contacts

Lul Abdi-Ali

Role: primary

Paolo Roberto Ferrari

Role: primary

Luisa Selletti

Role: primary

Filippo Castoldi

Role: primary

Marco Invernizzi

Role: primary

Matteo Formica

Role: primary

Maria Chiara Meloni

Role: primary

Alberto Migliore

Role: primary

Danilo Chiapale

Role: primary

Bruno Frediani

Role: primary

Luca Dalle Carbonare

Role: primary

Other Identifiers

2021-003124-33

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

SPA-S-899-01-21

Identifier Type: -

Identifier Source: org_study_id