| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
| degenerative disease 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10023476 |
| E.1.2 | Term | Knee osteoarthritis |
| E.1.2 | System Organ Class | 100000004859 |
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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 assess the effects of different dosages of intra-articular disodium clodronate on the reduction in target knee pain, compared to placebo. |
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| E.2.2 | Secondary objectives of the trial |
• To assess the effects of different dosages of intra-articular disodium clodronate on functional disability and rescue medication consumption;
• To evaluate the safety and local tolerability of different dosages of disodium clodronate intra-articular injections.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and female patients, aged 50–75 years;
2. Patients affected by knee osteoarthritis (OA), as defined by American College of Rheumatology (ACR) clinical and radiographic criteria for OA of the knee, and meeting the following conditions:
- Kellgren-Lawrence Grade 2 to 3 severity OA of the knee with presence of osteophytes determined from X-rays of the knee obtained within 6 months from the Screening visit; i.e. in the tibio-femoral compartment of the target knee with at least 1 osteophyte and measurable joint space, as diagnosed by standard X-rays (anterior-posterior view [weight bearing extension or semi-flexion] and lateral). In the case that a patient has not a valid X-ray within 6 months prior to Screening, the exam is to be performed during the screening period;
- Patients suffering from OA symptoms of the target knee for at least 6 months prior to the Screening visit. Note: patients with bilateral OA of the knee will be allowed as long as they can differentiate pain in the target knee, do not need to use analgesics for treatment of their contralateral knee, and do not expect to receive treatment of the contralateral knee during the study. In the case that both knees are eligible for the study based on pain intensity, the knee with the greater Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Score at rest will be selected as the target knee joint as long as the contralateral knee OA will not exclude the patient from the study and all other entry criteria are satisfied. If one knee is ineligible for the study, the eligible knee will be selected as the target knee as long as the contralateral (ineligible) knee do not exclude the patient from the study and all other entry criteria are met;
3. Patients with spontaneous pain at the target knee of moderate to moderately severe intensity, defined as a score ≥40 mm and ≤ 80 mm at the screening visit in pain at rest, as measured by means of a 100 mm Visual Analogue Scale (VAS) in the WOMAC pain subscale. This is to be confirmed at the baseline visit;
4. Patients able to read and understand the language and content of the study material, understand the requirements for follow-up visits, willing to provide information at the scheduled evaluations and willing and able to comply with the study requirements;
5. Patients having discontinued use of all systemic analgesic/non-steroidal anti-inflammatory drugs (NSAIDs) therapy prior to the screening visit and agree not to resume them during study. Note: paracetamol will be provided to patients as rescue medication;
6. If female of child-bearing potential, must have a negative urine pregnancy test at the screening visit and use a reliable form of contraception for a least 1 month prior to Screening and throughout the study. Note: to be considered females of non-child-bearing potential, females must be surgically sterile or postmenopausal as documented in medical history for at least 1 year. Highly effective birth control methods include: combined hormonal contraception (containing estrogens and progestogen) associated with inhibition of ovulation (oral, intravaginal, transdermal); progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable); intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomised partner; sexual abstinence*;
7. Patients having undergone the informed consent process and having signed an approved consent form.
*Note: According to 4.1 paragraph “Birth control methods which may be considered as highly effective” of the Clinical Trial Facilitation Group (CTFG)/Recommendations related to contraception and pregnancy testing in clinical trials
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| E.4 | Principal exclusion criteria |
1. Patients with body mass index (BMI) > 40 kg/m2;
2. Patients with osteoarthritis secondary to other articular diseases;
3. Patients with history of septic arthritis in any joint;
4. Patients that are candidate for knee replacement within next 6 months;
5. Patients with clinically significant effusion of the target knee;
6. Patients with significant pain outside the target knee, including significant hip or back pain;
7. Patients with clinically significant valgus/varus deformities, ligamentous laxity, or meniscal instability as assessed by the Investigator;
8. Patients with any musculoskeletal condition affecting the target knee that would impair assessment of the effectiveness in the target knee (e.g. Paget’s disease of bone);
9. Patients with presence of infections and/or skin diseases and/or skin wounds in the area of injection site;
10. Patients have had arthroplasty at the target knee at any time;
11. Patients having received viscosupplementation of the target knee or any other joint within 6 months before Screening;
12. Patients having received any topical prescription products (e.g., corticosteroids, NSAIDs, or capsaicin) for the target knee in the 2 weeks before Screening (Note: use of over-the-counter topical products such as antibiotics and 1% hydrocortisone are allowed for areas other than the target knee);
13. Patients having received systemic administration of steroidal anti-inflammatory drugs in the previous 8 weeks or systemic NSAIDs in the previous 7 days;
14. Patients having received paracetamol in the previous 12 hours;
15. Patients having received any intra-articular drug administration in the target knee in the previous 3 months (including any formulation of corticosteroids, or any investigational product);
16. Patients having received glucosamine, chondroitin-sulfate, diacerein and matrix metalloproteinase (MMP) inhibitors in the 4 weeks before Screening;
17. Patients having received parenteral or oral bisphosphonates in the 12 months before screening;
18. Patients having received denosumab in the 12 months before screening;
19. Patients having had any previous surgery in the target knee within 6 months prior to Screening, or any planned surgery throughout the duration of the study;
20. Patients having had diagnostic or surgical knee arthroscopy, or knee lavage in the target knee in the 6 months prior to Screening;
21. Patients with presence of serious 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;
22. Patients with a current malignancy or had treatment for a malignancy, except non-melanoma skin cancer, within the past 5 years;
23. Patients with medical history of osteonecrosis of the jaw in the previous 24 months or at risk of osteonecrosis of the jaw;
24. Patients with history of kidney failure or renal insufficiency (creatinine > 2.0 mg/dl);
25. Patients with clinically significant abnormalities of laboratory parameters measured at the screening visit;
26. Known hypersensitivity to study drug or other bisphosphonates, including paracetamol (rescue medication);
27. Patients receiving treatments which can interfere with either the local application of study drug, or the evaluations of results;
28. Patients having received treatment with any other investigational product within 3 months of the screening visit;
29. Pregnant (positive urine test) or breastfeeding women, or planning to become pregnant during the study;
30. Patients with history of alcoholism or drug dependence;
31. Patients with inability to provide the informed consent.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline of WOMAC pain at rest in the target knee (0-100 mm VAS from item 4 of the WOMAC pain subscale), expressed as the best (i.e. the maximum decrease) of the pain intensity difference (PID) from baseline among measurements performed from Week 8 to Week 16, inclusive (i.e. the identified time frame in which the maximal effect over placebo can be expected). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From week 0 (Baseline) to week 24 inclusive |
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| E.5.2 | Secondary end point(s) |
• Change from baseline of WOMAC pain at rest in the target knee (0-100 mm VAS from the WOMAC pain subscale) at each individual post-baseline time point;
• Change from baseline to Week 24 (end of study) or early discontinuation of WOMAC pain at rest in the non-target knee in patients with bilateral knee OA;
• Change from baseline of WOMAC total score, subscales (pain, stiffness and physical function) and single items (24 items), measured in the target knee using a 0-100 mm VAS) at each individual post-baseline time point;
• Change from baseline of pain on active movement at the target knee, measured by means of a 100 mm VAS at each individual post-baseline visit;
• Patient assessment of Clinical Global Impression-Improvement (CGI-I) at each individual post-baseline visit;
• Change from baseline to Weeks 4, 8, 12, 16 and 24 in Short-form 36 (SF-36) total score, physical and mental components, single domains and single items;
• Use of rescue medication (paracetamol): number and proportions of users, and average pill count per day.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• From week 0 (Baseline) at each individual post-baseline time point;
• From week 0 (Baseline) to Week 24 (end of study);
• From week 0 (Baseline) at each individual post-baseline time point;
• From week 0 (Baseline) at each individual post-baseline visit;
• At each individual post-baseline visit;
• From week 0 (Baseline) to Weeks 4, 8, 12, 16 and 24;
• At each individual post-baseline visit.
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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 | No |
| 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 | 5 |
| 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 | 25 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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