Adaptative, multicenter, randomized, double-blind, parallel-group, placebo controlled, clinical trial, on the efficacy and tolerability of different escalating doses of intra-articular clodronate in patients with painful knee osteoarthritis

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Spa Societa Prodotti Antibiotici S.p.A.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

Trial duration

12 Oct 2023 → ongoing

Decision date (initial)

2024-08-13

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-511961-12-00

EudraCT number

2021-003124-33

ClinicalTrials.gov

NCT06263517

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Efficacy, Safety

PHASE II

- to assess the safety and tolerability of different escalating doses of IA clodronate in terms of serious adverse events (SAEs), adverse events (AEs), and abnormal laboratory or any clinical signs of intolerance.
- to set the DTD to be used in Phase III, as the lowest clodronate dose leading to a ≥ 8.5 mm reduction in the VAS of knee pain at Week 7 vs. Placebo.

PHASE III

- to assess and confirm the therapeutic efficacy of DTD in patients with knee OA based on VAS score of knee pain at Week 7 vs. Placebo.
- to assess the safety and tolerability of DTD in patients with knee OA in terms of SAEs, AEs, and abnormal laboratory or any clinical signs of intolerance.

Secondary objectives 6

1. Phase II: to assess the VAS knee pain at each visit.
2. Phase II: to describe the effects of different escalating doses of IA clodronate on knee function by means of Lequesne Algofunctional Index and Western Scale Ontario MacMaster (WOMAC).
3. Phase II: to assess the knee range of motion by means of knee extension and knee flexion.
4. Phase II: to measure the use of rescue drug consumption (paracetamol) in patients treated with different escalating doses of IA clodronate.
5. Phase III: to assess the effects of DTD on knee function by means of Lequesne Algofunctional Index and WOMAC index in patients with knee OA.
6. Phase III: to measure the use of rescue drug consumption (paracetamol) in patients with knee OA treated with DTD.

Conditions and MedDRA coding

Knee osteoarthritis

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Female and male patients aged 50 up to 75 years at the signature of informed consent form (ICF).
2. Diagnosis of knee OA according to the American College of Rheumatology, confirmed by Rx during the screening (a Rx performed in the last three (3) months before Screening Visit is accepted).
3. Kellgren-Lawrence radiographic score between 2 and 3 degrees in the tibiofemoral joint.
4. 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).
5. Female patients of childbearing potential must have a negative pregnancy test before each treatment and during the Visit 5 – Week 4 and they must use adequate methods of contraception throughout the course of the study.
6. A signed ICF by the patient after exhaustive study discussion with the investigators.

Exclusion criteria 21

1. BMI > 35 kg/m2 (Class II obesity).
2. 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.
3. Otherwise located lower limb pain, such as hip pain.
4. Other musculoskeletal disorders related to the target knee.
5. Any treatment with IA drugs in the last three (3) month before Day 0- Baseline (including any formulation of corticosteroids, or hyaluronic acid injections).
6. Corticosteroid use by any systemic route, and hyaluronic acid injections or in-tra-articular corticosteroids for any other joint in the previous month will be not permitted.
7. Any treatment with systemic non-steroidal anti-inflammatory drugs (NSAIDs) in the week before Baseline, or any steroid anti-inflammatory drugs and chon-droprotective drugs in the thirty (30) days before Baseline.
8. Any treatment with systemic bisphosphonates in the last twelve (12) months before Baseline.
9. Any treatment with glucosamine or chondroitin sulfate, diacerein and matrix metalloproteinase (MMP) inhibitors in the 4 weeks before Baseline.
10. Any treatment with denosumab in the 12 months before Baseline.
11. Any treatment with paracetamol in the twelve (12) hours before Baseline.
12. Any knee surgery in the past or knee arthroplasty.
13. Any diagnostic or surgical arthroscopy of the knee in the six (6) months before Baseline.
14. Any jaw osteonecrosis in the last twenty-four (24) months before Baseline or at a risk of jaw osteonecrosis.
15. Any known hypersensitivity to the drug in the study and to its excipients or other bisphosphonates, and any hypersensitivity to paracetamol (rescue drug).
16. 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).
17. Inadequate organ function defined by the following laboratory parameters: Absolute Neutrophil Count (ANC) < 1500/^l ; Haemoglobin (Hb) < 9 g/dl (< Hb 5.6 mmol/L) ; Platelet Count < 100.000/^l ; Serum Creatinine > 1.5 x ULN or eGFR < 60 mL/min (as per Cockroft-Gault formula) ; ALT or AST > 1.5 x ULN ; Serum Total Bilirubin > 1.5 x ULN
18. Pregnant or breastfeeding women, or women planning to become pregnant during the study.
19. Any positive or suspected history of alcoholism or drug use.
20. 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.
21. Patients unwilling or unable to comply with the protocol.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. A clodronate dose will be considered as effective when a ≥ 8.5 mm reduction in the VAS of knee pain will be observed at Week 7 vs. Placebo.

Secondary endpoints 6

1. Mean changes in the VAS of knee pain observed at each other visit than Week 7 vs. Placebo and vs Baseline.
2. Mean changes in the VAS of knee pain observed 120 minutes after IA injection at Baseline, Weeks 1, 2 and 3 vs predose assessment.
3. Mean changes in the Lequesne Algo-functional Index at each visit vs Placebo and vs Baseline.
4. Mean changes in the WOMAC Index at each visit vs Placebo and vs Baseline.
5. Mean changes in the Range of Motion at each visit vs Placebo and vs Baseline.
6. Use of rescue drug consumption (paracetamol) across the patients visits.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Spa Societa Prodotti Antibiotici S.p.A.

Sponsor organisation

Spa Societa Prodotti Antibiotici S.p.A.

Address

Via Biella 8

City

Milan

Postcode

20143

Country

Italy

Scientific contact point

Organisation

Spa Societa Prodotti Antibiotici S.p.A.

Contact name

Maria Rosa Galmozzi

Public contact point

Organisation

Spa Societa Prodotti Antibiotici S.p.A.

Contact name

Maria Rosa Galmozzi

Third parties 1

Locations

1 EU/EEA country · 14 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 15 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

9 submissions — initial application plus substantial / non-substantial modifications