Efficacy and Safety Evaluation of Bovine vs. Marine Chondroitin Sulfate 800 mg in Patients with Knee Osteoarthritis

Trial ID: 2024-516337-12-00
Protocol: 23EU-Ct11
Sponsor: IBSA Institut Biochimique SA

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Diseases & Conditions

Pain Osteoarthritis

Objectives

The primary objective of this multinational, multicentre, double-blind study is to demonstrate the **non-inferiority** of efficacy of bovine chondroitin sulfate 800 mg tablets compared to marine chondroitin sulfate 800 mg tablets over a 24-week period in the treatment of pain and functional impairment due to knee **osteoarthritis**. This is clinically relevant as it aims to establish an effective treatment option for patients suffering from moderate to severe pain associated with knee osteoarthritis, potentially offering a viable alternative based on the origin of chondroitin sulfate.

Secondary objectives include:

Assessing the efficacy of the two investigational medicinal products (IMPs) on quality of life in patients with knee osteoarthritis.
Evaluating both the patient's and investigator's assessment of the efficacy of the two IMPs.
Assessing the consumption of rescue medication for pain management due to knee osteoarthritis.
Evaluating compliance with the treatment regimen involving the two IMPs.
Assessing the safety of the two IMPs.

Participants

The clinical trial involves participants diagnosed with **knee osteoarthritis** experiencing moderate to severe pain. The study population includes both male and female outpatients aged 50 years and older. Participants are required to have a history of knee osteoarthritis in one or both knees for more than six months, with radiographic confirmation of the condition. The trial does not involve a vulnerable population. Participants must demonstrate a specific range of pain and functional impairment scores, as measured by standardized scales, to qualify for the study. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified, but participants must be able to understand and follow study requirements, including the use of electronic devices. Female participants of child-bearing potential must adhere to specific contraceptive guidelines to ensure safety throughout the study duration.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy and safety of **bovine chondroitin sulfate** 800 mg tablets compared to **marine chondroitin sulfate** 800 mg tablets in treating pain and functional impairment due to **knee osteoarthritis**. The trial aims to demonstrate the non-inferiority of the bovine formulation over a 24-week treatment period. Participants will be randomly assigned to receive either the bovine or marine chondroitin sulfate, with both groups receiving identical-looking tablets to maintain blinding. The trial is expected to commence recruitment on December 9, 2024, and conclude by January 1, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, diagnosis of knee osteoarthritis, and pain levels. Following successful screening, participants will be enrolled and randomized on Day 1. Subsequent visits will occur at Weeks 4, 12, and 24, with assessments including changes in pain and functional scores using the **Numeric Rating Scale (NRS)** and the **Western Ontario and McMaster Universities Arthritis Index (WOMAC®)**. The primary endpoints are the change in average daily pain and WOMAC® function subscale scores from baseline to Week 24. Secondary endpoints include changes in quality of life, global evaluations, and rescue medication usage.

The expected duration of participant involvement is approximately 36 weeks, including a 24-week treatment phase and a 12-week follow-up period. Conditions that may lead to early termination from the study include adverse events, withdrawal of consent, or non-compliance with study procedures. The trial is conducted under strict adherence to ethical guidelines, ensuring the safety and well-being of all participants throughout the study duration.

Treatment

The clinical trial involves the administration of two **experimental medications** to evaluate their efficacy and safety in the treatment of knee osteoarthritis. The first experimental medication is **chondroitin sulfate (marine)**, which is provided in the form of a **tablet**. Each tablet contains 800 mg of the active substance, and the medication is administered **orally**. Participants are instructed to take the medication once daily, with a maximum daily dose of 800 mg. The treatment period for this medication is set for 24 weeks, equivalent to 6 months. Compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.

The second experimental medication is **chondroitin sulfate sodium**, marketed under the name **CONDROSULF 800 mg tabletta**. This medication is also provided in **tablet** form, with each tablet containing 800 mg of the active substance. Similar to the first medication, it is administered **orally** once daily, with a maximum daily dose of 800 mg. The treatment duration is also 24 weeks, or 6 months. Participant compliance with the dosing regimen is closely monitored to maintain the integrity of the study results.

Both medications are evaluated in a double-blind manner, meaning neither the participants nor the investigators know which treatment is being administered to each participant. This design helps to eliminate bias and ensure the reliability of the study outcomes. No additional non-experimental treatments, such as standard-of-care therapy or placebo, are used in this trial. The primary objective is to demonstrate the non-inferiority of the efficacy of bovine chondroitin sulfate compared to marine chondroitin sulfate in alleviating pain and improving functional impairment associated with knee osteoarthritis.

Efficacy

The efficacy of the clinical trial will be assessed by evaluating the change in pain and functional impairment in patients with knee osteoarthritis. The primary endpoints include the change from baseline to week 24 in the weekly mean of the average daily pain in the target knee, as measured by the Numeric Rating Scale (NRS) ranging from 0 to 10 points, and the change in the mean score of the Western Ontario and McMaster Universities Arthritis Index (WOMAC®) function subscale, also measured by the NRS.

Secondary endpoints will further assess efficacy through various measures. These include the change from baseline to each week until week 24 in the weekly mean of the average daily pain in the target knee, the change from baseline to the end of the follow-up period (12 weeks after the end of treatment) in daily pain, and responder rates at each visit using response definitions of ≥ 30% or ≥ 50% decrease from baseline in the weekly mean of the average daily NRS pain intensity score. Additional secondary endpoints include changes from baseline to weeks 4, 12, and 24 in the mean WOMAC® total score and all subscores, patient quality of life as measured by EQ-5D-5L, and both patient and investigator global evaluations at weeks 4, 12, and 24 using a 5-point rating scale. The consumption of rescue medication, specifically paracetamol, will also be monitored, including the number and proportion of users, the number of daily intakes, and the total dose per day.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Voluntarily given informed consent to study participation in writing encompassing consent to personal data processing;
Outpatient of either sex, aged ≥ 50 years;
Patients affected by knee OA, as defined by American College of Rheumatology (ACR) clinical and radiographic criteria;
History of knee OA in one or both knees for > 6 months (including regular pain and functional impairment) as confirmed by the Investigator, based on available written documentation and/or patient reporting;
Radiographic findings of knee OA classified by Kellgren-Lawrence (K-L) grade of 2 or 3 based on an antero-posterior weight-bearing X-ray view of the target knee taken within 6 months prior to inclusion in the study. In the case that a patient has not a valid X-ray within 6 months prior to screening, the exam has to be performed during the screening period (in case that both knees have an equal intensity of pain, the target knee will be selected subjectively by the Investigator on the basis of the X-ray that will be requested for both knees);
Pain in the target knee verifying the following conditions: A mean score of ≥ 5 to ≤ 9 on the 24-hour average daily pain score in the target knee (on a 0-10 numeric rating scale [NRS]), where the mean is calculated over all values that are available in the 7 days prior to randomization (Day 1), and it is required that at least 5 pain score values will be available during that period; - An individual 24-hour average daily pain score in the target knee ≥ 1and ≤ 9 for all values that are available in the 7 days prior to randomization (Day 1);
Functional impairment in the target knee, with a mean score ≥ 3 to ≤ 9 (on a 0-10 NRS) in the Western Ontario andMcMaster Universities Arthritis Index (WOMAC®) function subscale at the baseline visit. To be eligible for the study, it is also required that patients will be able to respond at least 14 items of the WOMAC® physical function subscale, with a maximum of 3 unanswered items
Patient is able to understand and follow the study requirements and is familiar with the use of electronic devices;
If female of child-bearing potential, patient is non-lactating and non- pregnant, and must have a negative urine pregnancy test at the screening visit and use a reliable form of contraception throughout the study. Note: to be considered females of non-child-bearing potential, females must be postmenopausal for at least 1 year or surgically sterile [bilateral tubal ligation, bilateral oophorectomy or hysterectomy]) or practicing one of the following medically acceptable methods of birth control: - Hormonal methods such as oral, implantable, injectable or transdermal contraceptives before IMP administration. - Agrees to abstain from heterosexual intercourse during study participation and to use a highly effective contraceptive (as described above) if they become sexually active during the study. Abstinence is only acceptable if this is the patient’s usual lifestyle. Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method are not acceptable methods of contraception. - Intrauterine device. - Double-barrier method (condoms, sponge, diaphragm, with spermicidal jellies, or cream).

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Exclusion Criteria

Patients with predominantly patella-femoral OA defined as moderate to severe femoro-patellar OA with only no or mild femoro-tibial OA;
Patients with severe ipsilateral hip OA that could possibly confound the patient’s assessment of target knee pain in the judgement of the Investigator;
Patients having had surgery of the target knee in the past 6 months (for arthroscopic surgery) or 12 months (for osteotomy or other surgery) prior to screening, had knee lavage in the target knee in the 6 months prior to screening, and/or significant injuries to the target knee in the 6 months prior to screening, or had knee replacement surgery on the target knee ever or has planned knee surgery on the target knee during the study;
Patients with body mass index (BMI) ≥ 34 kg/m2;
Patients with large intra-articular effusion of the target knee requiring arthrocentesis or active infection of the target knee;
Patients with significant pain outside the target knee, including significant back pain;
Patients with excessive malalignment (i.e. genu varum or valgum) that would justify an osteotomy;
Patients with clinically significant ligamentous laxity, or meniscal instability as assessed by the Investigator;
Patients with any musculoskeletal condition affecting the target knee that would impair assessment of the effectiveness in the knee;
Patients with systemic inflammatory arthropathies (rheumatic disease, inflammatory or infective joint diseases or systemic lupus; recurrent clinical chondrocalcinosis; crystal arthropathies), metabolic joint diseases, osteo-articular pathologies differing from arthrosis, ochronosis, acromegaly, collagen gene mutations, or metabolic arthropathies or Paget’s illness;
Patients with widespread chronic musculoskeletal pain syndrome (e.g., fibromyalgia);
Patients with an allergy or hypersensitivity to the active substance or to any other ingredient of the IMP (i.e., CS tablets) or has a strict vegan (i.e., does not consume fish-based or meat-based products) lifestyle;
Patients with any clinically severe or significant uncontrolled concurrent disease that could interfere with the outcome of the study or the patient’s ability to comply with study requirements;
Patients with any other concurrent diseases requiring chronic use of analgesics/non-steroidal anti-inflammatory drugs (NSAIDs);
Patients having received: - Corticosteroids by systemic administration (oral or parenteral) in the past 30 days prior to the inclusion or corticosteroid by intra- articular administration in the past 3 months prior to the inclusion. Patients on treatment with inhaled corticosteroids can be included in the study; - Systemic short-acting (with a half-life ≤ 6 hours) (e.g., ibuprofen, ketoprofen) or long-acting NSAIDs (e.g., piroxicam, naproxen). The wash-out period begins ≥ 5 half-lives of the drug prior to Day -7 and needs to be completed prior to Day -7. For patients taking these drugs at the screening visit, patients may continue taking these drugs, provided that the indicated wash-out period is respected from 7 days prior to randomization (Day 1); - Hypnotics, muscle relaxants and anxiolytics: if intake has started < 8 days before screening and wash-out not completed prior to Day - 7; - Paracetamol or other analgesics (washout period begins ≥ 5 half- lives of the drug prior to Day -7 and needs to be completed prior to Day -7). Note: patients will be informed that, if strictly necessary, they can take rescue medication (paracetamol) in the period before Day 1 (Visit 2, baseline visit) with the exception of the 24 hr before Day 1 (Visit 2, baseline visit); - Basic treatment of arthritis with food supplements for joint care (CS, glucosamine sulphate, diacereine, hyaluronic acid, etc.) within 6 months prior to the inclusion; - Viscosupplementation, tidal lavage, platelet-rich plasma, or stem cell injection within 6 months prior to the inclusion; - Planned treatments with physical or other alternative therapies (i.e. laser therapy, ultrasound therapy, antalgic electrotherapy, tecar therapy, physiotherapy, mesotherapy, acupuncture) for the duration of the study period;
Patients with presence of clinically relevant psychiatric illness hindering the protocol compliance;
Patients with known and documented renal and/or hepatic and/or heart failure;
Concomitant participation in other clinical trials or participation in the evaluation of any investigational product during 3 months before this study or previous participation in the same study; months before this study or previous participation in the same study;
Participation in the study is also not permitted to employees of the Investigator or study site with direct involvement in the trial or in other trials under the direction of that Investigator, as well as family members of the employees or of the Investigator;
At the Baseline visit, patients not compliant with e-Diary use (i.e., has < 5 entries in the e-Diary during the last 7 days before the Day 1/Baseline).