Joints-comprising bone, cartilage, ligaments, and synovial fluid-enable stable daily movement but may deteriorate with age, excess body weight, overuse, injury, or disease. Such degeneration, common from age 40 onward, underlies joint disorders like osteoarthritis, particularly in the knees, hips, hands, and spine, and is a major cause of chronic pain and disability. While antiinflammatory analgesics remain the standard approach to symptom control, they neither cure disease nor regenerate cartilage and can produce significant long-term adverse effects (gastrointestinal, hepatic, renal, and cardiovascular). These limitations motivate interest in natural or complementary strategies with safer profiles. Within this context, marine algae, especially agar derived from red seaweed, have attracted attention for potential intestinal, metabolic, and joint benefits, aided by their fiber content. Another promising option is undenatured type II collagen (UC-II), the principal structural component of articular cartilage, whose endogenous production declines with age; clinical studies indicate that a daily intake of 40 mg UC-II can improve mobility, reduce pain, and enhance quality of life in individuals with osteoarthritis or exercise-related joint discomfort. Based on these considerations, an agar-agar supplement has been developed to relieve knee joint symptoms.
The primary objective of this study was to evaluate the effect of agar-agar (A-A), the combination of A-A with undenatured type II collagen (A+UC-II), and undenatured type II collagen (UC-II) on knee joint pain, assessed by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), in subjects with mild to moderate joint pain without a diagnosis of osteoarthritis, compared with a control compound. The secondary objectives were to evaluate the effects of A-A, A+UC-II, and UC-II consumption on: * Knee joint stiffness and functional capacity (subjective assessment). * Overall perception of knee health (subjective assessment). * Pain, stiffness, and functional capacity of the hand (subjective assessment). * Range of motion of the knee. * Functional capacity of the knee (objective assessment). * Functional capacity of the hand (objective assessment). * Frequency of medication use for joint pain relief (anti-inflammatories, analgesics). * Inflammatory blood markers. * Blood markers of collagen and bone metabolism. * Body composition. The primary endpoint is patient-reported knee joint pain, assessed using the Pain subscale of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire. This is a randomized, placebo-controlled, triple-blind, parallel-group nutritional intervention with an allocation ratio of 1:1:1:1. A total of 80 participants (men and women) will be enrolled. Following a pre-screening visit to verify inclusion and exclusion criteria, eligible participants will be randomly assigned to one of four groups (n=20 per group) to consume, once daily for 12 weeks, one of the following products: agar-agar (A-A), A-A+UC-II (A+UC-II), UC-II alone, or placebo. Each participant will complete three in-person visits and one interim telephone follow-up: a pre-screening visit (eligibility assessment), a baseline visit to initiate the intervention, a mid-study telephone follow-up, and an end-of-study visit. The total duration per participant will be 13 weeks. The primary endpoint is patient-reported knee joint pain, assessed using the Pain subscale of the WOMAC questionnaire.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
80
2.4 g of agar-agar (Rhodophyceae group) presented in capsule form will be given.
2.4 g of agar- agar + 40 mg of undenatured collagen type II, presented in capsule form will be given.
40 mg of undenatured collagen type II + 2.4 g of maltodextrin will be given in capsule form
2.4 g Maltodextrin will be given in capsule form
Eurecat, Technological Center of Catalonia, Nutrition and Health Unit
Reus, Tarragona, Spain
RECRUITINGChange in perception of knee joint pain.
This will be determined using the pain subscale of the Western Ontario and McMaster Universities Osteoarthritis Index questionnaire. The questionnaire assesses clinically meaningful changes in symptoms and physical disability in individuals with osteoarthritis or those experiencing joint discomfort. It evaluates the perceived intensity of knee pain using the Likert scale (0: no pain; 1: mild pain; 2: moderate pain; 3: severe pain; 4: extreme pain).
Time frame: Before (baseline), during (6 weeks) and after treatment period (12 weeks).
Body weight.
Body weight will be measured by Tanita TBF-300 (Body Composition Analyzer, Brooklyn NY, USA) as a descriptive variable.
Time frame: at week 1.
Height.
Height will be measured by standardized method.
Time frame: At week 1.
Body mass index (BMI) (kg/m^2).
BMI will be determined using the Tanita TBF-300 (Body Composition Analyzer, Brooklyn, NY, USA) as a descriptive variable.
Time frame: At week1.
Age.
Age will be recorded in years.
Time frame: At week 1.
Changes in systolic and diastolic blood pressure and resting heart rate.
It will be measured using an automatic sphygmomanometer.
Time frame: Before (baseline) and after treatment period (12 weeks).
Changes in body weight.
Body weight will be measured by Inbody 970.
Time frame: Before (baseline) and after treatment period (12 weeks).
Change in BMI.
Weight and height will be combined to report BMI in kg/m\^2.
Time frame: Before (baseline) and after treatment period (12 weeks).
Changes in the amount of body fat.
Body fat in kg will be measured with Inbody 970.
Time frame: Before (baseline) and after treatment period (12 weeks).
Changes in the amount of body fat.
Body fat percentage will be measured with Inbody 970.
Time frame: Before (baseline) and after treatment period (12 weeks).
Changes in the amount of muscle mass.
Muscle mass in kg will be measured by Inbody 970.
Time frame: Before (baseline) and after treatment period (12 weeks).
Changes in the amount of muscle mass.
Muscle mass percentage will be measured by Inbody 970.
Time frame: Before (baseline) and after treatment period (12 weeks).
Changes in the amount of bone mass.
Bone mass (kg) will be measured by Inbody 970.
Time frame: Before (baseline) and after treatment period (12 weeks).
Changes in the amount of total body water.
Total body water (Kg) will be measured by Inbody 970.
Time frame: Before (baseline) and after treatment period (12 weeks).
Change in the amount of lean mass.
The total lean mass (Kg) will be measured by Inbody 970.
Time frame: Before (baseline) and after treatment period (12 weeks).
Changes in bone mineral content.
This will be measured, in Kg, by Inbody 970.
Time frame: Before (baseline) and after treatment period (12 weeks).
Changes in segmental impedance.
This will be measured by Inbody 970.
Time frame: Before (baseline) and after treatment period (12 weeks).
Changes in segmental phase angle.
The phase angle (kHz) will be measured by Inbody 970.
Time frame: Before (baseline) and after treatment period (12 weeks).
Change in perception of knee joint stiffness.
This variable will be assessed using the rigidity subscale of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire. It consists of two items. The perceived intensity of knee stiffness will be evaluated in two different situations: in the morning, immediately after waking up, and during the day, following a period of rest or inactivity, using the Likert scale (0: no stiffness; 1: mild stiffness; 2: moderate stiffness; 3: severe stiffness; 4: extreme stiffness) (total scale 0-8).
Time frame: Before (baseline) during ( 6 weeks) and after treatment period (12 weeks).
Change in perception of knee functional capacity.
This variable will be assessed using the rigidity subscale of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire. It consists of 17 items. The difficulty in performing various activities-such as climbing or descending stairs, walking, bending, or carrying out daily tasks-will be evaluated using the Likert scale (0: no difficulty; 1: mild difficulty; 2: moderate difficulty; 3: severe difficulty; 4: extreme difficulty) (total scale 0-68).
Time frame: Before (baseline) during ( 6 weeks) and after treatment period (12 weeks).
Changes in the perception of the general health status of the knee
This variable will be assessed using the rigidity subscale of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire. It will be obtained by summing the scores of the three subscales: pain, stiffness, and physical function. The total score ranges from 0 to 96, reflecting the best and worst possible knee condition, respectively.
Time frame: Before (baseline) during ( 6 weeks) and after treatment period (12 weeks).
Perception of pain in the hand joint
This variable will be assessed using the pain subscale of the Australian-Canadian Hand Osteoarthritis Index (AUSCAN) questionnaire. The questionnaire consists of 5 items that assess, over the previous 48 hours, the intensity of pain at rest and while grasping, lifting, turning, and squeezing objects, using a Likert scale (0: no pain; 1: mild pain; 2: moderate pain; 3: severe pain; 4: extreme pain).
Time frame: Before (baseline) during ( 6 weeks) and after treatment period (12 weeks).
Changes in perception of hand joint stiffness
This variable will be assessed using the pain subscale of the Australian-Canadian Hand Osteoarthritis Index (AUSCAN) questionnaire. It consists of 1 item that assesses, over the previous 48 hours, the intensity of hand stiffness upon waking, using a Likert scale (0: no stiffness; 1: mild stiffness; 2: moderate stiffness; 3: severe stiffness; 4: extreme stiffness).
Time frame: Before (baseline) during ( 6 weeks) and after treatment period (12 weeks).
Changes in perception of the functional capacity of the hand joint
This variable will be assessed using the pain subscale of the Australian-Canadian Hand Osteoarthritis Index (AUSCAN) questionnaire. It consists of 7 items that assess, over the previous 48 hours, the difficulty in turning, holding, opening, carrying, grasping, and squeezing various objects with the hand, using a Likert scale (0: no difficulty; 1: mild difficulty; 2: moderate difficulty; 3: severe difficulty; 4: extreme difficulty).
Time frame: Before (baseline) during ( 6 weeks) and after treatment period (12 weeks).
Changes in knee range of motion
This variable will be measured using a digital goniometer.
Time frame: Before (baseline) and after treatment period (12 weeks).
Changes in the functional capacity of the hand joints
Hand grip strength will be measured, in kilograms, using the InGrip digital dynamometer.
Time frame: Before (baseline), and after treatment period (12 weeks)
Changes in the speed when going up and down stairs.
This variable will measured by The "Stair Climb Test" , in which the volunteer must climb and descend 10 standard steps (between 15 and 20 cm) without the aid of a handrail. The time (minutes and seconds) taken by the volunteer to complete the test will be recorded.
Time frame: Before (baseline) and after treatment period (12 weeks).
Changes in pain perception at the end of the Stair Climb Test
At the end, perceived pain will be measured using a 100 mm visual analog scale, where 0 indicates "no pain" and 100 indicates "all the pain you can experience".
Time frame: Before (baseline) and after treatment period (12 weeks).
Changes in plasma interleukin 6 (IL-6) concentration.
Plasma IL-6 levels will be measured by ELISA kits
Time frame: Before (baseline) and after treatment period (12 weeks).
Changes in plasma tumor necrosis alpha (TNF-a) concentration.
Plasma TNF-a levels will be measured by ELISA kit.
Time frame: Before (baseline) and after treatment period (12 weeks).
Changes in plasma monocyte chemotactic protein 1 (MCP-1) concentration
Plasma MCP-1 levels will be measured ELISA kit.
Time frame: Before (baseline) and after treatment period (12 weeks).
Changes in serum High-sensitivity C-reactive protein (hsCRP) concentration.
Serum hsCRP levels will be measured by chemiluminescence method.
Time frame: Before (baseline) and after treatment period (12 weeks).
Changes in serum levels of C-terminal telopeptide of type 1 collagen (CTX1).
Serum CTX1 will be measured by electrochemiluminescence method.
Time frame: Before (baseline) and after treatment period (12 weeks).
Changes in serum levels of N-terminal propeptide of type I collagen (PINP).
Serum PINP will be measured by electrochemiluminescence method.
Time frame: Before (baseline) and after treatment period (12 weeks).
Changes in serum levels of hyaluronic acid (HA).
Serum HA will be measured by ELISA kits.
Time frame: Before (baseline) and after treatment period (12 weeks).
Changes in serum levels of cartilage oligomeric matrix protein (COMP).
Serum COMP will be measured by ELISA kits.
Time frame: Before (baseline) and after treatment period (12 weeks).
Dietary control.
The intake of foods containing bioactive components that could alleviate pain will be assessed using an adapted food frequency questionnaire. The following scale will be used: "I have not used it"; "1 time a week"; "2-4 times a week"; "5-6 times a week"; "7-10 times a week"; "10-20 times a week"; "\>20 times a week"
Time frame: Before (baseline), during (6 week) and after treatment period (12 weeks).
Changes in dietary supplement use.
The consumption of supplements and dietary products by the volunteers will be monitored through the analysis of the supplement and dietary product records in the case report form.
Time frame: Before (baseline), during (6 week) and after treatment period (12 weeks).
Changes in concomitant medications.
The consumption of concomitant medication will be monitored through the analysis of the concomitant medication records in the case report form.
Time frame: Before (baseline), during (6 week) and after treatment period (12 weeks).
Changes in pain-relieving medication use.
This will be assessed by recording concomitant medications in the data collection form.
Time frame: Before (baseline), during (6 week) and after treatment period (12 weeks).
Physical activity levels.
This will be determined by analyzing the Physical Activity Questionnaire, Quick Physical Activity Classifier, adapted from the Generality of Catalonia (PEFS) guidelines.
Time frame: Before (baseline), and after treatment period (12 weeks).
Monitoring of adverse effects.
The presence of adverse events reported by the participant in the data collection form will be recorded using the Adverse Effects Form.
Time frame: During (6 week) and after treatment period (12 weeks).
Treatment adherence rate.
Treatment adherence will be calculated using the following formula: (number of capsules the volunteer should have taken / number of capsules actually taken) \* 100
Time frame: During (6 week) and after treatment period (12 weeks).
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