The Marigot Osteoarthritis Nutritional Intervention (MOANi) Trial

Study Overview
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Brief Summary
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The purpose of the study is to test 30 individuals with mild-moderate knee joint osteoarthritis to investigate whether the combination of Aquamin (a calcium-rich marine multi-mineral) and a polyphenol-rich pine bark extract (Enzogenol), when taken as a food supplement for 3 months has comparable or superior benefits to glucosamine sulphate in patients with painful knee osteoarthritis (KOA). From here on in we refer to Aquamin's combination product as Aquamin-plus. The main outcome measure is a reduction in pain. Provision of data that demonstrate preliminary equivalency or superiority to current, non-pharmaceutical options such as glucosamine will broaden consumer choice, and provide them with an option that is supported by science, rather than marketing alone. The hypothesis of the study is that the consumption of Aquamin-plus will have comparable effects on reducing pain in individuals with Knee Joint OA to glucosamine.

Detailed Description
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This project will be a double blinded randomized cross-over control (pilot) trial that will investigate whether the combination of Aquamin (a calcium-rich marine multi-mineral) and a polyphenol-rich pine bark extract (Enzogenol), when taken as a food supplement for 3 months (12 weeks) has comparable or superior benefits to glucosamine sulphate in patients with painful knee osteoarthritis (KOA). From here on in we refer to Aquamin's combination product as Aquamin-plus. The main outcome measure is a reduction in pain (WOMAC index) and improve physical function (6MWD and TUG). The hypothesis of the study is that the consumption of Aquamin-plus for a period of 3 months will have comparable or superior effects on to glucosamine sulphate in reducing pain and improving physical function in individuals with KOA. According to the Food and Drug Administration et al. osteoarthritis (OA) can be defined as a serious disease or condition because, among other aspects, it is …associated with morbidity that has substantial impact on day-to-day functioning… . Furthermore, the current Osteoarthritis Research Society International (OARSI) definition of OA has been proposed as, OA is a disorder involving movable joints characterized by cell stress and extracellular matrix degradation initiated by micro- and macro-injury that activates maladaptive repair responses including pro-inflammatory pathways of innate immunity. The disease manifests first as a molecular derangement (abnormal joint tissue metabolism) followed by anatomic, and/or physiologic derangements (characterized by cartilage degradation, bone remodeling, osteophyte formation, joint inflammation and loss of normal joint function), that can culminate in illness The condition can be characterized as a branch of rheumatic disease that is a progressive condition of synovial joints and is caused by the failure of a joint to repair following damage. This damage may have been caused by stresses due to an abnormality in the articular cartilage, subchondral bone, ligaments, menisci, periarticular muscles, peripheral nerves or synovium. Failure of these normal biological processes leads to breakdown of cartilage and bone and is characterized by symptoms of pain, stiffness, functional disability and can and lead to negative effects on fatigue, mood, sleep and overall quality of life. OA has the highest frequency of all rheumatic diseases and is one of the most prevalent chronic diseases in the modern day. According to the Global Burden of Disease (GBD) study, progressive ageing of the population could make OA the ninth cause of disability-adjusted life years (DALYs) in developed countries by the year 2020, with KOA accounting for 83% of the total OA burden. Investigations into the heritability of OA have identified some interesting results. In a British twin cohort, the genetic contribution to radiographically defined hip and KOA was estimated to 39-65% in women with a Danish twin studies finding similar variance in hip arthroplasty due to OA (47%) but only 18% for knee arthroplasty due to OA. However, more recent data from a larger cohort (n = 9058) showed a heritability of 73% and 45% in hip and knee arthroplasty, respectively. Interestingly, identified that while hip OA associated arthroplasty remains highly heritable regardless of environmental factors, while the genetic component of KOA (for arthroplasty) was significantly modifiable with increasing BMI. These data show the requirement for clinical interventions to focus on symptomatic KOA, particularly considering the exponentially increasing BMI and obesity in the western world. Data from The Irish Longitudinal Study on Ageing (TILDA) show that approximately 13% (women-17.3%, men-9.4%; self-reported) of Irish residence over the age of 50 suffer from symptomatic OA, with 19.2% of those reporting symptomatic KOA. These are similar to data from Arthritis Research UK showing an 18% prevalence of patients visiting a general practitioner presenting with symptoms of KOA. Moreover, these reported incidence rates are estimated to raise in tandem with population age (Arthritis Research UK, 2013). In fact, the prevalence of KOA in the US is 25% and increases by 2% each year, likely due to the aging population (as in the UK) and raising obesity rate, with a lifetime risk of symptomatic KOA as high as 60.5 % in obese individuals. Joint pain is the most common complaint among those who seek medical care for OA and as a result of OA pain 80% of individuals with have some degree of movement limitation, 25% cannot perform major activities of daily living and 11% of adults with KOA need help with personal care. Consequentially, OA can lead to negative effects on quality of life, mood, fatigue and sleep. Interestingly, poor sleep occurs in  70% of older individuals with OA and is linked with fatigue, which in turn is associated with a greater fall risk in the elderly and identifies fatigue as a further concern, in addition to joint instability, of fall-related complications. OA is a progressive condition with no cure, however treatments do exist aimed at reducing symptoms and slowing progression of the disease. This in turn will improve mobility, quality of life and leads to a reduction in the need joint replacement surgery in the long-term and consequently reduces the demand on healthcare resource. Non-steroidal anti-inflammatory drugs (NSAID) are the traditional approach for clinical management of mild-to-moderate OA symptoms, however NSAIDs have been associated with potentially harmful side effects such as gastrointestinal complications, renal disturbances and cardiovascular events. Therefore, non-pharmaceutical alternatives have been developed such as glucosamine compounds, however the reported efficacy for reducing OA symptoms varies. Nonetheless, while glucosamine compounds have a lower risk of adverse effects compared to NSAIDs and other symptomatic slow-acting drugs for OA (SYSADOA), glucosamine compounds show higher risk of adverse side effects than placebo and as such alternatives should be sought. Further to possible adverse health effects, NSAIDs and SYASDOAs are costly and greatly affect the socioeconomic health of patients with OA. A recent meta-analysis of global generalized OA has shown that the individual annual incremental healthcare costs ranged from €705 to €19,715 and concluded that the social cost of OA could be between 0.25% and 0.50% of a country's GDP. More specifically, the individual cost of KOA (both social healthcare and private) can range from €528 to €11293 depending of severity. In fact, Hunter et al. recently called for urgent action to focus attention on opportunities to reduce the individual and socioeconomic burden of OA. Glucosamine supplementation for the treatment of OA and OA related phenotypes spans many decades, with the first (to the authors' knowledge) patent filled in 1969 and research on human derived glucosamine published long before. The earliest identifiable mention (to the authors' knowledge) of Aqumin is from the late 90's with a patent, containing Aqumin, filled for human consumption in 2003, Algae-based food supplement. Therefore, there is a significant advantage for glucosamine in the accumulation of large high quality studies into its therapeutic effects. Nonetheless, the few small pilot studies concerned with the therapeutic effects of Aquamin supplementation show promising results in comparison to both placebo and Glucosamine formulas. In fact, for some important OA phenotypes, Aquamin performs better, particularly in the reduction of NSAID use. While the proposed mechanisms of action differ considerable between the two supplements, inflammatory reduction occurs because of both. Currently, there have been no long-term trials concerned with the efficacy of Aquamin in the reduction of KOA related joint structural decline however, because Aquamin reduces inflammatory markers of KOA, albeit in only one small human study, it is possible that Aquamin might improve joint structural decline and KOA prognosis through possibly reducing joint tissue damage. This project will be a double blinded randomized cross-over control trial with a sample size of 30 participants (based off a sample size calculation detailed below). The project will investigate two supplements on their effects on self-reported pain, quality of life, knee extensor/flexor strength, knee extensor/flexor myoelectric activity, functional mobility and biomarkers associated with inflammation. The participants will first be assessed for baseline measurements of the outcome measures mentioned above. They will then be randomly allocated to either group A or B and will take either supplement A or B for a period of 12 weeks. Following this there will be follow up assessments of the same outcome measures. This will be followed by a 4-week washout period prior to each subjects' baseline measures being reassessed and each participant allocated the 'other' supplement. After 12 weeks' supplementation, the subjects will then be retested for a final time. An a priori sample size calculation indicated a total of 29 patients was required to enter this two-treatment crossover study to assess the primary outcomes. The probability is 80 percent that the study will detect a treatment difference at a two-sided 0.05 significance level, if the true difference between treatments is 12.000 units. This is based on the assumption that the within-patient standard deviation of the response variable is 15.62.

Official Title
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Investigating the Potential for Marigot's Nutrition Supplement to Improve Symptoms and Physical Function in Those With Mild to Moderate Knee Osteoarthritis (KOA) Versus the Current Market Leader (Glucosamine Sulphate)

Conditions
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Knee Osteoarthritis

Intervention / Treatment
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* Dietary Supplement: Aquamin-Plus
* Dietary Supplement: Glucosamine sulphate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The project will focus on patients with a diagnosis of a mild-moderate KOA (level 1-3 Kellgren and Lawrence and WOMAC in the lower two quartiles), in the target knee, (Frestedt et al., 2008) and a BMI between 20 and 30 kg/m2. Exclusion Criteria: [1] rheumatoid arthritis [2] gout [3] pseudo gout [4] Paget's disease [5] seizure disorder [6] insulin dependent diabetes mellitus [7] uncontrolled hypertension [8] unstable cardiovascular disease [9] active hepatic or renal disease [10] active cancer and/or HIV infection, involved in other clinical trial or experimental treatments in the past 3 months; pregnant, lactating, or at risk of becoming pregnant; intramuscular/systemic corticosteroid injection within 4 weeks; intra-articular corticosteroid injection within 2 months; or inter-articular hyaluronic acid injection within 4 months prior to enrollment.

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: The project is a double blind randomized controlled clinical trial (pilot), with a cross-over design. Participants, will be randomized to begin taking either Aquamin-plus or Glucosamine sulphate following medical diagnosis and baseline assessment. Following 12 weeks of supplementation of Glucosamine sulphate or Aquamin-plus there will be a 4-week washout period before participants consume the other supplement.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Glucosamine sulphate<br>Glucosamine sulphate will be consumed as either supplement A or B (i.e. blinded) for a period of 12-weeks. Glucosamine will be taken 2 times daily with food. After 12 weeks of supplementation, participants will begin taking the alternative supplement (Aquamin-plus), after a washout period of not less than 1 month between the intervention arms of the study. | Dietary Supplement: Aquamin-Plus<br>* Aquamin (a calcium-rich marine multi-mineral) - 666.7mg magnesium hydroxide - 66.66mg pine bark - 30mg vitamin d3 - 2.5μg Dosage: 4 Capsules is equal to effective dose<br>Dietary Supplement: Glucosamine sulphate<br>* The Glucosamine sulphate supplement contains 500mg of the active ingredient Glucosamine sulphate per serving (one capsule). Dosage: 4 Capsules is equal to effective dose<br>|
| Experimental: Aquamin-plus<br>Aquamin-plus will be consumed as either supplement A or B (i.e. blinded) for a period of 12-weeks. Aquamin-plus will be taken 2 times daily with food. After 12 weeks of supplementation, participants will begin taking the alternative supplement (Glucosamine sulphate), after a washout period of not less than 1 month between the intervention arms of the study. | Dietary Supplement: Aquamin-Plus<br>* Aquamin (a calcium-rich marine multi-mineral) - 666.7mg magnesium hydroxide - 66.66mg pine bark - 30mg vitamin d3 - 2.5μg Dosage: 4 Capsules is equal to effective dose<br>Dietary Supplement: Glucosamine sulphate<br>* The Glucosamine sulphate supplement contains 500mg of the active ingredient Glucosamine sulphate per serving (one capsule). Dosage: 4 Capsules is equal to effective dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Self reported KOA pain | The primary outcome measure will be an assessment of the participants' knee pain. This will be measured using the validated Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain and function sub-scale. This will allow for the determination of the comparability, superiority or otherwise of Aquamin-plus compared to glucosamine sulphate in improving participant's self-reported knee pain and function. Change from baseline assessed. | Baseline, mid intervention (4 and 8 weeks) post intervention (12 weeks), post washout period (16 weeks), mid intervention (20 and 24 weeks) post intervention (28 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of life questionnaire | This will be quantified by the EuroQoL-5D. The EuroQoL-5D will assess participants on their levels of function surrounding mobility, self-care, usual activities, pain / discomfort, anxiety / depression. Change from baseline assessed. | Participants will be assessed on 4 separate occasions: Baseline, post intervention (12 weeks), post washout period (16 weeks), post intervention (28 weeks) | 
| Knee flexor and extensor muscle strength | Participants knee joint strength will be assessed using an isokinetic dynamometer (Cybex). Specifically isometric strength of the quadricep and hamstring muscles. Change from baseline assessed. | Participants will be assessed on 4 separate occasions: Baseline, post intervention (12 weeks), post washout period (16 weeks), post intervention (28 weeks) | 
| Knee flexor and extensor muscle electrical activity | Muscles activation (via electromyography) during the performance of the isometric testing will be assessed for the quadricep and hamstring muscles. Both the agonist and antagonist muscle activity will be assessed and a co-contraction value will be calculated. Change from baseline assessed. | Participants will be assessed on 4 separate occasions: Baseline, post intervention (12 weeks), post washout period (16 weeks), post intervention (28 weeks) | 
| Biomarkers | Biomarkers known to be involved in the biological response to KOA will be assessed to investigate possible mechanistic effects and differences of both interventions. As such, in order to investigate these possible mechanistic parameters include venous blood sampling (10 mL). Change from baseline assessed. | Participants will be assessed on 4 separate occasions: Baseline, post intervention (12 weeks), post washout period (16 weeks), post intervention (28 weeks) | 
| Functional mobility | This will be assessed using the Six-minute Walk Test (6MWT) and the Timed Up and Go Test (TUG). These tests indicate levels of functional. Change from baseline assessed. | Participants will be assessed on 4 separate occasions: Baseline, post intervention (12 weeks), post washout period (16 weeks), post intervention (28 weeks) | 
| Body Composition | A Dule-Energy X ray Absorptimetry (DEXA) will be used to assess participants body composition. Change from baseline assessed. | Participants will be assessed on 4 separate occasions: Baseline, post intervention (12 weeks), post washout period (16 weeks), post intervention (28 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Knee pain, Glucosamine, WOMAC, Osteoarthritis