This small preliminary randomised, double blind, placebo controlled parallel group study investigated the effect of Aquamin on NSAID dose reduction in subjects with OA of the knee. We used anecdotal information along with our experience from a previous study with a similar endpoint to estimate the number of subjects that might be needed for this small pilot study .
This study was reviewed by Quorum Review Inc, a central IRB (Seattle, WA), performed in compliance with all the applicable regulations and guidelines (e.g. Good Clinical Practice Guidelines, the Declaration of Helsinki, 21CFR50-Protection of Human Subjects and 21CRF56-Institutional Review Boards) and was monitored and audited according to Minnesota Applied Research Center Standard Operation Procedures (SOPs). Subject data was kept confidential and study records were stored in a locked and secure storage area.
Study center and subject selection
This study was conducted at the Minnesota Applied Research Center (Edina, MN). Subjects of either gender were included if they voluntarily gave informed consent, were ambulatory, 35–75 years old, with normal digestion and absorption and were diagnosed with symptomatic moderate to severe OA of the knee according to their previous medical history and the modified clinical criteria of the American College of Rheumatology . All subjects were required to have a WOMAC total scores ≤ 75 at entry and were currently taking NSAIDs daily for pain management. The target knee was identified by physical examination as the most severely affected knee for each subject and the cut off point for the WOMAC score was enforced as a means of standardizing the extent of pain and immobility in the small number of subjects recruited for this trial. A waiver to the selection criteria was made for one subject who had a WOMAC score of 76 and was enrolled in the trial.
Subjects were excluded from this trial if they had rheumatoid arthritis, gout, pseudogout, Paget's disease, seizure disorder, insulin dependent diabetes mellitus, uncontrolled hypertension, unstable cardiovascular disease, active hepatic or renal disease, active cancer, HIV infection; if they required prescription drugs to control pain; if they had other clinical trial or experimental treatments in the past 3 months; if they were pregnant, lactating or at risk of becoming pregnant; or if they had intramuscular or systemic corticosteroid administration within 1 month, intra-articular corticosteroid injection within 2 months or intra-articular hyaluronic acid injection within 4 months prior to study enrollment.
Study visits and treatments
The study was conducted over 14 weeks with a total of 6 visits to the study centre at -2 (screening), 0 (baseline), 2, 4, 8 and 12 weeks on treatment. During the initial two-week screening period (-2 to 0 weeks), subjects were asked to discontinue any prescription, over-the-counter or alternative therapy treatments for pain management but were allowed to use their preferred NSAID for pain management. In order to establish a standardised calcium intake across all treatments, subjects were asked not to change their usual dietary patterns during this trial except to consume a diet with approximately 600 mg calcium per day (e.g. two dairy servings) which was estimated to be 40–60% of their Recommended Daily Allowance (RDA) for calcium (depending on their age). Subjects were also asked to maintain the same amount of exercise throughout the study even if their joint pain was reduced. Qualified subjects were randomised (1:1) to receive either placebo or Aquamin and the trial activities remained double blinded throughout the trial to avoid bias. The subjects were blindly allocated to one of two treatment groups, according to a randomisation table, in the order of their enrollment in the study. The computer generated randomisation table was created by an independent statistician and the investigators were not aware of the group code assignments. A third party was responsible for labelling the test article and placebo according to the subject number and the randomisation table and the group code assignments.
At the baseline visit, all subjects received pre-packaged two-piece hard shell capsules containing either Aquamin (267 mg Aquamin + 167 mg maltodextrin) (34% calcium, 88.1 mg) or placebo (434 mg maltodextran). The bottles (and the capsules inside) appeared identical and subjects were instructed to consume three capsules, with a glass of water, three times per day. After taking either Aquamin or placebo for 2 weeks (0–2 weeks), subjects were asked to reduce NSAID use by 50% for a period of 2 weeks (2–4 weeks) and to eliminate NSAID use completely after 4 weeks and for the remainder of the study (4–12 weeks). Pain was managed with acetaminophen (325 mg per tablet with 1–2 tablets to be taken every 4–6 hours as needed for pain).
Vital signs, adverse events and the amounts of acetaminophen used for pain were assessed at each visit. Laboratory tests were performed and subjects completed WOMAC questionnaires as well as 6-minute walking distance (6 MWD) and range of motion (ROM) tests. Subject compliance was assessed at each visit by pill count, interview, and review of the medication diary. The WOMAC Osteoarthritis Index is a validated questionnaire including scores for pain, stiffness and activity as well as a composite (total) score. The 6 MWD was conducted by marking off a 100-foot distance in an interior hallway and asking subjects to walk as far as they could as quickly as possible over 6 minutes. The total distance was measured and recorded. ROM tests for the effected knee were measured using a goniometer.
An independent statistician analysed the data using t-tests (for single between-group comparisons), ANCOVA (for between-group comparisons at specific timepoints, using baseline score as a covariate) and a mixed linear regression model on repeated measures data (for between-group comparisons across all timepoints) to analyze data for an Intent to Treat Group (including all subjects enrolled and treated in this trial with values imputed for their Last Observation Carried Forward (LOCF) for any subjects who did not complete the trial) and a Completer's Group (including only data from subjects who completed the trial per protocol).