A natural seaweed derived mineral supplement (Aquamin F) for knee osteoarthritis: A randomised, placebo controlled pilot study

Study design

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 [12].

Ethics

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 [13]. 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).

Study measurements

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.

Statistical analyses

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).

Subject enrollment and disposition

This study was initially designed to enroll 50 volunteers; however, recruitment was terminated after 29 subjects were screened due to a lack of volunteers. The subjects expressed a fear that they would have OA pain symptoms following the complete discontinuation of NSAIDs as required for the study. Of the initial 29 subjects enrolled, 13 were assigned to the Aquamin group, 15 were assigned to the Placebo group, and one was not randomized to a group assignment. Seven (7) of the 29 subjects did not to fit the trial protocol requirements at their baseline visit and were discontinued from the study. Of these seven subjects, 5 were allocated to the Aquamin arm, 1 was allocated to the placebo arm and one was not yet randomized to a group assignment. Therefore, 22 of the initial 29 subjects went on to the treatment phase of the trial, with 8 subjects allocated to the Aquamin arm and 14 subjects allocated to the placebo arm.

A total of 14 (64%) of the 22 treated subjects completed the trial with treatment for the expected 12 weeks (84 days) (Table 2). Eight (36%) subjects withdrew from the trial including five subjects from the placebo arm and three from the Aquamin arm. Two subjects withdrew from the Aquamin arm at days 1 and 10 of treatment (prior to any reduction in NSAID usage) because they were unable to maintain adequate compliance with one or more aspects of the protocol and one subject withdrew from the Aquamin arm on day 65 due to increasing knee pain. In contrast, five subjects withdrew from the placebo arm due to increasing knee pain in the latter stages of the trial (41 +/- 14 days [mean +/- SD] – at 28, 32, 39, 41, and 64 days) when NSAID use had been completely eliminated. Although considerably more subjects withdrew due to increasing pain levels in the placebo group (n = 5) than the Aquamin group (n = 1) this was not statistically significant (Figure 1).

Baseline characteristics

Test article and rescue medications

No significant differences were found between the two groups for test article or rescue medication consumption at any single timepoint or over time in this trial. Although not statistically significant, the use of pain meds increased over time from V4 to V5 to V6 for both groups indicating parallel courses for both groups over the time period of this trial.

WOMAC

ROM

No differences were found between the two groups when ROM scores were compared across all available visits; however significant differences were found when changes from baseline to specific time endpoints were compared separately using a conventional univariate analysis of variance (ANCOVA) approach. Groups were compared at each treatment timepoint (V3, V4, V5, V6) and LOCF separately while adjusting for baseline (V2) score. Groups differed significantly in the change from V2 (baseline) to V4 (one month on treatment and after two weeks with NSAID dose at 50%). Significantly higher ROM for passive and active extension (0.83° ± 1.54 vs. -1.54° ± 2.43; difference, 5.2° ± 2.2, p = 0.028) were recorded for the Aquamin group (Figure 2 and Table 4) following the 50% reduction in NSAID use. No statistically significant changes were noted between the groups for active or passive flexion ROM.

6 MWD

No differences were found in 6 MWD when scores were compared across all visits from V2 to V6; however, analysis of each time-point separately while adjusting for the baseline (V2) score showed significant differences between the two groups in the change from V2 (baseline) to V4 (one month on treatment and after two weeks with NSAID dose at 50%). The distance covered during a 6 minute timed walk was significantly improved within the Aquamin group compared to the placebo group (150 ± 48 ft vs. 12.5 ± 31.5 ft; difference, 136 ± 57 ft, p = 0.03) (Figure 3 & Table 4) indicating a significant improvement in the Aquamin treated group when NSAID use was reduced by 50%.

Adverse events