An interventional study of Gold in Inflammation and Osteo Arthritis Knee, sponsored by Sten Rasmussen, MD, PhD. Completed at 1 site in Denmark. Open to participants aged 40 Years to 75 Years. Per ClinicalTrials.gov, last updated 2021-08-12.
Sponsored by Sten Rasmussen, MD, PhD · Not applicable, Interventional, and Basic science
The aim of this study is to use gold particles as a model compound to modulate specifically and selectively the function of macrophages and mast cells and investigate how this modulates pain and pain sensitization in the osteoarthritic knee assessed by mechanistic pain assessment technologies
Osteoarthritis (OA) of the knee and hip is the most common musculoskeletal joint disease worldwide. Although a major symptom of OA is chronic joint pain, which has a significant effect on patients' quality of life, the pain mechanisms remain largely unknown.
Recently, clinical studies have suggested the existence of a neuropathic component in OA pain [5]. Accumulating evidence has been indicating that painful OA patients show peripheral and central sensitization [3,16]. Quantitative sensory testing (QST) is a relevant way to assess peripheral and central sensitization in joint pain [9]. The majority of studies have administered mechanical stimuli, and the most commonly used modality have been pressure. A recent review concluded that that people with OA have lower Pressure Pain Thresholds (PPT), facilitated temporal summation and impaired conditioned (CPM) compared with healthy controls [5]. Also, recent evidence have link QST profiles to the development of chronic pain [29,38], which emphasises the importance of studying the central nervous system.
Inflammation markers have been correlated with the pain intensity [35], and systemic inflammation can leads to sensitization of peripheral nociceptors [1]. Recently it was reported that higher preoperative levels of TNF-α, MMP-13 and IL-6 in synovial fluid may indicate a smaller improvement in pain 2 years after TKR [15].
Injectable solutions of gold-thio-compounds have been used to treat rheumatoid arthritis for nearly 100 years [13,21]. Several studies suggest that gold ions reduces pain, joint swelling, inflammation, and increase joint motility [24,31,33]. Gold salt therapy (auranofin; RidauraR) has been vetted by the FDA and approved (May 1985) and recommended by the American College of Rheumatology as a Disease Modifying Anti Rheumatic Drug - DMARD (https://www.rheumatology.org).
Gold salts, whether injected or given orally, have been shown to be effective [33,37] in reducing joint pain. Studies report patients going to total remission [28] and others report a 30% reduction in symptoms [20,27]. In addition, Clark et al., 1997 [8] concluded in a Cochrane meta-analysis that systemic treatment with gold was highly effective compared to placebo.
The use of gold salt given systemically have been criticized, since when gold compounds are made to circulate systemically via the circulatory system after oral or parenteral administration, the gold ions reach essentially all tissues and organs. In some patients, organs that are not involved in the arthritic disease, such as the kidneys, liver, and skin are adversely affected by gold. About 30% of patients develop such remote-organ "side effects" and discontinue gold treatment [20]. In addition, newer drugs have been developed with efficacy almost equal to gold ions in many patients, and less toxic.
To overcome the toxicity, a method that captures the efficacy of the gold ions but eliminates the remote side effects have been developed[10,23]. Briefly, the method isolates the gold ions within the affected joints by injecting solid gold metal directly into the diseased joint, whereby a very slow dissolution and local diffusion deliver the therapeutic gold ions to affected areas within the joint. In this therapy, 99.99% pure gold implants are injected into the body.
Individual single beads are implanted with a 15-16 gauge needle based on an X-ray picture in deeply anesthetized animals close to the capsule of the affected joint(s) (videos www.goldtreat.com). Over 3000 dogs, and more than 100 horses have had this treatment for osteoarthritis at 50+ veterinary clinics and hospitals throughout Europe. (www.goldtreat.com ). Success rates of 50 - 70% are quoted (www.goldtreat.com), and a double-blind, placebo controlled study on dogs showed improvement in over 80% of the dogs, which continues for 18 months [18] as the gold particles remain in the joint[26].
The systemic concentration of released gold ions is low but clinically effective and because the gold ions do not spread in the organism, but instead stay local, the technique is safe [12]. The trials to date indicate that only one local application is needed to obtain lifelong clinical effect [12].
To date it is still debated how much the inflammation per se contributes to pain in osteoarthritis. A variety of studies have investigates various aspects such as synovitis but still no clear associations to pain have been found[30]. Many studies have attempted to modulate the effect of the inflammatory mediators on the pain receptors by e.g. interacting with the arachidonic acid pathways[4]. As such compounds have both peripheral and central effects it is difficult to use such compounds a specific modulators of specific local inflammatory processes. No compounds have so far been used to modulate selectively the local organelles specifically involved in the inflammatory processes of joint pain.
Gold particles seems as the only known method to obtain such a local effect on one specific element involved in the inflammatory process - the macrophages and the mast cells.
If a foreign object gets embedded in the body, macrophages will attack the object and digest it.
If the foreign object has a diameter bigger than 20 microns the macrophage cannot engulf it. Instead the macrophages create a membrane on the surface of the foreign body and starts a chemical attack in order to dissolve it.
If the foreign body consist of gold the macrophages will cause release of gold ions from the foreign body.
Gold ions, taken up by the macrophages, causes them to malfunction[10,11,23]. As the macrophage is 'conductor' of the inflammatory process it causes a drastic restraint of the inflammation and finally bring it to a stop[22,25]. The released gold ions will be taken up by the macrophages themselves, but also diffuse out into the surrounding tissue where they are taken up by other cells as well e.g. mast cells and other connective tissue cells[7,32]. When the gold ions accumulate in the secretory granules of mast cells it blocks histamine release and thereby decrease the local oedema and additionally suppresses pain.
The amount of bio-released gold ions are related to the intensity of inflammation. Only few gold ions are released in immunological nonreactive tissue. This means that if a local inflammation that has been treated with gold implants, the increase in macrophages will cause an immediate inhibition of the inflammation.
The combined effect of gold ions on macrophages and mast cells is together believed to causes the significant reduction in pain following treatment with metallic gold particles. If this principle can be validated it may provide important information for development of new and better treatments for e.g. joint pain.
Recently, Seifert et al.[34] called for studies providing new insights into the mode of action of gold ions and suggest investigating the effects on key mechanisms involved in arthritis or other inflammatory conditions.
3,536 studies on the registry are indexed under Inflammation; 642 are open to participants now.
This study's enrollment of 32 is below the median of 50 across 2,577 interventional studies indexed under Inflammation.
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Exclusion Criteria:
Approximately 72000, 20-40 my-meter diameter, sterilised gold particles (=20 mg) will be provided in vials (The Berlock® Gold Implants).
Other: Gold
Approximately 72000, 20-40 my-meter diameter, sterilised gold particles (=20 mg) will be provided in vials (The Berlock® Gold Implants). 5-10 ml of synovial fluid is aspirated (20G needle) from most affected OA-knee. The vial of gold particles are mixed with the synovial fluid, and the mix of gold and synovial fluid is injected intra-articularly into the patients knee.
WOMAC
The WOMAC\[6\] is a subject-rated instrument that measures Osteoarthritis (OA)
Time frame: 8 weeks, 2 years
Quantitative sensory testing
Pressure Pain Sensitivity Cuff Pressure Algometry
Time frame: 8 weeks
Weekly pain diary
Subjects rated their pain intensity on a VAS scale every day at home. On the VAS scale ''0" indicates ''no pain", and ''10" indicates ''maximal pain". Subjects rated the pain severity for: Average Pain Score (APS) for the last 24 hours Worst pain for the last 24 hours Pain severity at night.
Time frame: 8 weeks
Inflammatory markers
Proteomic analysis of blood and synovial fluid
Time frame: 8 weeks
PainDetect questionnaire (PD-Q
The PD-Q is a validated, easy to use screening tool that predicts the likelihood of a neuropathic pain component in chronic pain disorders\[14\]. It shows higher sensitivity and specificity in comparison with other neuropathic pain screening questionnaires. The questionnaire is comprised of 3 major components: gradation of pain, pain course pattern and radiating pain. There are 7 questions evaluating gradation of pain. Each question is scored by the patient using a 0 to 5 score with 0 = never, 1 = hardly notice, 2 = slightly, 3 = moderately, 4 = strongly and 5 = very strongly. There is one question evaluating pain course pattern. Patients select from one of four pictures to indicate which pattern of pain best describes their course of pain. Each picture is associated with a unique score of 0, -1, or +1 (2 pictures have this score possible). There is one question evaluating radiating pain with a yes (score of +2) or no (score of 0) response option.
Time frame: 8 weeks, 2 years
Global Rating of Change Scale
we asked the question, "Concerning your knee, how will you describe yourself compared to immediately before injection of gold into your knee" and evaluated the answer at an 11-point scale from very much worse (-5) to complete recovered (5).
Time frame: 2 years
Plan to share: Yes — Inflammatory markers may be shared with other researchers
Supporting information: Study protocol, Statistical analysis plan, Informed consent form
Time frame: After publication information is available.
Access criteria: At the reasonable request to Sten Rasmusssen. (sten.rasmussen@rn.dk;s_rasmussen@dcm.aau.dk
Ran from Dec 2017 to primary completion in Dec 2018, 12 months.
Of 877 non-industry interventional studies with no phase under Inflammation, half reached primary completion within 18 months of starting (the median), counting those still running; a quarter within 8 and three quarters within 36. This study's 12 months is below that.
Counting every sponsor, half of 924 studies reached it within 18 months; a quarter within 8 and three quarters within 36.
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This study is completed, as verified in Aug 2021. You cannot join it, but the record below documents what was studied.
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