Experience with a Placebo-Controlled Randomized Clinical Trial of a Disease-Modifying Drug for Osteoarthritis: The Doxycycline Trial
Section snippets
The doxycycline trial
This article describes the results of a recent randomized placebo-controlled trial (RCT) designed to examine the DMOAD effect in humans of the tetracycline antibiotic doxycycline (doxy), and reviews the experience gained from other recent DMOAD trials in humans. The details of the doxy RCT are published elsewhere [4].
Caveats and conclusions
The subjects in the doxy study were homogeneous with respect to sex, BMI, age, and discordance in the severity of OA disease in their two knees, limiting the generalizability of these results. One cannot assume that the protective effect of doxy noted in the index knee would occur at other joint sites (eg, hips, hands), in subjects of all age groups, or in men. Furthermore, given the higher rate of adverse reactions in the doxy group than in the placebo group, the subjects may not have been
Acknowledgments
Data for the doxycycline trial were collected at six clinical research centers: Indiana University Medical Center (John D. Bradley, MD, and Steven T. Hugenberg, MD), the Arthritis Research Foundation (Frederick Wolfe, MD), University of Pittsburgh (Susan Manzi, MD, and Chester V. Oddis, MD), University of Alabama at Birmingham (Larry W. Moreland, MD, and Louis W. Heck, MD), Northwestern University Center for Clinical Research (Thomas J. Schnitzer, MD, and Leena Sharma, MD), and University of
References (55)
The role of nitric oxide in articular cartilage damage
Rheum Dis Clin North Am
(1999)- et al.
Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial
Lancet
(2001) - et al.
Intermittent treatment of knee osteoarthritis with oral chondroitin sulfate: a one-year, randomized, double-blind, multicenter study versus placebo
Osteoarthritis Cartilage
(2004) - et al.
Arthroscopic evaluation of potential structure modifying activity of hyaluronan (Hyalgan) in osteoarthritis of the knee
Osteoarthritis Cartilage
(1997) - et al.
Contribution of meniscal extrusion and cartilage loss to joint space narrowing in osteoarthritis
Clin Radiol
(1999) Non-surgical treatment of osteoarthritis: a half century of “advances”
Ann Rheum Dis
(2004)- et al.
Finding clinical endpoints and biosurrogates in preclinical knee osteoarthritis
J Rheumatol
(2005) - et al.
Which is the best radiologic/radiographic protocol for a clinical trial of a structure-modifying drug in patients with knee osteoarthritis? Proceedings of January 17–18, 2002 Workshop in Toussus-le-Noble, France
J Rheumatol
(2002) - et al.
Effect of doxycycline on progression of osteoarthritis
Arthritis Rheum
(2005) - et al.
Doxycycline inhibits type XI collagenolytic activity of extracts from human osteoarthritic cartilage and of gelatinase
J Rheumatol
(1991)
Activation of recombinant human neutrophil procollagenase in the presence of doxycycline results in fragmentation of the enzyme and loss of enzyme activity
Arthritis Rheum
A novel mechanism of action of tetracyclines: effects on nitric oxide synthases
Proc Natl Acad Sci U SA
Minocycline reduces gingival collagenolytic activity during diabetes. Preliminary observations and a proposed new mechanism of action
J Periodontal Res
Reduction of the severity of canine osteoarthritis by prophylactic treatment with oral doxycycline
Arthritis Rheum
Oral administration of doxycycline reduces collagenase and gelatinase activities in extracts of human osteoarthritic cartilage
J Rheumatol
Treatment of destructive arthritis disorders with MMP inhibitors
Ann N Y Acad Sci
Incidence and progression of osteoarthritis in women with unilateral knee disease in the general population: the effect of obesity
Ann Rheum Dis
Patient compliance and the conduct and interpretation of therapeutic trials
Control Clin Trials
The use of a run-in to enhance compliance
Stat Med
Treatment and prophylaxis of bacterial infections
Doxycycline disrupts chondrocyte differentiation and inhibits cartilage matrix degradation
Arthritis Rheum
Accuracy and precision of joint space width measurements in standard and macroradiographs of osteoarthritic knees
Ann Rheum Dis
Patellofemoral disorders: physical and radiographic evaluation. Part II: Radiographic examination
Clin Orthop Relat Res
Quantitative measurements of joint space during progression of osteoarthritis: chondrometry
Pitfalls in the accurate measurement of joint space narrowing in semiflexed anteroposterior radiographs of the knee
Arthritis Rheum
Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee
J Rheumatol
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2018, Osteoarthritis and CartilageCitation Excerpt :Existing data and biospecimens from the completed randomized placebo-controlled doxycycline (DOXY) trial (NCT00000403)18 provided the means of achieving this objective and evaluate the potential modification of these inflammatory biomarkers in the context of a trial in which doxycycline modestly slowed knee OA progression18,19. Previously, doxycycline was shown to be chondroprotective for human knee OA18–20. The chondroprotective effect demonstrated in these human trials was consistent with a number of prior trials showing chondroprotection by doxycycline in animal models of OA, including in guinea pigs21, rabbits22, dogs21,23 and horses24.
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2011, Osteoarthritis and CartilageCitation Excerpt :It is the life-blood of any clinical trial; however, recruiting for a primary prevention trial imposes requirements that are not always evident in treatment trials. Recruitment could be enhanced by using complementary strategies coupled with a system that provides feedback on each strategy’s effectiveness and cost35. Mass mailings and media (newspaper, television, internet) may be effective in some settings.
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2011, DifferentiationCitation Excerpt :There are a lack of reliable techniques and methods to stimulate growth of new tissue to treat degenerative diseases and trauma (Wong et al., 2005). Currently, there are no effective pharmaceutical treatments for OA, although some medications slow its progression (Brandt and Mazzuca, 2006; Steinert et al., 2007). There are also no surgical approaches to treat OA; however, surgery is an important tool for the repair of cartilage injuries, which if left untreated may result in secondary OA.
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2007, International Journal of GerontologyGenetic influence on the progression of radiographic knee osteoarthritis: a longitudinal twin study
2007, Osteoarthritis and CartilageCitation Excerpt :It may reflect greater random variability and error in the measurement of the lateral compartment but may relate to why OA targets the medial compartment more commonly than the lateral compartment17. Indeed, lateral progression in the current study was far less common, particularly for lateral JSN, as has been found in recent trials18. Numerous genome-wide linkage scans of OA have been conducted and several regions have been identified as harbouring susceptibility genes for OA, although most of them focused on hand and hip joints19.
Supported in part by National Institutes of Health Grants R01 AR43348, P60 AR20582, and R01 AR44370.