(from the application): Osteoarthritis (OA) of the knee is the most common cause of chronic disability in this country and has enormous socio-economic impact. Notably, management of OA today is limited to symptomatic therapy. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most popular agents used to treat OA but elderly women, in whom OA is especially common, are at greatest risk of developing serious side effects from NSAIDs. Notablly, however, several drugs have been shown to prevent, or slow progression of, cartilage damage in animal models of 0A, and drugs are currently being developed to inhibit protease-induced cartilage damage, with a view to their use in OA. We have shown that prophylactic oral administration of doxycycline (doxy) markedly reduces the severity of cartilage damage in a canine model of OA; even when therapy was initiated after cartilage lesions were established, a protective effect was apparent. Similar results have been noted in guinea pig and rabbit models of OA. The effect is associated with reduction in the levels of collagenase and gelatinase in the OA cartilage. Based on the encouraging data in animal models of OA, we propose to conduct a multi-center, double-blind, placebo-controlled clinical trial of doxy in subjects with OA. It is our hypothesis that doxy will decrease the severity, or rate of progression, of OA. Because a disease-modifying drug for OA will, presumably, be more likely to show an effect in the early stages of the disease than when OA pathology is more advanced, our study population will be 2 obese females, 45-60 years old, with x-ray evidence of unilateral tibiofemoral OA in whom x-ray changes have been reported to develop in the contralateral knee in nearly 50% within 2 years. Subjects (n=432) will be randomized to receive doxy, 100 mg bid, or placebo for 2-1/2 years. No attempt will be made to influence NSAID and/or analgesic treatment or other measures prescribed in the course of routine clinical care. Several strategies will be employed to maximize compliance with the study medications and retention of subjects in the study, including a """"""""faintness-of-heart"""""""" test, which will be used at the outset to eliminate noncompliers, and use of a computerized medicine cap to provide information concerning compliance with the prescribed dosing regimen between visits, permitting study personnel to aim their efforts to enhance compliance at those subjects who can best benefit from them. Our primary outcome variables will be the rate joint space narrowing (JSN, measured by a computerized system on a digitized AP radiograph of the semi-flexed knee taken with a technique to markedly reduce variability in radioanatomic positioning) and the severity of individual radiographic features of OA, e.g., osteophytes, in the contralateral knee. Because the rate of JSN in the contralateral knee is uncertain, whereas published data indicate that in knees which exhibit bony changes of OA (e.g., osteophytes) it is sufficiently rapid to permit detection of a reasonable drug effect during the study period, radiographic progression in the index knee will also serve as a primary outcome variable. In addition, we will examine changes in an algofunctional index (WOMAC), global arthritis activity, general health status (SF-36). and utilization of health services in the two treatment groups. This study should answer the question whether oral treatment with doxy - a relatively safe, readily available and inexpensive drug with which decades of clinical experience have accrued - can modify the natural history of OA in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR043348-03
Application #
2748651
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Project Start
1996-09-30
Project End
2001-07-31
Budget Start
1998-08-01
Budget End
1999-07-31
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Mazzuca, Steven A; Brandt, Kenneth D; Katz, Barry P et al. (2007) Risk factors for early radiographic changes of tibiofemoral osteoarthritis. Ann Rheum Dis 66:394-9
Merle-Vincent, F; Vignon, E; Brandt, K et al. (2007) Superiority of the Lyon schuss view over the standing anteroposterior view for detecting joint space narrowing, especially in the lateral tibiofemoral compartment, in early knee osteoarthritis. Ann Rheum Dis 66:747-53
Otterness, Ivan G; Brandt, Kenneth D; Le Graverand, Marie-Pierre Hellio et al. (2007) Urinary TIINE concentrations in a randomized controlled trial of doxycycline in knee osteoarthritis: implications of the lack of association between TIINE levels and joint space narrowing. Arthritis Rheum 56:3644-9
Mazzuca, S A; Brandt, K D; Eyre, D R et al. (2006) Urinary levels of type II collagen C-telopeptide crosslink are unrelated to joint space narrowing in patients with knee osteoarthritis. Ann Rheum Dis 65:1055-9
Brandt, Kenneth D; Mazzuca, Steven A (2006) Experience with a placebo-controlled randomized clinical trial of a disease-modifying drug for osteoarthritis: the doxycycline trial. Rheum Dis Clin North Am 32:217-34, xi-xii
Mazzuca, S A; Brandt, K D; Katz, B P et al. (2006) Comparison of quantitative and semiquantitative indicators of joint space narrowing in subjects with knee osteoarthritis. Ann Rheum Dis 65:64-8
Mazzuca, Steven A; Poole, A Robin; Brandt, Kenneth D et al. (2006) Associations between joint space narrowing and molecular markers of collagen and proteoglycan turnover in patients with knee osteoarthritis. J Rheumatol 33:1147-51
Radiography Working Group of the OARSI-OMERACT Imaging Workshop; Le Graverand, M-P H; Mazzuca, S et al. (2006) Assessment of the radioanatomic positioning of the osteoarthritic knee in serial radiographs: comparison of three acquisition techniques. Osteoarthritis Cartilage 14 Suppl A:A37-43
Mikesky, Alan E; Mazzuca, Steven A; Brandt, Kenneth D et al. (2006) Effects of strength training on the incidence and progression of knee osteoarthritis. Arthritis Rheum 55:690-9
Hellio Le Graverand, M-P; Brandt, K D; Mazzuca, S A et al. (2006) Association between concentrations of urinary type II collagen neoepitope (uTIINE) and joint space narrowing in patients with knee osteoarthritis. Osteoarthritis Cartilage 14:1189-95

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