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A 2-year randomised, double-blind, placebo-controlled, multicentre study of oral selective iNOS inhibitor, cindunistat (SD-6010), in patients with symptomatic osteoarthritis of the knee

Hellio le Graverand, Marie-Pierre; Clemmer, Ray S; Redifer, Patricia; Brunell, Robert M; Hayes, Curtis W; Brandt, Kenneth D; Abramson, Steven B; Manning, Pamela T; Miller, Colin G; Vignon, Eric
OBJECTIVE: To determine if inhibition of inducible nitric oxide synthase (iNOS) with cindunistat hydrochloride maleate slows progression of osteoarthritis (OA) METHODS: This 2-year, multinational, double-blind, placebo-controlled trial enrolled patients with symptomatic knee OA (Kellgren and Lawrence Grade (KLG) 2 or 3). Standard OA therapies were permitted throughout. Patients were randomly assigned to cindunistat (50 or 200 mg/day) or placebo. Randomisation was stratified by KLG. Radiographs to assess joint space narrowing (JSN) were acquired using the modified Lyon-schuss protocol at baseline, week 48 and 96. RESULTS: Of 1457 patients (50 mg/day, n=485; 200 mg/day, n=486; placebo, n=486), 1048 (71.9%) completed the study. Patients were predominantly women; 56% had KLG3. The primary analysis did not demonstrate superiority of cindunistat versus placebo for rate of change in JSN. In KLG2 patients, JSN after 48 weeks was lower with cindunistat 50 mg/day versus placebo (p=0.032). Least-squares mean+/-SE JSN with cindunistat 50 mg/day ( -0.048+/-0.028 mm) and 200 mg/day (-0.062+/-0.028 mm) were 59.9% (95% CI 6.8% to 106.9%) and 48.7% (95% CI -8.4% to 93.9%) of placebo, improvement was not maintained at 96 weeks. No improvement was observed for KLG3 patients at either time-point. Cindunistat did not improve joint pain or function, but was generally well tolerated. CONCLUSIONS: Cindunistat (50 or 200 mg/day) did not slow the rate of JSN versus placebo. After 48-weeks, KLG2 patients showed less JSN; however, the improvement was not sustained at 96-weeks. iNOS inhibition did not slow OA progression in KLG3 patients. CLINICAL TRIAL LISTING: NCT00565812.
PMID: 23144445
ISSN: 0003-4967
CID: 217372

A 2-year randomized, double-blind, placebo-controlled, multicenter study of an oral selective iNOS inhibitor in subjects with symptomatic osteoarthritis of the knee [Meeting Abstract]

Hellio, Le Graverand-Gastineau M -P; Clemmer, R; Redifer, P; Brunell, R M; Hayes, C W; Brandt, K; Abramson, S B; Manning, P T; Miller, C G; Vignon, E
Purpose: To determine whether inhibition of inducible nitric oxide synthase (iNOS) can slow progression of knee osteoarthritis (OA), using the rate of joint space narrowing (JSN) in the medial tibiofemoral compartment as the primary outcome measure. Methods: This was a 2-year multinational, multicenter, double-blind, parallel group trial enrolling subjects with symptomatic knee OA in which subjects were randomly assigned to receive once daily 50 mg or 200 mg of the selective iNOS inhibitor, SD-6010, or placebo. Subjects were required to have a body mass index (BMI) >=25 and <= 40 kg/m2 and Kellgren and Lawrence Grade (KLG) 2 or 3 in the study knee. Randomization was stratified by KLG. Radiographs were acquired using the modified Lyon-schuss protocol, at baseline, 48 and 96 weeks for measuring JSN. Clinical benefit was recorded at 12-week then every 24 weeks; use of acetaminophen, NSAIDs and/or weak opioids was permitted throughout the trial. The primary analysis of the rate of JSN used a continuous time random coefficients MMRM model. The slope over the entire 96 week period was used to assess the rate of change in joint space width (JSW). Results: Of 1457 randomized subjects (SD-6010 50mg, n=485; SD-6010 200mg, n=486; placebo, n=486), 1048 (71.9%) completed the study. Subjects were predominantly female (76.5%) with mean age 61. 0 years and mean BMI of 31.8 kg/m2. Fifty-six percent had KLG3. The primary analysis did not demonstrate the superiority of SD-6010 in either treatment group over placebo. In an exploratory discrete time MMRM analysis of KLG2 subjects, the loss of JSW after 48 weeks was significantly smaller with SD-6010 (50 mg or 200 mg) than placebo. Least squared (LS) mean +/- standard error (SE) losses in JSW for SD-6010 50mg (-0.048 +/- 0.028 mm) and 200mg (-0.062 +/- 0.028 mm) were 59.9% (95% CI: 6.8%, 106.9%) and 48.7% (95% CI: -8.4%, 93.9%) of placebo (-0.120 +/- 0.028 mm; P=0.032 and P=0.081, respectively). After 96 weeks, the LS mean losses in JSW for SD-6010 50mg (-0.132 +/- 0.036 mm) and 200mg (-0.156 +/- 0.037 mm) were 20.9% (95% CI: -50.5%, 64.0%) and 6.8% (95% CI: -72.7%, 51.7%) of the LS-mean JSW loss in the placebo group (-0.167+/-0.036 mm) (P=0.460 and P=0.812, respectively). In a similar analysis of KLG3 subjects, no improvement in JSN was observed. Although SD-6010 showed no efficacy with respect to improvement in joint pain or function, it was generally safe and well tolerated in this population. Conclusions: During the first 48 weeks of treatment, subjects with mild OA who were treated with an iNOS inhibitor had a lower rate of JSN; however, this improvement was not sustained at 96 weeks. iNOS inhibition did not slow OA progression in subjects with more severe radiographic OA. The observed early effect on JSN in subjects with mild OA supports the role of iNOS in OA pathogenetic mechanisms. However, the loss of efficacy over time and the lack of effect in subjects with more severe disease suggest that alternative biochemical catabolic pathways overcame the effects of nitric oxide inhibition alone or that in more severe radiographic OA, biomechanical factors may not be amenable to iNOS inhibition
EMBASE:70755847
ISSN: 1063-4584
CID: 169271

Malalignment and subchondral bone turnover in contralateral knees of overweight/obese women with unilateral osteoarthritis: Implications for bilateral disease

Mazzuca, Steven A; Brandt, Kenneth D; Lane, Kathleen A; Chakr, Rafael
OBJECTIVE: To explore whether the risk of incident tibiofemoral (TF) osteoarthritis (OA) in the radiographically normal contralateral knee of overweight/obese women with unilateral knee OA is mediated by malalignment and/or preceded by increased turnover of subchondral bone. METHODS: We used data of post hoc analyses from a randomized controlled trial. Cross-sectional analyses evaluated the baseline association between frontal plane alignment and bone turnover in the medial TF compartment in 78 radiographically normal contralateral knees. Longitudinal analyses ascertained whether incident radiographic OA (TF osteophyte formation within 30 months) was associated with malalignment and/or increased bone turnover at baseline. Alignment subcategories (varus/neutral/valgus) were based on the anatomic axis angle. (99m) Tc-methylene diphosphonate uptake in a late-phase bone scan was quantified in regions of interest in the medial tibia (MT) and medial femur (MF) and adjusted for uptake in a reference segment of the ipsilateral tibial shaft (TS). RESULTS: MF and MT uptake in varus contralateral knees was 50-55% greater than in the TS. Adjusted MT uptake in varus contralateral knees was significantly greater than that in neutral and valgus contralateral knees (mean 1.55 versus 1.38 and 1.43, respectively; P < 0.05). Among 69 contralateral knees followed longitudinally, 22 (32%) developed TF OA. Varus angulation was associated with a marginally significant increase in the odds of incident OA (adjusted odds ratio 3.98, P = 0.067). CONCLUSION: While the small sample size limited our ability to detect statistically significant risk factors, these data suggest that the risk of developing bilateral TF OA in overweight/obese women may be mediated by varus malalignment
PMID: 22034115
ISSN: 2151-4658
CID: 142150

Why should we expect a structure-modifying osteoarthritis drug to relieve osteoarthritis pain? [Editorial]

Brandt, Kenneth D
PMID: 21622770
ISSN: 1468-2060
CID: 142147

Methodology and statistical analysis in the Glucosamine/Chondroitin Arthritis Intervention Trial: comment on the article by Sawitzke et al [Letter]

Brandt, Kenneth D; Mazzuca, Steven A; Katz, Barry P
PMID: 19877051
ISSN: 0004-3591
CID: 142139

Commentary: is it useful to subset "primary" osteoarthritis? A critique based on evidence regarding the etiopathogenesis of osteoarthritis [Comment]

Brandt, Kenneth D; Dieppe, Paul; Radin, Eric L
PMID: 19796724
ISSN: 1532-866x
CID: 142137

Etiopathogenesis of osteoarthritis

Brandt, Kenneth D; Dieppe, Paul; Radin, Eric
Because of the implications for prevention and treatment, how a clinician views osteoarthritis (OA) matters. We view OA as an attempt to contain a mechanical problem in the joint and as failed repair of damage caused by excessive mechanical stress on the joint. OA is organ failure of the synovial joint. Because of insufficient focus on reduction of the habitually loaded contact area of the joint and on aberrant loading, we believe that therapeutic efforts aimed at pathogenetic mechanisms in OA have been misdirected: neither the large role that a reduction of excessive levels of mechanical stress plays in promoting the healing response in OA nor the evidence that relief of joint pain and improvement in function, rather than the appearance of the articular surface, are the most important outcomes of the healing process have been sufficiently emphasized. Various mechanical abnormalities can trigger the processes involved in repair and attempts by the joint to contain the mechanical insult, but without a return to mechanical normality, attempts at healing will fail. In our view, drugs may be helpful symptomatically, but cannot accomplish this. In our view, as long as the joint remains in the same adverse mechanical environment that got it into trouble in the first place, it is unlikely that a drug that inhibits a specific enzyme or cytokine in the pathways of cartilage breakdown, or further stimulates the already increased synthesis of cartilage matrix molecules will solve the problem of OA. Also, because the subchondral bone is critically important in containing the mechanical abnormalities that damage the cartilage, emphasis on cartilage repair alone is likely to be futile. On the other hand, if the abnormal stresses on the joint are corrected, intervention with a structure-modifying drug may be superfluous
PMID: 19059018
ISSN: 0025-7125
CID: 142134

Etiopathogenesis of osteoarthritis

Brandt, Kenneth D; Dieppe, Paul; Radin, Eric L
In this article, the authors posit that, because osteoarthritis (OA) involves all of the tissues of the synovial joint, the emphasis on the loss of cartilage, in particular, is misguided. In contrast, the authors view OA as a process that is attempting to contain a mechanical problem in the joint. They argue that OA is best defined as failed repair of damage that has been caused by excessive mechanical stress on joint tissues. Because the body's innate mechanisms for repairing the damaged tissues cannot be effective in the face of the overwhelming mechanical abnormality, they cannot solve the problem of OA
PMID: 18687271
ISSN: 1558-3163
CID: 142133

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

Otterness, Ivan G; Brandt, Kenneth D; Le Graverand, Marie-Pierre Hellio; Mazzuca, Steven A
OBJECTIVE: To use the collagenase cleavage site neoepitope, TIINE, a marker of type II collagen breakdown in cartilage, to analyze the mechanism underlying the slowing of joint space narrowing (JSN) in patients with knee osteoarthritis treated with doxycycline. METHODS: The creatinine-adjusted urinary TIINE concentration was determined at baseline and every 6 months thereafter in a subset of patients who completed a 30-month randomized, placebo-controlled study of the effect of doxycycline on radiographic progression of JSN. The subset was selected a priori to permit comparison of 60 radiographic progressors with 60 radiographic nonprogressors. JSN was determined in highly standardized, semiflexed anteroposterior images. RESULTS: The coefficient of variation of TIINE concentrations over the 5 study visits was 30%. At the 5 semiannual followup visits, the mean TIINE concentration for doxycycline-treated patients was higher than that for the placebo group. In both treatment groups, the correlation between TIINE levels and JSN in the index knee was weak (for doxycycline, r(2) = 0.06, P = 0.08; for placebo, r(2) = 0.06, P = 0.05). CONCLUSION: High variability from visit to visit limits the sensitivity of the TIINE assay for detecting changes in individual patients and restricts its utility to group comparisons. The increase in TIINE concentration with treatment indicates that inhibition of collagenase-mediated breakdown of type II collagen in articular cartilage is unlikely to have accounted for the observed reduction of JSN in the index knees of patients in the doxycycline treatment group
PMID: 17968918
ISSN: 0004-3591
CID: 142131

The futility of current approaches to chondroprotection - a different perspective: comment on the article by Felson and Kim [Letter]

Brandt, K D; Radin, E L; Dieppe, P A; van de Putte, L
PMID: 17968876
ISSN: 0004-3591
CID: 642622