Use of a medication control officer to reduce bias in a clinical trial: lessons learned from the scleroderma lung study.

BACKGROUND: Scleroderma Lung Study (SLS) was designed to evaluate the efficacy and safety of oral cyclophosphamide (CYC) versus placebo taken for 1 year for scleroderma-associated interstitial lung disease. An independent medication control officer (MCO), usually a physician, at each center was assigned to monitor laboratory and clinical toxicity of study medication and regulate its dosing based on these results. By having an MCO who watched and managed toxicity, the study investigators were free to care for study patients and to assess study outcomes without the potential bias of knowing toxicity data (toxicity from cyclophosphamide is distinctive - cytopenias and hematuria in particular). PURPOSE: To assess the usefulness of an MCO, whose chief role was to maintain safety while retaining the blinding in the clinical trial. METHODS: Patients had safety laboratory testing every 2-4 weeks and results were sent directly to the MCO within 2 days of the test. Other clinical adverse events (AEs) were reported by the patient to a nurse coordinator who reported them to the MCO who then managed the AEs to preserve the blinding of investigators caring for the patients. The MCO was provided pre-determined algorithms for dose adjustments of test medication based on the presence and severity of laboratory abnormalities. RESULTS: Safety monitoring by the MCO was effective in the early detection of drug toxicity with provision of appropriate medical intervention on a timely basis. At the same time, investigator blinding appeared to be maintained. LIMITATIONS: The testing of MCO effectiveness in maintaining blinding and consistency was not defined as an a priori hypothesis and thus complete data relating to the efficacy of the MCO were not collected in a prospective fashion. CONCLUSION: An MCO and pre-specified monitoring and dosing guidelines, coupled with uniform pre-specified responses to AEs, may be used effectively to preserve investigator blinding and provide consistency in response to AEs in a clinical trial setting, even when AEs of the test medication are distinctive.

Severity of joint pain and Kellgren-Lawrence grade at baseline are better predictors of joint space narrowing than bone scintigraphy in obese women with knee osteoarthritis.

OBJECTIVE: To compare the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of a baseline late-phase bone scan and assessments of the radiographic and symptomatic severity of knee osteoarthritis (OA) at baseline as predictors of loss of articular cartilage thickness, as reflected in joint space narrowing (JSN) in the medial tibiofemoral compartment. METHODS: Subjects (174 obese women, 45-64 yrs of age, with unilateral knee OA) were a subset of a larger cohort who participated in a placebo controlled trial of a disease modifying OA drug. Uptake of technetium medronate (99mTc-MDP) in anteroposterior (AP) and lateral views of a late-phase bone scan was measured at baseline in a region of interest drawn around the medial tibia, and was adjusted for (i.e., expressed as a ratio to) uptake in a reference segment of the tibial shaft, which served as an internal standard. Each subject underwent a fluoroscopically standardized radiographic examination of the knees (semiflexed AP view) and a pain assessment with the WOMAC OA Index at baseline, 16 months, and 30 months. RESULTS: Controlling for baseline joint space width and treatment group, multiple linear regression models showed that the adjusted 99mTc-MDP uptake at baseline was a significant predictor of joint space narrowing (JSN) in the index knee at 16 months (b = 0.180, p = 0.015) and 30 months (b = 0.221, p = 0.049). In the contralateral knee, uptake was only a marginally significant predictor of JSN at 30 months (b = 0.246, p = 0.083). Uptake in the upper and middle tertiles of the distribution predicted subjects who would exhibit JSN >/= 0.50 mm within 16 months with 65% sensitivity (PPV 23%) and 36% specificity (NPV 77%). In contrast, a prediction rule based solely on the presence of Kellgren-Lawrence grade 3 OA severity and greater than median WOMAC Pain score identified progressors with 65% sensitivity (PPV 48%) and 79% specificity (NPV 88%). CONCLUSION: Although the level of adjusted 99mTc-MDP uptake was significantly associated with JSN in knees with established radiographic OA, baseline bone scintigraphy is inferior to the radiographic severity of OA and knee pain (alone or in combination) as a predictor of loss of articular cartilage in subjects with knee OA.

Antineutrophil cytoplasmic antibody vasculitis associated with mycobacterium avium intracellulare infection.

A variety of possible associations between infection and antineutrophil cytoplasmic antibody (ANCA) associated vasculitis have been reported. We describe a 75-year-old woman who presented with chronic nonproductive cough, migratory polyarthralgias, and microscopic hematuria. She had an elevated perinuclear ANCA and antimyeloperoxidase antibody. She had a positive PPD test and a cavitary lesion in the right upper lung lobe; biopsy of the lung lesion showed granulomatous vasculitis, but the culture grew Mycobacterium avium intracellulare (MAI). There are clinical and histiologic similarities between ANCA vasculitis and pulmonary MAI infection. Treatment of vasculitis with immunosuppressive agents could be detrimental in patients with MAI infection. Thus, when ANCA associated vasculitis is considered, mycobacterium infection should be excluded before starting immunosuppressive therapy.

Effects of doxycycline on progression of osteoarthritis: results of a randomized, placebo-controlled, double-blind trial.

OBJECTIVE: To confirm preclinical data suggesting that doxycycline can slow the progression of osteoarthritis (OA). The primary outcome measure was joint space narrowing (JSN) in the medial tibiofemoral compartment. METHODS: In this placebo-controlled trial, obese women (n = 431) ages 45-64 years with unilateral radiographic knee OA were randomly assigned to receive 30 months of treatment with 100 mg doxycycline or placebo twice a day. Tibiofemoral JSN was measured manually in fluoroscopically standardized radiographic examinations performed at baseline, 16 months, and 30 months. Severity of joint pain was recorded at 6-month intervals. RESULTS: Seventy-one percent of all randomized subjects completed the trial. Radiographs were obtained from 85% of all randomized subjects at 30 months. Adherence to the dosing regimen was 91.8% among subjects who completed the study per protocol. After 16 months of treatment, the mean +/- SD loss of joint space width in the index knee in the doxycycline group was 40% less than that in the placebo group (0.15 +/- 0.42 mm versus 0.24 +/- 0.54 mm); after 30 months, it was 33% less (0.30 +/- 0.60 mm versus 0.45 +/- 0.70 mm). Doxycycline did not reduce the mean severity of joint pain, although pain scores in both treatment groups were low at baseline and remained low throughout the trial, suggesting the presence of a floor effect. However, the frequency of followup visits at which the subject reported a > or = 20% increase in pain in the index knee, relative to the previous visit, was reduced among those receiving doxycycline. In contrast, doxycycline did not have an effect on either JSN or pain in the contralateral knee. In both treatment groups, subjects who reported a > or = 20% increase in knee pain at the majority of their followup visits had more rapid JSN than those whose pain did not increase. CONCLUSION: Doxycycline slowed the rate of JSN in knees with established OA. Its lack of effect on JSN in the contralateral knee suggests that pathogenetic mechanisms in that joint were different from those in the index knee.

Subject retention and adherence in a randomized placebo-controlled trial of a disease-modifying osteoarthritis drug.

OBJECTIVE: To describe the methods by which remarkable levels of subject retention and adherence were achieved in a 30-month multicenter randomized placebo-controlled trial (RCT) of a disease-modifying osteoarthritis drug (DMOAD). METHODS: Subjects were obese 45-64-year-old women with unilateral knee osteoarthritis. Before randomization, each volunteer completed a 4-week "faintness-of-heart" (FOH) test, during which she was required to demonstrate reliable appointment keeping and > or =80% adherence to the dosing regimen. Subjects who passed the FOH test were randomized to treatment with doxycycline or placebo for 30 months. The double-blind phase entailed 15 bimonthly followup visits; intervisit adherence data were downloaded from the dosing monitor and used to estimate therapeutic coverage and to identify correctable patterns of nonadherence. Subjects received token incentives and a small cash payment at each followup visit. Measures to prevent or treat side effects of doxycycline were dispensed free of charge. Study coordinators monitored safety and reinforced participation through between-visit telephone calls. RESULTS: Of 463 eligible volunteers, 32 (7%) failed the FOH test and were excluded from the double-blind phase. Among the 431 subjects randomized to treatment groups, 307 (71%) completed the 30-month RCT and 124 discontinued the study drug prematurely. Nearly half of the dropouts returned for their 16- and 30-month radiographs, resulting in loss to followup of 14.8% of randomized subjects. The 2 treatment groups did not differ significantly with respect to rates of discontinuation or retention. Therapeutic coverage over 30 months was very high in both groups. CONCLUSION: The rate of discontinuation in this 30-month RCT (29%) was lower than that of any DMOAD trial of > or =2 years duration published to date. The proportion of subjects for whom 30-month radiographs were available (85%) and adherence to the dosing regimen (mean >80%) also were remarkably high.