Jared Christensen

Time to failure after rotator cuff repair: a prospective imaging study.

BACKGROUND Failure of tendon healing after a rotator cuff repair is demonstrated by magnetic resonance imaging (MRI) as a fluid-filled defect within the tendon. The frequency of, and factors associated with, failure of the tendon repair to heal have been the focus of many clinical studies. The timing of when these defects occur has not been previously studied in a large prospectively defined patient population, to our knowledge. It was our hypothesis that the majority of failures occur within twelve weeks after surgery. METHODS One hundred and thirteen patients were enrolled in a multi-institutional prospective study. All patients had a standardized arthroscopic repair of a full-thickness tear of 1 to 4 cm as well as sequential MRI studies at six intervals from two weeks to fifty-two weeks. MRIs were reviewed at the time of imaging by the treating surgeon. Standardized patient-oriented clinical data were collected, physical examination was performed, and strength measurements were made preoperatively and postoperatively. RESULTS The treating surgeons diagnosed a recurrent tear with MRI in nineteen (17%) of the 113 patients within one year after surgery. The mean time to the retear was 19.2 weeks. There was a linear increase in retears over the first twenty-six weeks after surgery, and one additional tear was diagnosed between twenty-six and fifty-two weeks after repair. CONCLUSIONS Retears primarily occur between six and twenty-six weeks after arthroscopic rotator cuff repair, and few additional tears occur thereafter. A substantial number of retears occur between twelve and twenty-six weeks after repair. LEVEL OF EVIDENCE Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Recombinant Human Bone Morphogenetic Protein-2: A Randomized Trial in Open Tibial Fractures Treated with Reamed Nail Fixation

BACKGROUND Recombinant human bone morphogenetic protein-2 (rhBMP-2) improves healing of open tibial fractures treated with unreamed intramedullary nail fixation. We evaluated the use of rhBMP-2 in the treatment of acute open tibial fractures treated with reamed intramedullary nail fixation. METHODS Patients were randomly assigned (1:1) to receive the standard of care consisting of intramedullary nail fixation and routine soft-tissue management (the SOC group) or the standard of care plus an absorbable collagen sponge implant containing 1.5 mg/mL of rhBMP-2 (total, 12.0 mg) (the rhBMP-2/ACS group). Randomization was stratified by fracture severity. The absorbable collagen sponge was placed over the fracture at wound closure. The primary efficacy end point was the proportion of subjects with a healed fracture as demonstrated by radiographic and clinical assessment thirteen and twenty weeks after definitive wound closure. RESULTS Two hundred and seventy-seven patients were randomized and were the subjects of the intent-to-treat analysis. Thirteen percent of the fractures were Gustilo-Anderson Type IIIB. The proportions of patients with fracture-healing were 60% and 48% at week 13 (p = 0.0541) and 68% and 67% at week 20 in the rhBMP-2/ACS and SOC groups, respectively. Twelve percent of the subjects underwent secondary procedures in each group; more invasive procedures (e.g., exchange nailing) accounted for 30% of the procedures in the rhBMP-2/ACS group and 57% in the SOC group (p = 0.1271). Infection was seen in twenty-seven (19%) of the patients in the rhBMP-2/ACS group and fifteen (11%) in the SOC group (p = 0.0645; difference in infection risk = 0.09 [95% confidence interval, 0.0 to 0.17]). The adverse event incidence was otherwise similar between the treatment groups. CONCLUSIONS The healing of open tibial fractures treated with reamed intramedullary nail fixation was not significantly accelerated by the addition of an absorbable collagen sponge containing rhBMP-2.

Efficacy and Safety of Recombinant Human Bone Morphogenetic Protein-2/calcium Phosphate Matrix for Closed Tibial Diaphyseal Fracture: A Double-blind, Randomized, Controlled Phase-ii/iii Trial

BACKGROUND Recombinant human bone morphogenetic protein-2 (rhBMP-2) applied on an absorbable collagen sponge improves open tibial fracture-healing as an adjunct to unreamed intramedullary nail fixation. We evaluated rhBMP-2 and a new, injectable calcium phosphate matrix (CPM) formulation in acute closed tibial diaphyseal fractures treated with reamed intramedullary nail fixation. METHODS Patients were randomized (1:2:2:1) to receive standard of care, which consisted of definitive fracture fixation within seventy-two hours of injury with a locked intramedullary nail after reaming; standard of care and injection with 1.0 mg/mL of rhBMP-2/CPM; standard of care and injection with 2.0 mg/mL of rhBMP-2/CPM; or standard of care and injection with buffer/CPM, to evaluate the activity of the CPM delivery matrix and provide for sponsor and investigator blinding. The co-primary end points of the study were the effects of rhBMP-2/CPM on the time to fracture union (based on blinded assessment of radiographs) and the time to return to normal function (based on blinded assessment of the time to full weight-bearing without pain at the fracture site) compared with standard of care alone. RESULTS Three hundred and sixty-nine patients were randomized and included in the intent-to-treat population. This study was terminated after an interim analysis (180 patients with six months of follow-up) revealed no shortening in the time to fracture union in the active treatment arms compared with the standard of care control (the SOC group). In the final primary analysis, the median time to radiographic fracture union was not significantly different for the SOC (13.1 weeks), 1.0-mg/mL rhBMP-2/CPM (13.0 weeks), 2.0-mg/mL rhBMP-2/CPM (15.9 weeks), or buffer/CPM (15.4 weeks) treatment groups. The median time to pain-free full weight-bearing was also not significantly different among the SOC (13.4 weeks), 1.0-mg/mL rhBMP-2/CPM (13.4 weeks), 2.0-mg/mL rhBMP-2/CPM (14.3 weeks), and buffer/CPM (16.4 weeks) treatment groups. CONCLUSIONS In patients with closed tibial fractures treated with reamed intramedullary nailing, the time to fracture union and pain-free full weight-bearing were not significantly reduced by rhBMP-2/CPM compared with standard of care alone. 24306696

Efficacy and safety of an interleukin 6 monoclonal antibody for the treatment of systemic lupus erythematosus: a phase II dose-ranging randomised controlled trial

Objectives This phase II trial evaluated the efficacy and safety of an interleukin (IL) 6 monoclonal antibody for systemic lupus erythematosus (SLE). Methods Patients with active disease were randomised to placebo or PF-04236921 10 mg, 50 mg or 200 mg, subcutaneously, every 8 weeks with stable background therapy. SLE Responder Index (SRI-4; primary end point) and British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) were assessed at week 24. Post hoc analysis identified an enriched population based upon planned univariate analyses. Results 183 patients received treatment (placebo, n=45; 10 mg, n=45; 50 mg, n=47; 200 mg, n=46). The 200 mg dose was discontinued due to safety findings and not included in the primary efficacy analysis. The SRI-4 response rates were not significant for any dose compared with placebo; however, the BICLA response rate was significant for 10 mg (p=0.026). The incidence of severe flares was significantly reduced with 10 mg (n=0) and 50 mg (n=2) combined versus placebo (n=8; p<0.01). In patients with greater baseline disease activity (enriched population), the SRI-4 (p=0.004) and BICLA (p=0.012) response rates were significantly different with 10 mg versus placebo. Four deaths (200 mg, n=3; 10 mg, n=1) occurred. The most frequently reported adverse events included headache, nausea and diarrhoea. Conclusions PF-04236921 was not significantly different from placebo for the primary efficacy end point in patients with SLE. Evidence of an effect with 10 mg was seen in a post hoc analysis. Safety was acceptable for doses up to 50 mg as the 200 mg dose was discontinued due to safety findings. Trial registration number NCT01405196; Pre-results.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Domagrozumab (PF-06252616), an Antimyostatin Monoclonal Antibody, in Healthy Subjects

Safety, tolerability, anabolic effects, pharmacokinetics, and pharmacodynamics of single ascending and multiple doses of domagrozumab, an antimyostatin monoclonal antibody, were assessed following intravenous (IV) and subcutaneous (SC) administration in healthy subjects. A range of single ascending dose levels between 1 and 40 mg/kg IV and multiple doses (3 doses) of 10 mg/kg IV were tested (n = 8 per cohort). Additionally, a 3 mg/kg SC (n = 8) cohort also received domagrozumab. Magnetic resonance imaging and whole‐body dual‐energy x‐ray absorptiometry imaging were conducted to investigate the anabolic effects of domagrozumab. Domagrozumab was well tolerated with no severe and 1 non–treatment‐related serious adverse event. The most commonly reported adverse events were headache (21 subjects) and fatigue, upper respiratory tract infections, and muscle spasms (10 subjects each). Domagrozumab demonstrated typical IgG1 pharmacokinetics, with slow SC absorption and slow clearance, low volume of distribution, and a long half‐life. Target engagement was observed with an increase in extent of myostatin modulation, plateauing at the 20 mg/kg IV dose. Downstream pharmacology following myostatin binding by domagrozumab was only observed in the 10 mg/kg single IV cohort (increase in whole‐body lean mass of 5.38% using dual‐energy x‐ray absorptiometry) and the 10 mg/kg repeat‐dose cohort (muscle volume increase of 4.49% using magnetic resonance imaging).

A Practical Guide to Data Monitoring Committees in Adaptive Trials

Adaptive clinical trials require access to interim data to carry out trial modification as allowed by a prespecified adaptation plan. A data monitoring committee (DMC) is a group of experts that is charged with monitoring accruing trial data to ensure the safety of trial participants and that in adaptive trials may also play a role in implementing a preplanned adaptation. In this paper, we summarize current practices and viewpoints and provide guidance on evolving issues related to the use of DMCs in adaptive trials. We describe the common types of adaptive designs and point out some DMC-related issues that are unique to this class of designs. We include 3 examples of DMCs in late-stage adaptive trials that have been implemented in practice. We advocate training opportunities for researchers who may be interested in serving on a DMC for an adaptive trial since qualified DMC members are fundamental to the successful execution of DMC responsibilities.

OP0185 Significant Clinical Improvement and Reduction of Severe Flares Following Administration of an IL-6 Monoclonal Antibody in Systemic Lupus Erythematosus (SLE) Subjects with High Disease Activity

Background PF-04236921 is a fully human monoclonal antibody (mAb) that binds to circulating IL-6 and neutralizes its activity. This may be beneficial in reducing the disease manifestations of active SLE. Objectives To assess the efficacy, safety, and tolerability of PF-04236921 in subjects with active SLE. Methods 183 subjects with active SLE (SLEDAI ≥6 and ≥1 BILAG 2004 A or ≥2 Bs) received 3 doses of PF-04236921 (10, 50, or 200mg) or placebo given subcutaneously every 8 wks. The primary endpoint was the proportion of SLE Responder Index 4 (SRI-4) responders at Wk 24 using a generalized linear mixed model. The BILAG-based Combined Lupus Assessment (BICLA), frequency of severe flares, and SF-36 were also evaluated. Results The majority of subjects were female (91.8%), mean age 40.4, with musculoskeletal and mucocutaneous organ system involvement. Baseline demographics were similar across groups. At Wk 24, there were more responders in the 10mg group vs placebo for the SRI (p=0.076) and BICLA (p=0.026). Improvement in the SF-36 PCS domain was also noted for the 10mg group vs placebo (p=0.092). For the 50mg group there were no significant differences vs placebo for the SRI (p=0.528) or BICLA (p=0.1). A post-hoc subgroup analysis was completed in subjects with high baseline disease activity [SLEDAI ≥10, detectable anti-dsDNA, low complement, or prednisone >7.5 mg/day (enriched population)]. In this subgroup, a significant effect size was observed for the SRI, BICLA, and SF-36 PCS domain for the 10mg group vs placebo. There was also a significant reduction in the frequency of severe SELENA-SLEDAI Flare Index (SFI) flares for the combined 10 and 50mg groups vs placebo for both the broad (p=0.004) and enriched populations (p=0.004). Adverse events (AEs), infectious AEs, and discontinuations due to AEs were comparable across groups. The rate of SAEs was highest in the placebo and 200mg groups and the rate of serious infections was highest in the 200mg group. There were 4 deaths; 3 in 200mg [cardiorespiratory arrest, urosepsis with pulmonary embolism (PE), and disseminated tuberculosis] and 1 in 10mg (suspected PE); further dosing of 200mg was subsequently terminated. Conclusions An efficacy signal was apparent in the broad population following administration of an IL-6 mAb notably with regard to severe flare reduction. Greater efficacy was observed across several key parameters for the 10mg group in the enriched population compared to the broad population. The safety profile with 10 and 50mg doses appeared acceptable for both the broad and enriched population; dosing with 200mg was terminated due to safety concerns. Disclosure of Interest J. Smolen Grant/research support from: Abbvie, Janssen, MSD, Pfizer Inc, Roche, UCB, Consultant for: Abbvie, Amgen, Astra-Zeneca, Astro, Celgene, GSK, Janssen, Eli-Lilly, Medimmune, MSD, Novartis-Sandoz, Novo-Nordisk, Pfizer Inc, Roche, Samsung, Sanofi-Aventis, UCB, S. Popa: None declared, I. Szombati: None declared, D. Wallace: None declared, M. Petri Consultant for: Pfizer Inc., P. Lipsky Consultant for: Pfizer Inc., J. Merrill Consultant for: Pfizer Inc., V. Strand Consultant for: Abbvie, Amgen, Anthera, Astra-Zeneca, Biogen Idec, Bristol-Myers Squibb, Genentech, GSK, Janssen, Merck Serono, Novartis, Pfizer Inc, Sanofi-Aventis, Takeda, UCB, P. Healey Employee of: Pfizer Inc., C. Li Employee of: Pfizer Inc., J. Christensen Employee of: Pfizer Inc., A. Diehl Employee of: Pfizer Inc., J. Beebe Employee of: Pfizer Inc., M. Vincent Employee of: Pfizer Inc., J. Wajdula Employee of: Pfizer Inc., S. Sridharan Employee of: Pfizer Inc.