Mark T. Brown

Core outcome domains and measures for pediatric acute and chronic/recurrent pain clinical trials: PedIMMPACT recommendations

UNLABELLED Under the auspices of the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT), 26 professionals from academia, governmental agencies, and the pharmaceutical industry participated in a 2-stage Delphi poll and a consensus meeting that identified core outcome domains and measures that should be considered in clinical trials of treatments for acute and chronic pain in children and adolescents. Consensus was refined by consultation with the international pediatric pain community through announcement of our recommendations on the Pediatric Pain List and inviting and incorporating comments from external sources. There was consensus that investigators conducting pediatric acute pain clinical trials should consider assessing outcomes in pain intensity; global judgment of satisfaction with treatment; symptoms and adverse events; physical recovery; emotional response; and economic factors. There was also agreement that investigators conducting pediatric clinical trials in chronic and recurrent pain should consider assessing outcomes in pain intensity; physical functioning; emotional functioning; role functioning; symptoms and adverse events; global judgment of satisfaction with treatment; sleep; and economic factors. Specific measures or measurement strategies were recommended for different age groups for each domain. PERSPECTIVE Based on systematic review and consensus of experts, core domains and measures for clinical trials to treat pain in children and adolescents were defined. This will assist in comparison and pooling of data and promote evidence-based treatment, encourage complete reporting of outcomes, simplify the review of proposals and manuscripts, and facilitate clinicians making informed decisions regarding treatment.

Efficacy and safety of tanezumab in the treatment of chronic low back pain.

Summary Intravenous tanezumab produces clinically and statistically superior analgesic efficacy compared to placebo and naproxen, with few adverse events in patients with chronic low back pain. Abstract Increased nerve growth factor levels are associated with chronic pain conditions, including chronic low back pain (LBP). This study examined safety and analgesic efficacy of tanezumab, a humanized anti‐nerve growth factor antibody, in adults with chronic LBP. Patients received intravenous tanezumab 200 &mgr;g/kg plus oral placebo (n = 88), intravenous placebo plus oral naproxen 500 mg twice a day (n = 88), or intravenous placebo plus oral placebo (n = 41). Primary outcome was average LBP intensity (aLBPI) at Week 6. Secondary outcomes were proportion of patients with ≥30% or ≥50% reduction in aLBPI, Roland–Morris Disability Questionnaire and Brief Pain Inventory–short form scores, Patients’ Global Assessment of LBP, Patients’ Global Evaluation of study medication, and rescue medication use. Mean aLBPI change from baseline to Week 6 was greater with tanezumab vs naproxen (P = 0.004) and placebo (P < 0.001). Greater proportions of patients reported ≥30% and ≥50% reduction in aLBPI with tanezumab vs naproxen (P ≤ 0.013) and placebo (P < 0.001), and greater improvements in Roland–Morris Disability Questionnaire (P < 0.001) and other secondary outcomes except rescue medication use. Tanezumab was associated with adverse events (AEs) of abnormal peripheral sensation that were generally mild and resolved before study completion; however, there were no serious AEs. Nine patients (4 of whom were tanezumab‐treated) discontinued due to AEs. In conclusion, tanezumab resulted in analgesic efficacy that was clinically and statistically superior to placebo and naproxen in patients with chronic LBP. Tanezumab clinical development is on regulatory hold due to AEs in osteoarthritis patients.

Tanezumab Reduces Osteoarthritic Knee Pain: Results of a Randomized, Double-Blind, Placebo-Controlled Phase III Trial

UNLABELLED The objective of this study was to compare the analgesic efficacy of tanezumab versus placebo in patients with osteoarthritis (OA) of the knee. This was a 32-week, randomized, double-blind, placebo-controlled phase III trial (NCT00733902). The patient criteria included diagnosis of OA; Western Ontario and McMaster Universities OA Index (WOMAC) Pain and Physical Function subscale scores of ≥5 and ≥4, respectively; Patients Global Assessment of Osteoarthritis (PGA) ≥3; and failure of nonopiate pain medications or candidacy for invasive interventions. Patients received 3 intravenous doses of tanezumab (2.5, 5, or 10 mg) or placebo. The co-primary efficacy end points were changes in WOMAC subscales and PGA at week 16. Adverse events were monitored throughout. Overall, 690 patients (61% female) were randomized and treated. Those treated with tanezumab showed significant improvement in the 3 co-primary end points (P ≤ .015 for all). The incidence of adverse events was 55 to 60% for tanezumab-treated patients versus 48% for placebo-treated patients. Joint replacement was reported in 4 patients, 1 in each treatment group; a total of 5 joints were replaced (1 index knee and 4 hips). The tanezumab OA clinical program is currently on clinical hold due to potential adverse reactions leading to joint replacement. PERSPECTIVE This is the first phase III randomized, controlled trial to demonstrate that nerve growth factor blockade by tanezumab has superior analgesic efficacy in OA of the knee compared with placebo. Tanezumab was well tolerated, and reports of worsening OA and/or joint replacement were evenly distributed across the treatment groups.

Long-term open-label study of tanezumab for moderate to severe osteoarthritic knee pain

OBJECTIVE This study was designed to evaluate the long-term safety and effectiveness of repeated doses of the humanized anti-nerve growth factor antibody, tanezumab, during open-label treatment of patients with OA knee pain. DESIGN The current study (clinicaltrials.gov identifier: NCT00399490) was a multicenter, phase II, open-label, multiple-dose extension of an earlier randomized clinical trial. All patients (N=281) received infusions of tanezumab 50μg/kg on Days 1 and 56 with subsequent doses administered at 8-week intervals (up to a total of eight infusions). The primary endpoint of this study was safety. Effectiveness evaluations included overall knee pain, Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index subscales, and subject global assessment (SGA) of response to therapy on 0-100 point visual analog scales. RESULTS Repeated administration of tanezumab resulted in a low incidence of treatment-related adverse events (AEs; 7.5%). The rate of serious AEs was also low (2.8%) with none considered treatment-related. Few AEs of abnormal peripheral sensation were reported; hypoesthesia was reported by nine patients (3.2%), paresthesia by seven patients (2.5%), and hyperesthesia, peripheral neuropathy, and sensory disturbance were each reported by one patient (0.4% for each). Most AEs of abnormal peripheral sensation were rated as mild (95%) and the majority (65%) resolved before study completion. At Week 8, overall knee pain and SGA improved from baseline by a mean (± standard error) of -12.8 (±1.78) and 8.0 (±1.66), respectively. Similar improvements occurred for WOMAC subscales. CONCLUSIONS Repeated injections of tanezumab in patients with moderate to severe knee OA provide continued pain relief and improved function with a low incidence of side effects. Additional studies to define the efficacy and duration of pain reduction and to provide a more complete assessment of long-term safety are warranted.

A phase III placebo- and oxycodone-controlled study of tanezumab in adults with osteoarthritis pain of the hip or knee

Summary Tanezumab is efficacious in a phase III clinical trial of patients with moderate to severe osteoarthritis pain of the hip or knee. ABSTRACT Tanezumab is a humanized monoclonal antinerve growth factor antibody in development for treatment of chronic pain. In a phase III, placebo‐ and active‐controlled study, we investigated the efficacy and safety of tanezumab for osteoarthritis (OA) hip or knee pain. Patients (N = 610) received up to 2 doses of intravenous tanezumab (5 or 10 mg in 8‐week intervals), controlled‐release oral oxycodone (10 to 40 mg every 12 hours), or placebo. The primary endpoint was mean change from baseline to week 8 in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain score for tanezumab versus placebo and oxycodone. Secondary endpoints included change from baseline in WOMAC Physical Function and Stiffness scores, Patients Global Assessment (PGA) of OA, and patient response, defined as ≥30%, ≥50%, ≥70%, and ≥90% improvement from baseline in WOMAC Pain score. Tolerability and safety also were assessed. Both tanezumab groups demonstrated significant improvements in WOMAC Pain score versus placebo (P < .001) and oxycodone (P ≤ .018). Tanezumab also provided significant improvements versus placebo and oxycodone for WOMAC Physical Function and Stiffness scores and PGA of OA (P ≤ .002 for all) at week 8. For all analyses, oxycodone did not differ from placebo. Adverse event frequency was higher with oxycodone (63.3%) than tanezumab (40.7% to 44.7%) or placebo (35.5%); serious adverse event frequency was similar among treatments. The adverse event profile for tanezumab was similar to previous tanezumab studies. Results indicate that tanezumab is efficacious in the treatment of OA pain; no new safety signals were identified.

Lack of sexual dysfunction with the selective noradrenaline reuptake inhibitor reboxetine during treatment for major depressive disorder.

&NA; Sexual side‐effects due to antidepressant treatment are an important consideration when selecting a treatment regimen and can influence patient compliance. Sexual function during treatment with the selective noradrenaline reuptake inhibitor reboxetine, the selective serotonin reuptake inhibitor (SSRI) fluoxetine and placebo has been assessed in a multicentre, randomized, 8‐week, double‐blind study of 450 patients diagnosed with major depressive disorder. Sexual function was measured by the Rush Sexual Inventory completed by male and female patients and administered at baseline, week 4 and week 8. The results indicate that reboxetine was similar to placebo and superior to fluoxetine in its effect on overall sexual function. There was a greater degree of sexual satisfaction in the reboxetine group compared to fluoxetine (P = 0.02). The percentage of female patients able to achieve orgasm increased during the study period for women who received reboxetine and placebo, but decreased for those who received fluoxetine. These results suggest that reboxetine may be of particular benefit for patients at risk for sexual dysfunction with SSRIs.

Efficacy and safety of tanezumab versus naproxen in the treatment of chronic low back pain

&NA; Tanezumab provides significantly greater improvement in pain, function, and global scores versus placebo and naproxen in patients with chronic low back pain. &NA; Tanezumab is a humanized monoclonal antibody that specifically inhibits nerve growth factor as a treatment for chronic pain. This phase IIB study investigated the efficacy and safety of tanezumab for chronic low back pain vs placebo and naproxen. Patients (N = 1347) received intravenous tanezumab (5, 10, or 20 mg every 8 weeks), naproxen (500 mg twice daily), or placebo. The primary efficacy end point was mean change in daily average low back pain intensity (LBPI) from baseline to week 16. Secondary end points included mean change from baseline to week 16 in the Roland Morris Disability Questionnaire and Patient’s Global Assessment (PGA) of low back pain. Tanezumab 10 and 20 mg had similar efficacy profiles and significantly improved LBPI, Roland Morris Disability Questionnaire, and PGA scores vs both placebo and naproxen (P ≤ .05). Tanezumab 5 mg provided improvement of PGA scores vs placebo (P ≤ .05), and naproxen resulted in significant improvement of LBPI vs placebo (P ≤ .05). Adverse event incidence was comparable across tanezumab doses but higher than with placebo or naproxen. Arthralgia, pain in extremity, headache, and paresthesia were the most commonly reported adverse events by tanezumab‐treated patients. The most frequently reported adverse events resulting in discontinuation of tanezumab treatment were arthralgia and paresthesia; the highest frequency was observed with tanezumab 20 mg (both 1.4%). Serious adverse event incidence was similar across treatments. In conclusion, tanezumab provided significantly greater improvement in pain, function, and global scores vs placebo and naproxen in patients with chronic low back pain.

Efficacy and safety of tanezumab monotherapy or combined with non-steroidal anti-inflammatory drugs in the treatment of knee or hip osteoarthritis pain

OBJECTIVE To evaluate whether subjects with knee or hip osteoarthritis (OA) pain on non-steroidal anti-inflammatory drugs (NSAIDs) received greater benefit when tanezumab monotherapy replaced or was coadministered with NSAIDs. METHODS Subjects (N=2700) received intravenous tanezumab (5 or 10 mg) or placebo every 8 weeks with or without oral naproxen 500 mg twice daily or celecoxib 100 mg twice daily. Efficacy was assessed as change from baseline to week 16 in three co-primary endpoints: Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Physical Function and Patients Global Assessment (PGA) of OA. Safety assessments included adverse events, physical and neurological examinations, laboratory tests and vital signs. RESULTS Although all tanezumab treatments provided significant improvements in WOMAC Pain and Physical Function over either NSAID alone, only tanezumab+NSAIDs were significant versus NSAIDs with PGA and met the prespecified definition of superiority. Combination treatment did not substantially improve pain or function over tanezumab monotherapy. Adverse event frequency was higher with tanezumab than with NSAIDs and highest with combination therapy. Higher incidence of all-cause total joint replacements occurred with tanezumab+NSAID versus tanezumab monotherapy or NSAIDs. Rapidly progressive OA incidence was significantly greater versus NSAID in all tanezumab groups except tanezumab 5 mg monotherapy. CONCLUSIONS Subjects receiving partial symptomatic relief of OA pain with NSAIDs may receive greater benefit with tanezumab monotherapy. While only coadministration of tanezumab with NSAIDs met the definition of superiority, combination treatment did not provide important benefits over tanezumab monotherapy; small differences in efficacy were negated by treatment-limiting or irreversible safety outcomes. TRIAL REGISTRATION NUMBER NCT00809354.

Efficacy and safety of tanezumab added on to diclofenac sustained release in patients with knee or hip osteoarthritis: a double-blind, placebo-controlled, parallel-group, multicentre phase III randomised clinical trial

Objectives Tanezumab, a monoclonal antibody, inhibits nerve growth factor and reduces chronic pain. This randomised, double-blind, controlled multicentre study was conducted to evaluate the efficacy and safety of tanezumab added to oral diclofenac sustained release (DSR) in patients with hip or knee osteoarthritis (OA) pain. Methods Patients (N=604) with moderate to severe knee or hip OA tolerating stable DSR were randomised and treated with DSR 75 mg twice daily combined with intravenous tanezumab 10, 5 or 2.5 mg or placebo at weeks 0, 8 and 16. Co-primary efficacy endpoints (Western Ontario and McMaster Universities OA Index (WOMAC) Pain and Physical Function subscales and patients global assessment of OA) were assessed at week 16. Results All co-primary endpoints were significantly improved for all tanezumab+DSR groups versus placebo+DSR (p≤0.039). The incidence of adverse events of abnormal peripheral sensation was lower than in previous tanezumab trials. No new safety signals emerged. Overall incidence of adverse events was higher with tanezumab+DSR (45.2%–49.7%) than with placebo+DSR (34.9%); serious adverse event rates were similar across treatments (5.3%–7.6%). Osteonecrosis was reported in six of 452 patients with tanezumab+DSR (1.3%), but an external adjudication committee did not confirm osteonecrosis in any patient. Conclusions Addition of tanezumab to DSR resulted in significant improvements in pain, function and global assessments in patients with OA. Although no new safety signals were observed, the higher incidence of adverse events in the tanezumab+diclofenac group suggests that combination therapy is unfavourable. Further investigations of tanezumab monotherapy for OA pain treatment are required. Clinical trial registration number NCT00864097

Efficacy and Safety of Intravenous Tanezumab for the Symptomatic Treatment of Osteoarthritis: 2 Randomized Controlled Trials versus Naproxen

Objective. Two studies evaluated efficacy and safety of tanezumab versus naproxen for treatment of knee or hip osteoarthritis (OA). Methods. Randomized controlled studies [NCT00830063 (Study 1015, n = 828) and NCT00863304 (Study 1018, n = 840)] of subjects with hip or knee OA compared intravenous tanezumab (5 mg or 10 mg) to placebo and naproxen (500 mg twice daily). Coprimary outcomes were Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Physical Function (0–10 numerical rating scale), and patient’s global assessment of OA at Week 16. Results. In both studies, tanezumab reduced pain versus placebo [least squares mean differences, 95% CI, tanezumab 5 mg: −1.21 (−1.72, −0.70); −1.13 (−1.65, −0.62); tanezumab 10 mg: −0.91 (−1.42, −0.40); −0.80 (−1.32, −0.29)], and improved function and global scores. Tanezumab 5 mg produced greater pain reduction [−0.76 (−1.28, −0.25); −0.69 (−1.21, −0.17)], and favorable functional and global outcomes versus naproxen. Pain reductions with tanezumab 10 mg versus naproxen did not reach significance, unlike functional (both studies) and global (1 study) outcomes; thus, tanezumab 10 mg was not superior to naproxen, and predefined statistical testing procedures were not met, allowing for conclusion of superiority of tanezumab 5 mg over naproxen despite replicated favorable coprimary outcomes. Tanezumab was associated with greater incidence of peripheral sensory adverse events (paresthesia, hyperesthesia, hypoesthesia, burning sensation), pain in extremity, peripheral edema, and arthralgia. Overall frequency and discontinuations as a result of adverse events were similar to placebo and naproxen. Conclusion. Tanezumab provides efficacious treatment of knee or hip OA and may have therapeutic utility in patients with OA who experience inadequate analgesia with nonsteroidal antiinflammatory drugs.