A 3-year follow-up study of outcomes associated with patterns of traditional acute and preventive migraine treatment: An administrative claims-based cohort study in the United States.

OBJECTIVE: To describe treatment patterns and direct healthcare costs over 3 years following initiation of standard of care acute and preventive migraine medications in patients with migraine in the United States. BACKGROUND: There are limited data on long-term (>1 year) migraine treatments patterns and associated outcomes. METHODS: This was a retrospective, observational cohort study using US claims data from the IBM® MarketScan® Research Database (January 2010-December 2017). Adults were included if they had a prescription claim for acute migraine treatments (AMT) or preventive migraine treatments (PMT) in the index period (January 2011-December 2014). The AMT cohort was categorized as persistent, cycled, or added-on subgroups; the PMT cohort was categorized PMT-persistent, switched without gaps, or cycled with gaps. Migraine-specific annual direct costs (2017 US$) across AMT and PMT cohort subgroups were summarized at baseline through 3 years from index (follow-up). RESULTS: During the index period, 20,778 and 42,259 patients initiated an AMT and a PMT, respectively. At the 3-year follow-up, migraine-specific direct costs were lower in the persistent subgroup relative to the non-persistent subgroups in both AMT (mean [SD]: $789 [$1741] vs. $2847 [$8149] in the added-on subgroup and $862 [$5426] for the cycled subgroup) and PMT cohorts (mean [SD]: $1817 [$5892] in the persistent subgroup vs. $4257 [$11,392] in the switched without gaps subgroup and $3269 [$18,540] in the cycled with gaps subgroup). Acute medication overuse was lower in the persistent subgroup (1025/6504 [27.2%]) vs. non-persistent subgroups (11,236/58,863 [32.2%] in cycled with gaps subgroup and 1431/6504 [39.4%] in the switched without gaps subgroup). Most patients used multiple acute (19,717/20,778 [94.9%]) or preventive (38,494/42,259 [91.1%]) pharmacological therapies over 3 years following treatment initiation. Gaps in preventive therapy were common; an average gap ranged from 85 to 211 days (~3-7 months). CONCLUSION: Migraine-specific annual healthcare costs and acute migraine medication overuse remained lowest among patients with persistent AMT and PMT versus non-persistent treatment. Study findings are limited to the US population. Future studies should compare costs and associated outcomes between newer preventive migraine medications in patients with migraine.

Effect size varies based on calculation method and may affect interpretation of treatment effect: an illustration using randomised clinical trials in osteoarthritis.

BACKGROUND: To illustrate how (standardised) effect sizes (ES) vary based on calculation method and to provide considerations for improved reporting. METHODS: Data from three trials of tanezumab in subjects with osteoarthritis were analyzed. ES of tanezumab versus comparator for WOMAC Pain (outcome) was defined as least squares difference between means (mixed model for repeated measures analysis) divided by a pooled standard deviation (SD) of outcome scores. Three approaches to computing the SD were evaluated: Baseline (the pooled SD of WOMAC Pain values at baseline [pooled across treatments]); Endpoint (the pooled SD of these values at the time primary endpoints were assessed); and Median (the median pooled SD of these values based on the pooled SDs across available timepoints). Bootstrap analyses were used to compute 95% confidence intervals (CI). RESULTS: ES (95% CI) of tanezumab 2.5 mg based on Baseline, Endpoint, and Median SDs in one study were - 0.416 (- 0.796, - 0.060), - 0.195 (- 0.371, - 0.028), and - 0.196 (- 0.373, - 0.028), respectively; negative values indicate pain improvement. This pattern of ES differences (largest with Baseline SD, smallest with Endpoint SD, Median SD similar to Endpoint SD) was consistent across all studies and doses of tanezumab. CONCLUSION: Differences in ES affect interpretation of treatment effect. Therefore, we advocate clearly reporting individual elements of ES in addition to its overall calculation. This is particularly important when ES estimates are used to determine sample sizes for clinical trials, as larger ES will lead to smaller sample sizes and potentially underpowered studies. TRIAL REGISTRATION: Clinicaltrials.gov NCT02697773, NCT02709486, and NCT02528188.

Treatment patterns of galcanezumab versus standard of care preventive migraine medications over 24 months: a US retrospective claims study.

OBJECTIVE: To describe long-term (24-month) treatment patterns of patients initiating galcanezumab versus standard of care (SOC) preventive migraine treatments including anticonvulsants, beta-blockers, antidepressants, and onabotulinumtoxinA using administrative claims data. METHODS: This retrospective cohort study, which used Optum de-identified Market Clarity data, included adults with migraine with ≥1 claim for galcanezumab or SOC preventive migraine therapy (September 1, 2018 - March 31, 2020) and continuous database enrollment for 12 months before (baseline) and 24 months after (follow-up) the index date (date of first claim). Baseline patient demographics, clinical characteristics, and treatment patterns were analyzed after 24-month follow-up, including adherence (measured as the proportion of days covered [PDC]), persistence, discontinuation (≥60-day gap), restart, and treatment switch. Propensity score matching (1:1) was used to balance the galcanezumab and SOC cohorts. RESULTS: The study included 2307 matched patient pairs with 24-month follow-up. The mean age across cohorts was 44.5 years (females: ∼87%). Patients in the galcanezumab versus SOC cohort demonstrated greater treatment adherence (PDC: 48% vs. 38%), with more patients considered adherent (PDC ≥80%: 26.6% vs. 20.7%) and persistent (322.1 vs. 236.4 d) (all p < .001). After 24-month follow-up, fewer galcanezumab-treated patients had discontinued compared with SOC-treated patients (80.1% vs. 84.7%; p < .001), of which 41.3% and 39.6% switched to a non-index medication, respectively. The most prevalent medication patients switched to in both cohorts was erenumab. Significantly greater proportions of patients who initiated galcanezumab versus SOC medications switched to fremanezumab (p < .001) and onabotulinumtoxinA (p = .016). CONCLUSION: Patients who initiated galcanezumab for migraine prevention had higher treatment adherence and persistence compared with those who initiated SOC medications after 24-month follow-up.

Only few patients (3 − 13%) with migraine, who qualify for preventive treatment, are using them. Conventional preventive treatments have not been developed specifically for migraine treatment, and more than half of the patients stop using them prematurely. Calcitonin gene-related peptide monoclonal antibodies such as galcanezumab, fremanezumab, and erenumab are newer treatments that provide migraine-specific preventive treatment. Prior studies have compared 6- to 12-month migraine medication use by patients starting galcanezumab versus those starting traditional standard of care (SOC) migraine preventive medications. We compared long-term (24-month) migraine medication use in patients starting galcanezumab versus those starting SOC migraine preventive medications to confirm if the results are sustained over a longer period. Over 24 months, patients who used galcanezumab followed the prescribed treatment regimen to a greater extent compared with those who used SOC medications (48% vs. 38%, respectively). Additionally, patients using galcanezumab continued treatment for a longer time compared with those using SOC. Over 24 months, about 85% of patients stopped taking SOC medications, while around 80% of patients stopped taking galcanezumab. Our findings indicate that patients with migraine are more likely to continue using galcanezumab as a preventive treatment for a longer period compared with SOC medications. This study helps identify gaps in the preventive treatment of migraine and provides insights on how they are not being used enough.

Effect size varies based on calculation method and may affect interpretation of treatment effect: an illustration using randomised clinical trials in osteoarthritis

Abstract Background To illustrate how (standardised) effect sizes (ES) vary based on calculation method and to provide considerations for improved reporting. Methods Data from three trials of tanezumab in subjects with osteoarthritis were analyzed. ES of tanezumab versus comparator for WOMAC Pain (outcome) was defined as least squares difference between means (mixed model for repeated measures analysis) divided by a pooled standard deviation (SD) of outcome scores. Three approaches to computing the SD were evaluated: Baseline (the pooled SD of WOMAC Pain values at baseline [pooled across treatments]); Endpoint (the pooled SD of these values at the time primary endpoints were assessed); and Median (the median pooled SD of these values based on the pooled SDs across available timepoints). Bootstrap analyses were used to compute 95% confidence intervals (CI). Results ES (95% CI) of tanezumab 2.5 mg based on Baseline, Endpoint, and Median SDs in one study were - 0.416 (- 0.796, - 0.060), - 0.195 (- 0.371, - 0.028), and - 0.196 (- 0.373, - 0.028), respectively; negative values indicate pain improvement. This pattern of ES differences (largest with Baseline SD, smallest with Endpoint SD, Median SD similar to Endpoint SD) was consistent across all studies and doses of tanezumab. Conclusion Differences in ES affect interpretation of treatment effect. Therefore, we advocate clearly reporting individual elements of ES in addition to its overall calculation. This is particularly important when ES estimates are used to determine sample sizes for clinical trials, as larger ES will lead to smaller sample sizes and potentially underpowered studies. Trial Registration Clinicaltrials.gov NCT02697773, NCT02709486, and NCT02528188.

Characterization of adverse joint outcomes in patients with osteoarthritis treated with subcutaneous tanezumab.

OBJECTIVE: Due to the risk of rapidly progressive osteoarthritis (RPOA), the phase III studies of subcutaneous (SC) tanezumab in patients with moderate to severe hip or knee osteoarthritis (OA) included comprehensive joint safety surveillance. This pooled analysis summarizes these findings. METHOD: Joint safety events in the phase III studies of SC tanezumab (2 placebo- and 1- nonsteroidal anti-inflammatory drug [NSAID]-controlled) were adjudicated by a blinded external committee. Outcomes of RPOA1 and RPOA2, primary osteonecrosis, subchondral insufficiency fracture, and pathological fracture comprised the composite joint safety endpoint (CJSE). Potential patient- and joint-level risk factors for CJSE, RPOA, and total joint replacement (TJR) were explored. RESULTS: Overall, 145/4541 patients (3.2%) had an adjudicated CJSE (0% placebo; 3.2% tanezumab 2.5 mg; 6.2% tanezumab 5 mg; 1.5% NSAID). There was a dose-dependent risk of adjudicated CJSE, RPOA1, and TJR with tanezumab vs NSAID. Patient-level cross-tabulation found associations between adjudicated RPOA with more severe radiographic/symptomatic (joint pain, swelling, and physical limitation) OA. Risk of adjudicated RPOA1 was highest in patients with Kellgren-Lawrence (KL) grade 2 or 3 OA at baseline. Risk of adjudicated RPOA2 or TJR was highest in patients with KL grade 4 joints at baseline. A higher proportion of joints with adjudicated RPOA2 had a TJR (14/26) than those with adjudicated RPOA1 (16/106). CONCLUSION: In placebo- and NSAID controlled studies of SC tanezumab for OA, adjudicated CJSE, RPOA, and TJR most commonly occurred in patients treated with tanezumab and with more severe radiographic or symptomatic OA. NCT02697773; NCT02709486; NCT02528188.

Peripheral Nerve Safety of Nerve Growth Factor Inhibition by Tanezumab: Pooled Analyses of Phase III Clinical Studies in Over 5000 Patients with Osteoarthritis.

BACKGROUND: Tanezumab, a humanized anti-nerve growth factor antibody, was developed for the treatment of pain associated with osteoarthritis. Due to its mechanism of action, peripheral nerve safety was assessed in all clinical studies. OBJECTIVES: To summarize the neurological safety of intravenous (IV) and subcutaneous (SC) tanezumab versus placebo in patients with osteoarthritis. METHODS: Data were pooled from 3389 patients across seven studies that investigated IV administration, and from 1840 patients across three studies that investigated SC administration. The treatment period of each study ranged from 16 to 24 weeks, and follow-up periods ranged from 8 to 24 weeks. Neurological safety evaluations focused on adverse events (AEs) of abnormal peripheral sensation (APS), neurologic examinations, and consultations. RESULTS: Across datasets, the incidence of AEs of APS was higher in tanezumab groups versus placebo. Paresthesia and hypoesthesia were the most frequently reported AEs in tanezumab-treated patients, compared with placebo. In both datasets, most AEs were of mild severity, resolved, and rarely resulted in discontinuation. In all treatment groups in both IV and SC studies, over 90% of patients had no new or worsened neurological examination abnormalities at the last study visit. Across datasets, mononeuropathy was diagnosed more frequently in tanezumab groups compared with placebo. Polyneuropathy was diagnosed in ≤ 0.9% of patients in tanezumab and placebo groups. CONCLUSIONS: Tanezumab IV or SC had an increased incidence of AEs of APS, such as paresthesia and hypoesthesia, and diagnoses of mononeuropathy compared with placebo. However, tanezumab was not associated with generalized peripheral neuropathy. GOV IDENTIFIERS: NCT00733902, NCT00744471, NCT00830063, NCT00863304, NCT00863772, NCT01089725, NCT00985621, NCT02697773, and NCT02709486.

A Randomized Placebo-Controlled Trial of the Anti-Nerve Growth Factor Antibody Tanezumab in Subjects With Cancer Pain Due to Bone Metastasis.

BACKGROUND: This phase III, randomized, double-blind, placebo-controlled, parallel-group study assessed the efficacy and safety of tanezumab in subjects with cancer pain predominantly due to bone metastasis receiving background opioid therapy. METHODS: Subjects were randomized (stratified by (1) tumor aggressiveness and (2) presence/absence of concomitant anticancer treatment) to placebo or tanezumab 20 mg. Treatment was administered by subcutaneous injection every 8 weeks for 24 weeks (3 doses) followed by a 24-week safety follow-up period. The primary outcome was change in daily average pain in the index bone metastasis cancer pain site (from 0 = no pain to 10 = worst possible pain) from baseline to week 8. RESULTS: LS mean (SE) change in pain at week 8 was -1.25 (0.35) for placebo (n = 73) and -2.03 (0.35) for tanezumab 20 mg (n = 72). LS mean (SE) [95% CI] difference from placebo was -0.78 (0.37) [-1.52, -0.04]; P = .0381 with α = 0.0478. The number of subjects with a treatment-emergent adverse event during the treatment period was 50 (68.5%) for placebo and 53 (73.6%) for tanezumab 20 mg. The number of subjects with a prespecified joint safety event was 0 for placebo and 2 (2.8%) for tanezumab 20 mg (pathologic fracture; n = 2). CONCLUSION: Tanezumab 20 mg met the primary efficacy endpoint at week 8. Conclusions on longer-term efficacy are limited since the study was not designed to evaluate the durability of the effect beyond 8 weeks. Safety findings were consistent with adverse events expected in subjects with cancer pain due to bone metastasis and the known safety profile of tanezumab. Clinicaltrials.gov identifier: NCT02609828.

Opioids for Osteoarthritis: Cross-Sectional Survey of Patient Perspectives and Satisfaction.

Patients often take opioids to relieve osteoarthritis (OA) pain despite limited benefits and potential harms. This study aimed to compare cross-sectional perspectives of patients that were taking prescription opioid (N = 471) or nonopioid medications (N = 185) for OA in terms of satisfaction, expectations of effectiveness, and concerns. Patients prescribed opioids (>7 days) reported more prior treatments (2.47 vs. 1.74), greater mean pain intensity (5.47 vs. 4.11), and worse quality of life (EQ-5D-5L index value mean 0.45 vs. 0.71) than patients prescribed nonopioid medications (all p < 0.0001). Based on linear regression models adjusting for demographics and pain intensity, patients prescribed opioids were less satisfied with overall regimen (3.40 vs. 3.67, p = 0.0322), had less belief that medications were meeting effectiveness expectations (2.72 vs. 3.13, p < 0.0001), and had more concerns about treatments being "not very good" (3.66 vs. 3.22, p = 0.0026) and addiction (3.30 vs. 2.65, p < 0.0001) than patients prescribed nonopioid regimens. When the models were replicated for subgroups with ≥30 days' medication regimen duration, the findings were consistent with the main analyses. Patients have concerns about the risk of opioid addiction, but those with greater disease burden and more prior treatments continue taking opioid regimens.

Reliability of Wearable Sensors for Assessing Gait and Chair Stand Function at Home in People With Knee Osteoarthritis.

OBJECTIVE: To assess the reliability of wearable sensors for at-home assessment of walking and chair stand activities in people with knee osteoarthritis (OA). METHODS: Baseline data from participants with knee OA (n = 20) enrolled in a clinical trial of an exercise intervention were used. Participants completed an in-person laboratory visit and a video conference-enabled at-home visit. In both visits, participants performed walking and chair stand tasks while fitted with 3 inertial sensors. During the at-home visit, participants self-donned the sensors and completed 2 sets of acquisitions separated by a 15-minute break, when they removed and redonned the sensors. Participants completed a survey on their experience with the at-home visit. During the laboratory visit, researchers placed the sensors on the participants. Spatiotemporal metrics of walking gait and chair stand duration were extracted from the sensor data. We used intraclass correlation coefficients (ICCs) and the Bland-Altman plot for statistical analyses. RESULTS: For test-retest reliability during the at-home visit, all ICCs were good to excellent (0.85-0.95). For agreement between at-home and laboratory visits, ICCs were moderate to good (0.59-0.87). Systematic differences were noted between at-home and laboratory data due to faster task speed during the laboratory visits. Participants reported a favorable experience during the at-home visit. CONCLUSION: Our method of estimating spatiotemporal gait measures and chair stand duration function remotely was reliable, feasible, and acceptable in people with knee OA. Wearable sensors could be used to remotely assess walking and chair stand in participant's natural environments in future studies.

Opioid Prescribing for Osteoarthritis: Cross-Sectional Survey among Primary Care Physicians, Rheumatologists, and Orthopaedic Surgeons.

Opioids are often prescribed for osteoarthritis (OA) pain, despite recommendations to limit use due to minimal benefits and associated harms. This study aimed to assess physicians' practice patterns and perceptions regarding opioids by specialty one year following the Centers for Disease Control and Prevention (CDC) published guidance on opioid prescribing. The 139/153 (90.8%) physicians who reported prescribing opioids in the previous year reported decreased prescribing for mild OA (51.3%, 26.5% and 33.3% of primary care physicians, rheumatologists, and orthopaedic surgeons, respectively), moderate OA (50.0%, 47.1% and 48.1%) and severe OA (43.6%, 41.2% and 44.4%). Prescribing changes were attributed to the CDC guidelines for 58.9% of primary care physicians, 59.1% of rheumatologists, and 73.3% of orthopaedic surgeons. Strong opioids were mostly reserved as third-line treatment. Although treatment effectiveness post-CDC guidelines was not assessed, perceptions of efficacy and quality of life with opioids significantly differed across specialties, whereas perceptions of safety, convenience/acceptability and costs did not. Physicians generally agreed on the barriers to opioid prescribing, with fear of addiction and drug abuse being the most important. Across specialties, physicians reported decreased opioid prescribing for OA, irrespective of OA severity, and in most cases attributed changes in prescribing to the CDC guideline.

Predicting Treatment Responses in Patients With Osteoarthritis: Results From Two Phase III Tanezumab Randomized Clinical Trials.

Prediction of treatment responses is essential to move forward translational science. Our question was to identify patient-based variables that predicted responses to treatments. We conducted secondary analyses on pooled data from two randomized phase III clinical trials (NCT02697773 and NCT02709486) conducted in participants with moderate to severe osteoarthritis randomized to subcutaneous placebo (n = 514) or tanezumab 2.5 mg (n = 514). We used gradient boosted regression trees to identify variables that predicted Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain subscale scores at Week 16 and marginal plots to determine the directional relationship between each variable category and responses to placebo or tanezumab within the models. We also used Virtual Twins models to identify potential subgroups of response to the active treatment vs. placebo. We found that responses to placebo were predicted by baseline WOMAC Physical Function, baseline WOMAC Pain, the radiographic classification of the index joint, and the standard deviation of diary pain scores at baseline. In contrast, baseline WOMAC Pain along with failure of prior medications, duration of disease, and standard deviation of diary pain scores at baseline were predictive of tanezumab responses as expressed by the WOMAC Pain scores at Week 16. Those who responded to tanezumab vs. placebo were identified based on the radiographic classification of the index joint and either age or smoking status. These secondary-data analyses identified distinct and common patient-based variables to predict response to placebo or tanezumab. These findings will inform the design of future clinical trials, helping to move forward clinical pharmacology and translational science.

The not so hidden impact of interictal burden in migraine: A narrative review.

Migraine is a highly prevalent neurological disease of varying attack frequency. Headache attacks that are accompanied by a combination of impact on daily activities, photophobia and/or nausea are most commonly migraine. The headache phase of a migraine attack has attracted more research, assessment tools and treatment goals than any other feature, characteristic, or phase of migraine. However, the migraine attack may encompass up to 4 phases: the prodrome, aura, headache phase and postdrome. There is growing recognition that the burden of migraine, including symptoms associated with the headache phase of the attack, may persist between migraine attacks, sometimes referred to as the "interictal phase." These include allodynia, hypersensitivity, photophobia, phonophobia, osmophobia, visual/vestibular disturbances and motion sickness. Subtle interictal clinical manifestations and a patient's trepidation to make plans or commitments due to the unpredictability of migraine attacks may contribute to poorer quality of life. However, there are only a few tools available to assess the interictal burden. Herein, we examine the recent advances in the recognition, description, and assessment of the interictal burden of migraine. We also highlight the value in patients feeling comfortable discussing the symptoms and overall burden of migraine when discussing migraine treatment needs with their provider.

Efficacy and safety of tanezumab, NSAIDs, and placebo in patients with moderate to severe hip or knee osteoarthritis and a history of depression, anxiety, or insomnia: post-hoc analysis of phase 3 trials.

Objective: Treatment outcomes for chronic pain can be poor in patients with depression, anxiety, or insomnia. This analysis evaluated the efficacy and safety of subcutaneous tanezumab, nonsteroidal anti-inflammatory drugs (NSAIDs), and placebo in patients with osteoarthritis (OA) and a history of these conditions using data from three phase 3 studies.Methods: A post-hoc analysis of data from two pooled placebo-controlled studies and one NSAID-controlled study of subcutaneous tanezumab. All patients had moderate to severe knee or hip OA that was inadequately controlled with standard-of-care analgesics. Efficacy outcomes were least-squares mean change from baseline to Week 16 in Western Ontario McMaster Universities OA Index (WOMAC) Pain, WOMAC Physical Function, Patient's global assessment of OA, and EQ-5D-5L scores. Results were summarized for patients with and without a history of depression, anxiety, or insomnia at baseline.Results: 1545 patients were treated in the pooled placebo-controlled studies (history of depression, 12%; anxiety, 8%; insomnia, 10%; any, 23%) and 2996 in the NSAID-controlled study (16%, 11%, 13%, 28%, respectively). In groups with positive histories, 38-80% took antidepressant or anxiolytic medications at baseline. Within treatments, largely similar improvements in efficacy outcomes were observed in patients with and without a history of depression, anxiety, or insomnia; the types of treatment-emergent adverse events were similar.Conclusions: Patients with OA and a history of depression, anxiety, or insomnia did not appear to experience reduced efficacy outcomes or an altered safety profile in response to tanezumab or NSAID treatment as compared with those without. NCT02697773; NCT02709486; NCT02528188.

Clinical Meaningfulness of Response to Tanezumab in Patients with Chronic Low Back Pain: Analysis From a 56-Week, Randomized, Placebo- and Tramadol-Controlled, Phase 3 Trial.

INTRODUCTION: A recent phase 3, randomized, placebo- and tramadol-controlled trial (56-week treatment/24-week safety follow-up) demonstrated efficacy of tanezumab 10 mg in patients with chronic low back pain (CLBP) and a history of inadequate response to standard-of-care analgesics. Here, we report on the clinical meaningfulness of treatment response in this study, focused on secondary measures of pain, interference with daily functions, overall disease status, and satisfaction with treatment. METHODS: Patients received placebo (up to week 16; n = 406), subcutaneously administered (SC) tanezumab 5 mg (every 8 weeks; n = 407), SC tanezumab 10 mg (every 8 weeks; n = 407), or orally administered tramadol prolonged-release (100-300 mg/day; n = 605) for 56 weeks. Patient's global assessment of low back pain (PGA-LBP), Brief Pain Inventory-short form (BPI-sf), Treatment Satisfaction Questionnaire for Medication (TSQM), and modified Patient-Reported Treatment Impact (mPRTI) were assessed at weeks 16 and 56. RESULTS: At week 16, significant (p < 0.05) improvements over placebo were evident with tanezumab for the PGA-LBP (10 mg) and most BPI-sf (both doses), TSQM (both doses), and mPRTI (both doses) items assessed. Improvements over baseline persisted for the PGA-LBP and BPI-sf at week 56. However, the magnitude of improvements was modestly lower at week 56 relative to week 16. Tramadol did not improve PGA-LBP or BPI-sf scores versus placebo at week 16. Most differences between tanezumab and tramadol at week 56 did not reach the level of statistical significance for all endpoints. CONCLUSIONS: The totality of the evidence as captured by measures of pain, interference with daily function, patient overall assessment of disease status, and satisfaction with treatment demonstrates the clinically meaningful benefit of tanezumab for some patients with CLBP compared with placebo. CLINICALTRIALS: gov: NCT02528253.

Characterizing 16-Week Responder Profiles Using Group-Based Trajectory Modeling in Over 4300 Clinical Trial Participants Receiving Pharmaceutical Treatment for Moderate to Severe Osteoarthritis.

INTRODUCTION: We sought to identify and characterize distinct responder profiles among osteoarthritis (OA) subjects treated with tanezumab, nonsteroidal anti-inflammatory drugs (NSAIDs), or placebo. METHODS: Subject-level data were derived from three randomized, double-blind, placebo- or NSAID-controlled trials of tanezumab in subjects with moderate-to-severe OA. Subjects received subcutaneous tanezumab (2.5 mg, n = 1527; 5 mg, n = 1279) every 8 weeks, oral NSAIDs (n = 994) daily, or placebo (n = 513). Group-based trajectory modeling (GBTM, an application of finite mixture statistical modeling that uses response trajectory to identify and summarize complex patterns in longitudinal data) was used to identify subgroups of subjects following similar patterns of response in each treatment arm, based on daily pain intensity scores from baseline through Week 16. We then examined whether subject-related variables were associated with any of the subgroups using multinomial logistic regression. RESULTS: A three-subgroup/four-inflection point trajectory model was selected based on clinical and statistical considerations. The subgroups were high responders (substantial pain improvement and a large majority of members achieved ≥ 30% improvement before Week 16), medium responders (gradual pain improvement and a majority of members achieved ≥ 30% improvement by Week 16), and non-responders (little to no pain improvement over 16 weeks). Across all treatments, fluctuation in pain intensity in the week prior to treatment was consistently associated with treatment response. Other variables were positively (age, body mass index, days of rescue medication use) or negatively (severity of disease based on Kellgren-Lawrence grading) associated with response but effects were small and/or varied across treatments. CONCLUSIONS: Across all treatments, GBTM identified three subgroups of subjects that were characterized by extent of treatment response (high, medium, and non-responders). Similar analyses (e.g., grouping of subjects based on response trajectory and identification of subgroup-related variables) in other studies of OA could inform clinical trial design and/or treatment approaches. (NCT02697773; NCT02709486; NCT02528188).

Factors associated with physician-reported treatment status of patients with osteoarthritis pain.

BACKGROUND: Osteoarthritis (OA) is typically associated with pain, but many patients are not treated. METHODS: This point in time study explored factors associated with treatment status, using logistic regression of data from the Adelphi OA Disease Specific Programme conducted in the United States. Patients' treatment status was based on physician-reported, current: 1) prescription medication for OA vs. none; and 2) physician treatment (prescription medication and/or recommendation for specified nonpharmacologic treatment for OA [physical or occupational therapy, acupuncture, transcutaneous electrical nerve stimulation, or cognitive behavior therapy/psychotherapy]) vs. self-management (no prescription medication or specified nonpharmacologic treatment). RESULTS: The 841 patients (including 57.0% knee OA, 31.9% hip OA) reported mild (45.4%) or moderate or severe (54.6%) average pain intensity over the last week. The majority were prescribed medication and/or recommended specified nonpharmacologic treatment; 218 were not prescription-medicated and 122 were self-managed. Bivariate analyses showed less severe patient-reported pain intensity and physician-rated OA severity, fewer joints affected by OA, lower proportion of joints affected by knee OA, better health status, lower body mass index, and lower ratings for cardiovascular and gastrointestinal risks, for those not prescribed medication (vs. prescription-medicated). Multivariate analyses confirmed factors significantly (p < 0.05) associated with prescription medication included (odds ratio): physician-rated current moderate OA severity (vs. mild, 2.03), patient-reported moderate OA severity 6 months ago (vs. mild, 1.71), knee OA (vs. not, 1.81), physician-recommended (0.28) and patient-reported (0.43) over-the-counter medication use (vs. not), prior surgery for OA (vs. not, 0.37); uncertain income was also significant. Factors significantly (p < 0.05) associated with physician treatment included (odds ratio): physician-recommended nonpharmacologic therapy requiring no/minimal medical supervision (vs. not, 2.21), physician-rated current moderate OA severity (vs. mild, 2.04), patient-reported over-the-counter medication use (vs. not, 0.26); uncertain time since diagnosis was also significant. Patient-reported pain intensity and most demographic factors were not significant in either model. CONCLUSIONS: Approximately 1 in 4 patients were not prescribed medication and 1 in 7 were self-managed, although many were using over-the-counter medications or nonpharmacologic therapies requiring no/minimal medical supervision. Multiple factors were significantly associated with treatment status, including OA severity and over-the-counter medication, but not pain intensity or most demographics.

WOMAC Meaningful Within-patient Change: Results From 3 Studies of Tanezumab in Patients With Moderate-to-severe Osteoarthritis of the Hip or Knee.

OBJECTIVE: To define meaningful within-patient change (MWPC) in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). METHODS: Data were analyzed separately from 3 phase III clinical trials (ClinicalTrials.gov: NCT02697773, NCT02709486, NCT02528188) of tanezumab, a novel treatment intended for the relief of signs and symptoms of moderate-to-severe osteoarthritis (OA), administered subcutaneously every 8 weeks. Patients with moderate-to-severe OA of the hip or knee completed the WOMAC and patient global assessment of OA (PGA-OA) at regular timepoints. A repeated measures longitudinal model with change in WOMAC Pain, Physical Function, or Stiffness domain score as the outcome and change in PGA-OA as the anchor was used to establish MWPC for WOMAC domains. RESULTS: In the 3 studies, there were 688, 844, and 2948 subjects available for analyses, respectively. Analysis showed that a linear relationship between changes in WOMAC domains and changes in PGA-OA was supported and justified. Moreover, the relationships between these changes were very similar for 2 trials and close for the third. The estimated MWPC for the 3 WOMAC domains were from 0.84-1.16 (0-10 numerical rating scale) and from 12.50-16.23%, depending on study and domain, that corresponded to a 1-category change on PGA-OA. For a 2-category change those values were from 1.68-2.31 and from 25.01-32.46%, respectively. CONCLUSION: These results establish MWPCs for WOMAC domains, at the individual patient level, for patients with moderate-to-severe OA of the hip or knee. [ClinicalTrials.gov: NCT02697773, NCT02709486, and NCT02528188].

Observed efficacy and clinically important improvements in participants with osteoarthritis treated with subcutaneous tanezumab: results from a 56-week randomized NSAID-controlled study.

BACKGROUND: A recent phase 3 study demonstrated that treatment with tanezumab, a nerve growth factor inhibitor, or nonsteroidal anti-inflammatory drugs (NSAIDs) improves pain and physical function in participants with moderate-to-severe osteoarthritis (OA) of the hip or knee. Here, we evaluated the time course and clinical importance of these initial efficacy findings using a mixture of primary, secondary, and post hoc endpoints. METHODS: Participants on stable NSAID therapy and with a history of inadequate response to other standard OA analgesics were enrolled in an 80-week (56-week treatment/24-week safety follow-up), randomized, NSAID-controlled, phase 3 study primarily designed to assess the safety of tanezumab for moderate-to-severe OA of the knee or hip. Participants received oral NSAID (twice daily naproxen, celecoxib, or diclofenac) or subcutaneous tanezumab (2.5mg or 5mg every 8 weeks). Non-responders were discontinued at week 16. Changes from baseline in WOMAC Pain and Physical Function, Patient's Global Assessment of Osteoarthritis (PGA-OA), and average pain in the index joint were compared between tanezumab and NSAID groups over the 56-week treatment period. Clinically meaningful response (e.g., ≥30% and ≥50% improvement in WOMAC Pain and Physical Function), rescue medication use, and safety were also assessed. RESULTS: All groups improved WOMAC Pain, WOMAC Physical Function, PGA-OA, and average pain in the index joint over the 56-week treatment period relative to baseline. Across all groups, improvements generally occurred from the time of first assessment (week 1 or 2) to week 16 and then slightly decreased from week 16 to 24 before stabilizing from weeks 24 to 56. The magnitude of improvement and the proportion of participants achieving ≥30% and ≥50% improvement in these measures was greater (unadjusted p≤0.05) with tanezumab than with NSAID at some timepoints on or before week 16. Adverse events of abnormal peripheral sensation, prespecified joint safety events, and total joint replacement surgery occurred more frequently with tanezumab than with NSAID. CONCLUSIONS: Tanezumab and NSAID both provided early and sustained (up to 56 weeks) efficacy relative to baseline. Improvements in pain and function were clinically meaningful in a substantial proportion of participants. Adverse events of abnormal peripheral sensation and joint safety events occurred more frequently with tanezumab than with NSAID. TRIAL REGISTRATION: ClinicalTrials.gov NCT02528188 . Registered on 19 July 2015.

Neurological safety of subcutaneous tanezumab versus NSAID in patients with osteoarthritis.

OBJECTIVE: To assess the long-term neurological safety of tanezumab, a monoclonal antibody against nerve growth factor. METHODS: Patients with osteoarthritis of the hip or knee received stable doses of oral nonsteroidal anti-inflammatory drugs (NSAIDs) before study entry and during a ≤ 37-day screening period. Patients were randomized 1:1:1 to double-dummy tanezumab (2.5 mg or 5 mg, subcutaneous every 8 weeks) or oral NSAIDs (twice-daily) for 56 weeks, with a 24-week follow-up. Neurological safety evaluation focused on peripheral and sympathetic adverse events (AEs), neurologic examinations, and consultations with blinded, external diagnostic reviews. RESULTS: During the treatment period, 6.2%, 9.0%, and 4.6% of patients experienced AEs of abnormal peripheral sensation (APS) in the tanezumab 2.5 mg, 5 mg, and NSAID groups, respectively. Hypoesthesia, paresthesia, and carpal tunnel syndrome were the most common AEs of APS. Clinically significant worsening on examination occurred in <1% in any treatment group at the last study assessment. Diagnoses following external neurological consultation included mononeuropathy (1.3%, 2.1%, and 1.0%), radiculopathy (0.9%, 0.4%, and 0.5%), and polyneuropathy (0.3%, 0.5%, and 0%) in tanezumab 2.5 mg, 5 mg, and NSAID groups, respectively. AEs potentially associated with sympathetic neuropathy were reported for 1.8%, 2.3%, and 2.9% of patients in the tanezumab 2.5 mg, 5 mg, and NSAID groups, respectively. No patient was diagnosed with sympathetic neuropathy. CONCLUSION: Tanezumab had an increased incidence of AEs of APS versus NSAID; these were typically mild/moderate in severity, resolved during the study, and rarely resulted in discontinuation. Tanezumab was not associated with peripheral neuropathy and did not adversely affect the sympathetic nervous system. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02528188 (https://clinicaltrials.gov/ct2/show/NCT02528188).

Impact of tanezumab on health status, non-work activities and work productivity in adults with moderate-to-severe osteoarthritis.

BACKGROUND: To evaluate the impact of tanezumab on health status, non-work activities, and work productivity in a pooled analysis of two large phase 3 osteoarthritis (OA) studies. METHODS: Subcutaneous tanezumab (2.5 mg and 5 mg) was tested in double-blind, placebo-controlled, 16-week (NCT02697773) and 24-week (NCT02709486) clinical trials in patients with moderate-to-severe OA of the hip or knee. At baseline and week 16, all patients completed EQ-5D-5L and the Work Productivity and Activity Impairment-OA (WPAI-OA) activity impairment item. Those currently employed also completed WPAI-OA work time missed, impairment while working, and overall work impairment items. Between-group differences in least squares (LS) mean changes from baseline at week 16 were tested using analysis of covariance. RESULTS: Of 1545 pooled patients, 576 were employed at baseline. Improvements in EQ-5D-5L index value at week 16 were significantly greater for the tanezumab 2.5-mg group (difference in LS means [95% confidence interval (CI), 0.03 [0.01, 0.05]; p = 0.0083) versus placebo. Percent improvements (95% CI) in activity impairment (- 5.92 [- 8.87, - 2.98]; p < 0.0001), impairment while working (- 7.34 [- 13.01, - 1.68]; p = 0.0112), and overall work impairment (- 7.44 [- 13.22, - 1.67]; p = 0.0116) at week 16 were significantly greater for the tanezumab 2.5-mg group versus placebo. Results for the tanezumab 5-mg group were generally comparable to the tanezumab 2.5-mg group, although, compared with placebo, percent improvement (95% CI) in work time missed was significantly greater for the tanezumab 5-mg group (- 3.40 [- 6.47, - 0.34]; p = 0.0294), but not the tanezumab 2.5-mg group (- 0.66 [- 3.63, 2.32]; p = 0.6637). CONCLUSIONS: These pooled analyses showed that health status, non-work activities, and work productivity were significantly improved following tanezumab administration, compared with placebo. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02697773, NCT02709486.