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PAIN 155 (2014) 1793–1801
www.elsevier.com/locate/pain
Long-term safety and effectiveness of tanezumab as treatment for chronic low back pain Joseph S. Gimbel a,⇑, Alan J. Kivitz b, Candace Bramson c, Mary Anne Nemeth c, David S. Keller c, Mark T. Brown c, Christine R. West c, Kenneth M. Verburg c a b c
Arizona Research Center, Phoenix, AZ, USA Altoona Center for Clinical Research, Duncansville, PA, USA Pfizer Inc, Groton, CT, USA
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
a r t i c l e
i n f o
Article history: Received 17 December 2013 Received in revised form 6 June 2014 Accepted 10 June 2014
Keywords: Effectiveness Low back pain Nerve growth factor Safety Tanezumab
a b s t r a c t A noncontrolled, randomized, multicenter study (NCT00924664) evaluated long-term safety and effectiveness of tanezumab in patients with chronic low back pain following a randomized placebo- and active-controlled parent study that evaluated analgesic efficacy. Patients were randomized to tanezumab 10 mg (n = 321) or 20 mg (n = 527) administered at 8-week intervals via 3 intravenous injections followed by 4 subcutaneous injections. Effectiveness analyses included change from parent study baseline in Brief Pain Inventory Short Form, Roland Morris Disability Questionnaire, and Patient’s Global Assessment of low back pain. Safety assessments included adverse event documentation, physical/neurological examinations, and laboratory tests. Mean treatment duration during the extension study was 194 and 202 days with tanezumab 10 and 20 mg, respectively. Both tanezumab doses provided similar and sustained improvements in all effectiveness outcomes. The most frequently reported adverse events were arthralgia, paresthesia, and hypoesthesia. Adverse events initially described as osteonecrosis were reported in 6 patients (tanezumab 10 mg, n = 2; tanezumab 20 mg, n = 4); 9 additional patients (tanezumab 10 mg, n = 7; tanezumab 20 mg, n = 2) underwent total joint replacement (TJR). A blinded, independent adjudication committee reviewed all 6 patients with reported osteonecrosis and 4 of the 9 patients undergoing TJR. Adjudication outcomes were osteonecrosis (n = 0), worsening osteoarthritis (n = 5; 1 rapidly progressive), and another diagnosis or indeterminate (n = 5). Tanezumab 10 mg had better tolerability than tanezumab 20 mg, and may represent an effective long-term treatment for chronic low back pain. Ó 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
1. Introduction Treatment of chronic low back pain remains a challenging clinical problem despite availability of numerous therapeutic interventions [5–7,26]. Low back pain is often a long-term condition, with up to one-third of patients reporting persistent pain of at least moderate intensity 1 year after an acute episode [7]. Therapeutic agents currently used in management of chronic low back pain include opioids and/or nonsteroidal antiinflammatory drugs (NSAIDs) despite a lack of completely effective pain relief in many patients and little-to-no evidence of long-term benefits [5,26]. In ⇑ Corresponding author. Address: Arizona Research Center, 2525 W. Greenway Road, Suite 114, Phoenix, AZ 85023, USA. Tel.: +1 602 863 6363. E-mail address: [email protected] (J.S. Gimbel).
addition, these agents are often poorly tolerated due to significant central nervous system, cardiovascular, and gastrointestinal side effects, especially with long-term use [2,3,5,7,9]. Thus, there remains an unmet need for novel pharmacological approaches and new analgesics to provide sustained relief of chronic low back pain. One approach to selecting targets for potential analgesic therapies has been identification of components of pain signaling cascades. The neurotrophin, nerve growth factor (NGF), has a key role in the developing nervous system where it mediates functional contacts of specific populations of sensory and sympathetic neurons with their targets [21]. In the adult, the primary function of NGF is that of a modulator of nociceptive neuronal activity [21]. NGF levels are elevated in several chronic pain conditions and are
http://dx.doi.org/10.1016/j.pain.2014.06.004 0304-3959/Ó 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
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associated with increased pain perception [33]. Inhibition of NGF decreases pain behavior in animal models of bone fracture [19], plantar incision [34], and arthritis [31], and reduces pain in patients with chronic pain conditions [4,12,20,22,23,30]. Tanezumab is a humanized monoclonal antibody that tightly binds NGF with high selectivity and specificity, thereby preventing NGF from interacting with the receptors, neurotrophic tyrosine kinase receptor type 1 (TrkA) and low-affinity NGF receptor (p75) [1,15]. In clinical studies of tanezumab, patients with osteoarthritis (OA) had significant and clinically meaningful improvements in pain, function, and global assessments; adverse events were generally mild to moderate in intensity [4,20,22,30]. Tanezumab also has demonstrated efficacy in patients with chronic low back pain [17,18]. In a Phase 2 double-blind, randomized clinical trial, a single 200 lg/kg intravenous (i.v.) dose of tanezumab was clinically and statistically superior to placebo and naproxen in patients with chronic low back pain [17]. In a subsequent Phase 2b double-blind, multi-dose, active- and placebo-controlled randomized clinical trial, tanezumab (10 mg or 20 mg i.v.) provided clinically significant analgesic efficacy vs both placebo and naproxen over 16 weeks of treatment [18]. In both studies, tanezumab significantly reduced pain and improved physical function and Patient’s Global Assessment (PGA) of low back pain [17,18]. Since chronic low back pain often requires long-term treatment, an open-label extension clinical trial was conducted to further assess tanezumab in this chronic pain condition using i.v. and subcutaneous (s.c.) fixed-dose regimens. The primary objective of this study was to evaluate long-term safety of tanezumab in patients with chronic low back pain. The secondary objective was to evaluate long-term effectiveness of tanezumab.
neurological, other pain, or psychological conditions; known history of rheumatoid arthritis, seronegative spondyloarthropathy, Paget’s disease of the spine, pelvis, or femur; fibromyalgia, and tumors or infections of the spinal cord. Key exclusion criteria for the extension study were screening failure in the parent study and withdrawal from the parent study for an adverse event or serious adverse event. 2.2. Study design All patients underwent a second randomization for the extension study to maintain blinding to tanezumab dose. Patients who received tanezumab 10 mg or tanezumab 20 mg in the parent double-blind study were re-randomized to the same dose, whereas patients who were randomly assigned to tanezumab 5 mg, placebo, or naproxen in the parent study were re-randomized to receive tanezumab 10 mg or tanezumab 20 mg in a 1:2 ratio. Patients received 3 i.v. injections of tanezumab 10 mg or 20 mg followed by up to 4 s.c. injections every 8 weeks (Fig. 1). U.S. Food and Drug Administration (FDA)-approved prescription analgesics, overthe-counter analgesics, or muscle relaxants were permitted as concomitant analgesic medications for chronic low back pain. Recruitment, enrollment, and study drug administration were discontinued in July 2010 following a partial clinical hold placed by the FDA on studies of chronic low back pain and other chronic pain conditions due to adverse events related to joint safety in tanezumab phase 3 OA studies. The intended treatment duration in this study was 64 weeks, but due to implementation of the partial clinical hold, too few patients remained in the study after week 24 to reliably estimate response to tanezumab beyond this time.
2. Methods
2.3. Effectiveness
This was a noncontrolled, randomized, dose-blinded, multicenter, parallel-group safety study (ClinicalTrials.gov identifier NCT00924664) conducted in patients with chronic low back pain. This study was an extension of a randomized, double-blind, placebo- and naproxen-controlled multiple-dose study of tanezumab (ClinicalTrials.gov identifier NCT00876187) [18]. The study was conducted in compliance with the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice guidelines. The protocol was reviewed and approved by institutional review boards at all study sites. Written informed consent was obtained from each patient before initiation of protocol-specified procedures.
Effectiveness was assessed as the change from baseline in Brief Pain Inventory Short Form (BPI-SF) score of average pain, Roland Morris Disability Questionnaire (RMDQ); PGA of low back pain, and the percentage of patients with P 30%, P 50%, P 70%, and P 90% reduction in BPI-SF score. BPI-SF was assessed on an 11-point numerical rating scale (range, 0 = no pain to 10 = pain as bad as you can imagine) [8]. RMDQ was assessed using a 25-point score (range, 0–24, with a lower score indicating better function) [27], and PGA of low back pain utilizes a 5-point scale (1 = very good, 2 = good, 3 = fair, 4 = poor, 5 = very poor) developed by Pharmacia (Pfizer Inc, New York, NY, USA) and adapted from assessments used in a variety of clinical trials of OA, rheumatoid arthritis, and chronic low back pain [18,32].
2.1. Study population 2.4. Safety For inclusion in the parent study, patients were required to have chronic low back pain with duration of P3 months, necessitating regular use of analgesic medication and classified as category 1 or 2 (primary location of low back pain between the 12th thoracic vertebra and the lower gluteal folds, with or without radiation into the posterior thigh) according to the Quebec Task Force on Spinal Disorders classification [25]; average low back pain intensity score while receiving current treatment of P4 (on an 11-point numerical rating scale), and PGA of low back pain of fair, poor, or very poor [18]. For the extension study, key inclusion criteria were treatment in the parent study, enrollment in the extension study at least 8 weeks but no longer than 12 weeks after last dose of study medication in the parent study and completion of the end of treatment visit or withdrawn for lack of efficacy in the parent study. Key exclusion criteria from the parent study were: history of lumbosacral radiculopathy within the past 2 years, vertebral fracture, major trauma, or back surgery in the past 6 months; significant cardiac,
Safety assessments included adverse event documentation (including severity and investigator’s opinion of relationship to study drug), vital signs, physical and neurological examinations, 12-lead electrocardiograms, injection site assessments, and laboratory tests. Adverse events reported for the extension study were those that started during this study (even if a separate event of the same adverse event term occurred in the parent study) or those that started during the parent study and worsened in this study. Severity of all adverse events and investigator’s opinion of the adverse event’s relationship to study drug were obtained and recorded. Any serious adverse event considered life threatening or resulting in death was reported immediately to the sponsor. Study investigators performed standardized neurological examinations at each clinic visit. Neurological examinations were scored using the Neurological Impairment Scale, a validated, standardized instrument for evaluation of signs of peripheral neuropathy [10].
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Parent study
Extension study
Placebo
Tanezumab 5 mg
Tanezumab 10 mg
Tanezumab 10 mg
Tanezumab 20 mg
Tanezumab 20 mg
Naproxen 500 mg BID
Week BL DB IV
8
16a
24
BL OL
8
16
24
32
40
48
IV
IV
IV
SC
SC
SC
SC
IV
56
64
Administration of study drug Fig. 1. Study design. BID, twice daily; BL, baseline; DB, double-blind; i.v., intravenous; OL, open-label (blinded to dose strength); SC, subcutaneous. aPreferred rollover time point to extension study.
Patients were referred to a neurologist (blinded to treatment arm) for further evaluation if any adverse event suggestive of a new or worsened peripheral neuropathy or any adverse event of abnormal peripheral sensation was reported, or if clinically significant changes were found upon neurological examination. After implementation of the clinical hold, a blinded, independent adjudication committee reviewed all adverse events initially reported as osteonecrosis, as well as reported total joint replacements (TJRs) of any causality if postbaseline radiographs were obtained and collected within approximately 9 months prior to TJR surgery. The adjudication committee reviewed radiographs and magnetic resonance images and source documentation, including progress notes; orthopedic consults; operative, radiology, and pathology reports; and pathology specimens (reviewed by an orthopedic pathologist who described findings to other committee members) [16,24]. Cases were classified as primary osteonecrosis, rapidly progressive OA, normal progression of OA, insufficient information to distinguish between rapid and normal progression of OA, other joint condition/diagnosis, or insufficient information to distinguish among primary osteonecrosis, worsening OA, or another diagnosis [16,24].
3. Results This study was conducted at 115 centers in the United States. Of the 1347 patients treated in the parent study, a total of 848 were randomized and treated in this extension study (Fig. 2). Patient demographics and baseline characteristics were comparable across treatments (Table 1). Mean combined treatment duration in the parent and extension studies were 270 and 259 days in the tanezumab 10-mg and 20-mg treatment groups, respectively. Before the study was terminated, the majority of patients reached week 24 of the extension study (tanezumab 10 mg: 224/ 321; 69.8%; tanezumab 20 mg: 358/527; 67.9%), of whom 155 (48.3%) patients in the tanezumab 10-mg group and 258 (49.0%) patients in the tanezumab 20-mg group had observed data for analysis at this time point (Fig. 2); only a small proportion (14/ 848, 1.7%) had visits beyond week 32. Most patients (52.9%) received 3 or more i.v. doses of tanezumab only or followed by 1 or more s.c. doses of tanezumab (28.3%, Table 1). The most frequent reason for discontinuation was study termination by the sponsor (529 patients [62.4%]; Fig. 2). 3.1. Effectiveness
2.5. Statistical analysis No minimum number of patients was required for evaluation of safety or effectiveness in the extension study. The maximum potential sample size of 427 in the tanezumab 10-mg group and 613 in the tanezumab 20-mg group (1040 patients over both treatments) would provide a 95% probability of seeing at least 1 patient with an adverse event, where the true ‘‘rare adverse event’’ rate was 0.29% or greater. Summary statistics (n, mean, SD, SEM, median, and range, or percentage response) were calculated for the effectiveness endpoints on the intent-to-treat population, which was defined as subjects who received P 1 study drug infusion and had P 1 evaluation postinfusion in the extension study. No statistical inferential tests were undertaken for the analysis of effectiveness in this study. Effectiveness results are presented through week 24 of the extension study. Safety was evaluated over the entire study.
Tanezumab treatment provided sustained improvements across all effectiveness endpoints. The decrease in the BPI-SF average pain from parent study baseline peaked at week 4 of the extension study and was generally similar regardless of previous treatment in the parent study in both tanezumab groups, (Fig. 3). Similar effectiveness was seen when considering only those patients treated with tanezumab in the parent and extension studies. This improvement in BPI-SF average pain was sustained throughout the study, since the mean change from baseline at week 24 was similar to week 4. Efficacy was comparable between the tanezumab 10-mg and 20-mg treatments; tanezumab 20-mg treatment provided only slightly greater reduction than tanezumab 10-mg treatment in BPI-SF average pain at all time points. Although all patients had improvement in mean BPI-SF average pain from baseline of the extension study, those who had received placebo, naproxen, or tanezumab 5 mg during the parent study had
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Screened, N = 851 Excluded, N = 2 Did not meet entrance criteria Total randomized, N = 849
Randomized to tanezumab 10 mg but not treated, n = 1
Randomized to and treated with tanezumab 10 mg, n = 321
Discontinuations from study, n (%) Adverse event, 0 (0.0) Lack of efficacy, 0 (0.0) No longer willing to participate in study, 3 (0.9) Lost to follow-up, 3 (0.9) Protocol violation, 0 (0.0) Withdrew due to pregnancy, 1 (0.3) Other, 1 (0.3) Study terminated by sponsor, 1 (0.3)
Patients evaluated at Week 4 of Extension Study, n = 312
Discontinuations from study, n (%) Adverse event, 18 (5.6) Lack of efficacy, 9 (2.8) No longer willing to participate in study, 28 (8.7) Lost to follow-up, 5 (1.6) Protocol violation, 1 (0.3) Withdrew due to pregnancy, 0 (0.0) Other, 14 (4.4) Study terminated by sponsor, 82 (25.5)
Patients evaluated at Week 24 of Extension Study, n = 155b
Discontinuations from study, n (%) Adverse event, 5 (1.6) Lack of efficacy, 1 (0.3) No longer willing to participate in study, 16 (5.0) Lost to follow-up, 2 (0.6) Protocol violation, 1 (0.3) Withdrew due to pregnancy, 0 (0.0) Other, 14 (4.4) Study terminated by sponsor, 116 (36.1)
Completed study n = 0
Randomized to and treated with tanezumab 20 mg, n = 527
Randomized to tanezumab 20 mg but not treated, n = 0
Discontinuations from study, n (%) Adverse event, 1 (0.3)a Lack of efficacy, 2 (0.4) No longer willing to participate in study, 7 (1.3) Lost to follow-up, 2 (0.4) Protocol violation, 0 (0.0) Withdrew due to pregnancy, 0 (0.0) Other, 2 (0.4) Study terminated by sponsor, 2 (0.4)
Patients evaluated at Week 4 of Extension Study, n = 511
Discontinuations from study, n (%) Adverse event, 34 (6.5)a Lack of efficacy, 12 (2.3) No longer willing to participate in study, 39 (7.4) Lost to follow-up, 9 (1.7) Protocol violation, 4 (0.8) Withdrew due to pregnancy, 1 (0.2) Other, 25 (4.7) Study terminated by sponsor, 129 (24.5)
Patients evaluated at Week 24 of Extension Study, n = 258b
Discontinuations from study, n (%) Adverse event, 6 (1.1) Lack of efficacy, 1 (0.2) No longer willing to participate in study, 25 (4.7) Lost to follow-up, 1 (0.2) Protocol violation, 1 (0.2) Withdrew due to pregnancy, 0 (0.0) Other, 25 (4.7) Study terminated by sponsor, 199 (37.8)
Completed study n = 0
Fig. 2. Patient disposition. aAdverse events include 2 patients who died during the study (these deaths were not considered related to study medication); bFour patients (n = 1, tanezumab 10 mg; n = 3 tanezumab 20 mg) with Week 24 data had missing Week 4 data, so the number of patients continuing in the study past Week 4 is larger than the number of patients with observed Week 4 data.
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J.S. Gimbel et al. / PAIN 155 (2014) 1793–1801 Table 1 Patient baseline and demographic characteristics. Tanezumab 10 mg n = 321
Tanezumab 20 mg n = 527
Gender, n (%) Female
167 (52.0)
277 (52.6)
Age, y Mean (range)
53.3 (18–90)
53.2 (22–88)
Race, n (%) White Black Asian Other Weight, mean (SD) kg Body mass index, mean (SD) kg/m2
265 (82.6) 40 (12.5) 5 (1.6) 11 (3.4) 85.7 (18.0) 29.5 (4.9)
436 (82.7) 72 (13.7) 6 (1.1) 13 (2.5) 87.1 (18.3) 29.7 (5.2)
Durationa since diagnosis of chronic low back pain, y Mean (range)
11.34 (0.30–55.9)
11.83 (0.28–63.8)
Primary etiologya, physician assessment, n (%) Degenerative joint disease/OA Injury/muscular strain Degenerative disc disease Other
113 (35.2) 114 (35.5) 91 (28.4) 3 (0.9)
233 (44.2) 148 (28.1) 134 (25.4) 12 (2.3)
Number of i.v. doses administered 1 2 3 4 5
59 93 169 0 0
102 145 276 3 1
Number of SC doses administered 1 2 3
71 8 1
111 42 7
Duration of treatment Mean, days (range)
193.8 (15–345)
202.3 (12–406)
OA, osteoarthritis; i.v., intravenous; SC, subcutaneous. a At parent study baseline.
the greatest improvements upon switching to 10 mg (Fig. 3B) or 20 mg tanezumab (Fig. 3C). In addition, few patients (25/848; 2.9%) discontinued due to lack of efficacy, further indicating that tanezumab treatment had persistent effectiveness. Sustained improvements in other effectiveness endpoints, including RMDQ and PGA, were also observed during the extension study, with the greatest improvement generally occurring at week 4 (data not shown). In addition, percentages of patients with P 30%, P 50%, P 70%, and P 90% reduction in BPI average pain remained high throughout the extension study. At week 24, the percentages of responders were similar, with tanezumab 10-mg and 20-mg treatment across all categories (Fig. 4). 3.2. Safety Overall incidence of adverse events and discontinuations due to an adverse event (all causalities) was higher with tanezumab 20 mg than with tanezumab 10 mg (Table 2). Paresthesia was the most frequent reason for discontinuation and occurred in 2 patients (0.6%) in the tanezumab 10-mg treatment group and 7 patients (1.3%) in the tanezumab 20-mg treatment group. Two patients died during the study and 1 patient died 4 days after withdrawing from the study (all had received tanezumab 20 mg). No death was considered related to the study drug. The first patient was an 85-year-old woman who died as a result of lung cancer.
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The second patient, a 78-year-old woman, died as a result of cardiac arrest. A third patient, an 84-year-old woman who discontinued the study on day 91 (no longer willing to participate), died from natural causes on study day 95. The percentage of patients reporting a serious adverse event was similar (Table 2). Serious adverse events were considered related to treatment in 5 patients (1.6%) in the tanezumab 10-mg group and in 5 patients (0.9%) in the tanezumab 20-mg group. The most frequently reported serious adverse event was OA (3 patients in each group), which met the criteria for a serious adverse event due to hospitalization for joint replacement surgery. Adverse events of abnormal peripheral sensation occurred at a higher incidence in the tanezumab 20-mg group (Table 3). Most (71.7%) adverse events of abnormal peripheral sensation resolved before last patient contact and most were mild to moderate in intensity. The majority of patients (89.2% and 91.5% in the tanezumab 10-mg and tanezumab 20-mg groups, respectively) had no new or worsened abnormalities in their final neurological examination (Table 4). Few patients had a clinically significant new or worsened abnormality at the last neurological examination (tanezumab 10 mg: 3.2%; tanezumab 20 mg: 1.7%). A total of 156 patients had adverse events of abnormal peripheral sensation or clinically significant new or worsened abnormality upon the neurological examination and were therefore referred for neurological consultation (Table 4). Altogether, 7.2% of patients were categorized by the consulting neurologist, with findings suggestive of a new or worsened peripheral neuropathy based on symptoms, clinically significant signs, or diagnostic tests at final neurological consultation. Adverse events initially described as osteonecrosis were reported by 6 patients (tanezumab 10 mg, n = 2 [0.6%]; tanezumab 20 mg, n = 4 [0.8%]; Fig. 5). Three of 6 patients with reported osteonecrosis had documented evidence of OA in the affected joint before enrolling in the parent study, 1 patient had a history of trauma in the affected joint, and the other 2 patients had insufficient information to determine whether OA was present in the affected joint at entry into the parent study. Four of the 6 patients with reported osteonecrosis underwent TJR. Nine additional patients (tanezumab 10 mg, n = 7 [2.2%]; tanezumab 20 mg, n = 2 [0.4%]) underwent TJR without osteonecrosis reported as an adverse event. Seven of these had history of OA, and 1 patient had history of knee pain; the remaining patient who underwent TJR did not have documented OA or prestudy X-rays. All 6 patients with reported osteonecrosis, and 4/9 patients undergoing TJR were evaluated by the adjudication committee. No patients were subsequently adjudicated as having primary osteonecrosis (Fig. 5). Instead, adjudication outcomes were worsening OA (n = 5), another diagnosis (n = 3), or lack of consensus and/or insufficient information to reach a conclusion (n = 2). Of the 5 patients adjudicated to worsening OA, 2 were adjudicated to normal progression of OA, 1 patient with a prior history of severe lateral knee OA in the affected joint was adjudicated to rapid progression of OA, and 2 patients had insufficient information to distinguish between rapid and normal OA progression. For the 3 patients adjudicated to another diagnosis, 1 had posttraumatic OA of the left ankle, 1 had posttraumatic fracture of the knee secondary to trauma, and 1 had a subchondral fracture of the lateral femoral condyle. Of the 15 patients with either investigatorreported osteonecrosis or TJR, 7 took NSAIDs at some time while they were treated with tanezumab in this study. The 1 patient adjudicated to rapid progression of OA had no history of concomitant NSAID use. Long-term tanezumab treatment was not associated with any meaningful changes in clinical laboratory values, vital signs, or electrocardiogram results.
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Fig. 3. Change from baseline in average Brief Pain Inventory Short Form score for all parent study patients who participated in extension study (A), patients receiving tanezumab 10 mg (B), or tanezumab 20 mg (C) in extension study by parent study treatment (ITT, observed data). BL, baseline; ITT, intent-to-treat. aGap between studies P 8 weeks and < 12 weeks. bPatients treated with either tanezumab 5 mg or 10 mg in parent study. cPatients treated with either tanezumab 5 mg or 20 mg in parent study.
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Fig. 4. Percentage of patients with P 30%, P 50%, P 70%, and P 90% reduction in Brief Pain Inventory average pain at week 24.
4. Discussion This randomized, parallel-group, multicenter study evaluated the long-term safety and effectiveness of tanezumab at doses of 10 mg and 20 mg in patients with chronic low back pain. The duration of chronic low back pain (nonspecific chronic low back pain with a duration averaging longer than 10 years), baseline pain scores, and functional impairment as measured by the RMDQ at entry in the parent study indicate this patient population had moderate-to-severe pain and disability despite daily treatment with an analgesic medication [18]. The most frequent reason for discontinuation was early study termination by the sponsor. Few patients who discontinued did so due to lack of efficacy, indicating a sustained analgesic effect of tanezumab. A decrease in the BPI-SF average pain from parent study baseline occurred during this study, with a peak at week 4. This improvement was sustained over 24 weeks of treatment in the extension study. Long-term effectiveness of tanezumab was Table 2 Incidence of adverse events, n (%).
Patients with adverse eventsa Patients with serious adverse events Patients discontinued due to adverse events
Tanezumab 10 mg n = 321
Tanezumab 20 mg n = 527
198 (61.7) 15 (4.7) 20 (6.2)
370 (70.2) 24 (4.6) 39 (7.4)
b
Adverse events occurring in P 3% in any group Arthralgia 41 (12.8) Paresthesia 31 (9.7) Hypoesthesia 23 (7.2) Pain in extremity 12 (3.7) Peripheral edema 11 (3.4) Headache 10 (3.1) Upper respiratory tract infection 11 (3.4) Musculoskeletal pain 14 (4.4) Diarrhea 6 (1.9) Myalgia 6 (1.9) Infusion site reaction 12 (3.7) Back pain 10 (3.1) Muscle strain 8 (2.5) Joint swelling 6 (1.9) Osteoarthritis 11 (3.4) Sinusitis 12 (3.7)
77 56 41 39 32 27 26 23 18 18 17 17 17 17 16 14
(14.6) (10.6) (7.8) (7.4) (6.1) (5.1) (4.9) (4.4) (3.4) (3.4) (3.2) (3.2) (3.2) (3.2) (3.0) (2.7)
a An adverse event was defined as one that started during this study (even if a separate event of the same adverse event term occurred in the parent study) or started during the parent study and worsened in this study. b Presentation order for adverse events based on incidence in the tanezumab 20-mg group.
supported by the categorical assessment of the BPI-SF average pain as measured by the percentage of patients with P 30%, P 50%, P 70%, or P 90% change from baseline. Clinically meaningful pain relief has been defined by others as a reduction in pain intensity of approximately 30% from baseline [28,29]. At week 24 in this study, more than 60% of patients had P 50% reduction in pain score, and thus, had clinically meaningful pain reduction. Similarly, sustained improvements were also observed for RMDQ and PGA of low back pain from week 4 through week 24 of the extension study. Across all effectiveness endpoints, no consistent benefit of 20 mg tanezumab over 10 mg tanezumab was noted. The adverse event profile was consistent with the parent study [18] and other long-term tanezumab studies [11,30]. The percentage of patients with a serious adverse event was similar in both groups, although these events were more frequently reported than in the parent study due to occurrence of serious adverse events initially reported as osteonecrosis or TJR in the extension study. Per study protocol, all patients reporting abnormal peripheral sensations, pain in extremity, or those with clinically significant neurological examination findings underwent examination by a neurologist. Rates of adverse events of peripheral polyneuropathies and neurological consultation categorizations of new or worsened peripheral neuropathies for the extension study were similar to those reported during the parent study [18], indicating that longer duration tanezumab treatment was not associated with additional peripheral neuropathy safety concerns. During the conduct of clinical studies of tanezumab and other NGF inhibitors in subjects with OA pain, a signal event initially described by investigators as osteonecrosis often leading to TJR raised concerns about joint-related safety of tanezumab and led to a partial clinical hold by the FDA on the entire NGF inhibitor class. Reports of osteonecrosis and other documented TJRs underwent careful and thorough investigation by an independent, expert adjudication committee [16,24]. No evidence was found to indicate that tanezumab is associated with an increased risk of osteonecrosis, a disease process quite distinct from osteoarthritis, although a
Table 3 Incidence of adverse events of abnormal peripheral sensation, n (%). Tanezumab 10 mg n = 321 Adverse events of abnormal peripheral sensationa,b Paresthesia 31 (9.7) Hypoesthesia 23 (7.2) Decreased vibratory sense 2 (0.6) Hyperesthesia 3 (0.9) Allodynia 0 Burning sensation 2 (0.6) Dysesthesia 1 (0.3) Neuropathy peripheral 1 (0.3) Sensory disturbance 4 (1.2) Hypoesthesia oral 0 Paresthesia oral 0 Neuralgia 0 Peripheral sensorimotor neuropathy 0 Polyneuropathy 0 Formication 1 (0.3)
Tanezumab 20 mg n = 527 56 (10.6) 41 (7.8) 14 (2.7) 11 (2.1) 11 (2.1) 8 (1.5) 7 (1.3) 7 (1.3) 2 (0.4) 1 (0.2) 1 (0.2) 1 (0.2) 1 (0.2) 1 (0.2) 0
a Adverse events of abnormal peripheral sensation included allodynia, axonal neuropathy, burning sensation, decreased vibratory sense, demyelinating polyneuropathy, dysesthesia, formication, hyperesthesia, hyperpathia, hypoesthesia, hypoesthesia facial, hypoesthesia oral, intercostal neuralgia, neuralgia, neuritis, neuropathy peripheral, paresthesia, paresthesia oral, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, polyneuropathy, polyneuropathy chronic, sensory disturbance, sensory loss, and thermohypoesthesia. b Presentation order for adverse events based on incidence in the tanezumab 20-mg group.
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Table 4 Summary of final neurological examinations and neurological consultations (intentto-treat population, observed data)a. Tanezumab 10 mg n = 321
Tanezumab 20 mg n = 527
Final neurological examination assessments, n (%) New or worsened abnormality Clinically significant Not clinically significant Total No new or worsened abnormality
10 (3.2) 24 (7.6) 34 (10.8) 282 (89.2)
9 (1.7) 35 (6.8) 44 (8.5) 471 (91.5)
Final neurological consultation categorization, n (%) Patients referred for consultation 46 (14.3)
110 (20.9)
Suggestive of new or worsened peripheral neuropathy, n (%) Total 19 (5.9) Based on symptoms only 4 (1.2) Based on clinically significant signs only 4 (1.2) Based on diagnostic tests 11 (3.4) Other neurological symptoms or signs 16 (5.0) No neurological symptoms or signs 11 (3.4)
42 (8.0) 8 (1.5) 7 (1.3) 27 (5.1) 41 (7.8) 27 (5.1)
a Neurological examinations were performed per protocol by study investigators. Neurological consultations were performed by neurologists following a neurological adverse event report or after significant neurological examination abnormalities were detected by investigators.
risk of rapidly progressive osteoarthritis was identified [23]. On March 12, 2012, the FDA Arthritis Advisory Committee reviewed these results, as well as those prepared by the FDA [13,14]. The
committee endorsed continued clinical development of the NGF inhibitor class of compounds, with additional measures to minimize the risk and further protect patient safety. On August 28, 2012, the FDA lifted the partial clinical hold on tanezumab related to joint safety. In this study, 6 patients reported adverse events initially classified as osteonecrosis, and 9 other patients underwent TJR related to OA. The adjudication committee reviewed all 6 of the patients reporting osteonecrosis and 4 of the 9 patients with TJR; none were adjudicated by the committee to primary osteonecrosis. One patient was adjudicated to rapidly progressive osteoarthritis. In conclusion, in patients with chronic low back pain, tanezumab i.v. and s.c. had a safety profile that was consistent with other clinical trials with tanezumab. Although both tanezumab 10 mg and 20 mg provided sustained effectiveness, tanezumab 10 mg had better tolerability. Tanezumab provided sustained pain relief, improvement in physical functioning, and improvement in global assessment of chronic low back pain in this long-term extension study. No new safety concerns were identified with long-term tanezumab use. Tanezumab may represent an effective long-term treatment for chronic low back pain. Conflict of interest statement Candace Bramson, Mary Anne Nemeth, David S. Keller, Mark T. Brown, Christine R. West, and Kenneth M. Verburg are employees of and hold stock options, restricted stock units, or stock in Pfizer Inc, and Alan Kivitz owns Pfizer stock.
Patients with TJR or investigatorreported AEs of ON, n = 15 Tanezumab 10 mg, n = 9 Tanezumab 20 mg, n = 6
Patients not adjudicated, n = 0
Patients with reported ON Tanezumab 10 mg, n = 2 Tanezumab 20 mg, n = 4
6/6 (100%)
Patients with TJR related to OA Tanezumab 10 mg, n = 7 Tanezumab 20 mg, n = 2
Patients not adjudicated, n = 5 X-rays unavailable, n = 3 Reported TJR after cutoff date, n = 2
4/9 (44%)
Patients adjudicated, n = 10 Tanezumab 10 mg, n (%) 5 (55.6) Tanezumab 20 mg, n (%) 5 (83.3)
Other diagnosis, n = 3 Subchondral fracture, knee, (tanezumab 20 mg), n = 1 Post-traumatic OA, ankle, (tanezumab 10 mg), n = 1 Post-traumatic fracture, knee, (tanezumab 20 mg), n = 1
Normal progression of OA, n = 2 Tanezumab 10 mg, n = 2 Tanezumab 20 mg, n = 0
Worsening OA, n = 5 Tanezumab 10 mg, n = 4 Tanezumab 20 mg, n = 1
Rapid progression of OA, n = 1 Tanezumab 10 mg, n = 0 Tanezumab 20 mg, n = 1
Lack of consensus or insufficient information to distinguish ON from worsening OA, n = 2 Tanezumab 10 mg, n = 0 Tanezumab 20 mg, n = 2
Insufficient information to determine rate of progression, n = 2 Tanezumab 10 mg, n = 2 Tanezumab 20 mg, n = 0
Fig. 5. Adjudication outcomes of joint safety events. OA, osteoarthritis; ON, osteonecrosis; TJR, total joint replacement.
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Acknowledgements These studies were funded by Pfizer Inc. Editorial support was provided by Joseph Oleynek of Engage Scientific Solutions and funded by Pfizer Inc. References [1] Abdiche YN, Malashock DS, Pons J. Probing the binding mechanism and affinity of tanezumab, a recombinant humanized anti-NGF monoclonal antibody, using a repertoire of biosensors. Protein Sci 2008;17:1326–35. [2] Airaksinen O, Brox JI, Cedraschi C, Hildebrandt J, Klaber-Moffett J, Kovacs F, Mannion AF, Reis S, Staal JB, Ursin H, Zanoli G. Chapter 4 European guidelines for the management of chronic nonspecific low back pain. Eur Spine J 2006;15(Suppl. 2):S192–300. [3] Bjordal JM, Ljunggren AE, Klovning A, Slordal L. Non-steroidal antiinflammatory drugs, including cyclo-oxygenase-2 inhibitors, in osteoarthritic knee pain: meta-analysis of randomised placebo controlled trials. BMJ 2004;329:1317. [4] Brown M, Murphy F, Radin D, Davignon I, Smith M, West C. Tanezumab reduces osteoarthritic knee pain: results of a randomized, double-blind, placebo-controlled phase 3 trial. J Pain 2012;13:790–8. [5] Chou R, Huffman LH. Medications for acute and chronic low back pain: a review of the evidence for an American Pain Society/American College of Physicians clinical practice guideline. Ann Intern Med 2007;147:505–14. [6] Chou R, Huffman LH. Nonpharmacologic therapies for acute and chronic low back pain: a review of the evidence for an American Pain Society/American College of Physicians clinical practice guideline. Ann Intern Med 2007;147: 492–504. [7] Chou R, Qaseem A, Snow V, Casey D, Cross Jr JT, Shekelle P, Owens DK. Diagnosis and treatment of low back pain: a joint clinical practice guideline from the American College of Physicians and the American Pain Society. Ann Intern Med 2007;147:478–91. [8] Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singapore 1994;23:129–38. [9] Deyo RA, Weinstein JN. Low back pain. N Engl J Med 2001;344:363–70. [10] Dyck PJ, Litchy WJ, Lehman KA, Hokanson JL, Low PA, O’Brien PC. Variables influencing neuropathic endpoints: the Rochester Diabetic Neuropathy Study of Healthy Subjects. Neurology 1995;45:1115–21. [11] Ekman E, Gimbel J, Bello A, Smith M, Keller D, Annis K, Brown M, West C, Verburg K. Efficacy and safety of intravenous tanezumab in osteoarthritis hip and knee pain: comparison to placebo and naproxen in two Phase III studies (NCT00830063 & NCT00863304). J Pain 2011;12(Suppl.):P55. Available from: http://download.journals.elsevierhealth.com/pdfs/journals/ 1526-5900/PIIS1526590011002707.pdf. [accessed 27.06.14]. [12] Evans RJ, Moldwin RM, Cossons N, Darekar A, Mills IW, Scholfield D. Proof of concept trial of tanezumab for the treatment of symptoms associated with interstitial cystitis. J Urol 2011;185:1716–21. [13] Food and Drug Administration Center for Drug Evaluation and Research. Background materials addendum. Available from: http://www.fda.gov/ downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Arthritis DrugsAdvisoryCommittee/UCM295203.pdf. [accessed 27.06.14]. [14] Food and Drug Administration Center for Drug Evaluation and Research. Background materials. Meeting of the Arthritis Advisory Committee (AAC). Available from: http://www.fda.gov/downloads/AdvisoryCommittees/ Committees MeetingMaterials/Drugs/ArthritisDrugsAdvisoryCommittee/ UCM295202.pdf. [accessed 27.06.14]. [15] Hefti FF, Rosenthal A, Walicke PA, Wyatt S, Vergara G, Shelton DL, Davies AM. Novel class of pain drugs based on antagonism of NGF. Trends Pharmacol Sci 2006;27:85–91.
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[16] Hochberg MC, Abramson SB, Hungerford DS, McCarthy E, Vignon EP, Smith MD, Tive L, Verburg KM, West CR. Adjudication of reported serious adverse joint events in the tanezumab clinical development program. Arthritis Rheum 2012;64:S113. [17] Katz N, Borenstein DG, Birbara C, Bramson C, Nemeth MA, Smith MD, Brown MT. Efficacy and safety of tanezumab in the treatment of chronic low back pain. PAINÒ 2011;152:2248–58. [18] Kivitz AJ, Gimbel JS, Bramson C, Nemeth MA, Keller DS, Brown MT, West CR, Verburg KM. Efficacy and safety of tanezumab versus naproxen in the treatment of chronic low back pain. PAINÒ 2013;154:1009–21. [19] Koewler NJ, Freeman KT, Buus RJ, Herrera MB, Jimenez-Andrade JM, Ghilardi JR, Peters CM, Sullivan LJ, Kuskowski MA, Lewis JL, Mantyh PW. Effects of a monoclonal antibody raised against nerve growth factor on skeletal pain and bone healing after fracture of the C57BL/6J mouse femur. J Bone Miner Res 2007;22:1732–42. [20] Lane NE, Schnitzer TJ, Birbara CA, Mokhtarani M, Shelton DL, Smith MD, Brown MT. Tanezumab for treatment of knee osteoarthritis pain. N Engl J Med 2010;363:1521–31. [21] Mantyh PW, Koltzenburg M, Mendell LM, Tive L, Shelton DL. Antagonism of nerve growth factor-TrkA signaling and the relief of pain. Anesthesiology 2011;115:189–204. [22] Nagashima H, Suzuki M, Araki S, Yamabe T, Muto C. Preliminary assessment of the safety and efficacy of tanezumab in Japanese patients with moderate to severe osteoarthritis of the knee: a randomized, double-blind, dose-escalation, placebo-controlled study. Osteoarthritis Cartilage 2011;19:1405–12. [23] Nickel JC, Atkinson G, Krieger JN, Mills IW, Pontari M, Shoskes DA, Crook TJ. Preliminary assessment of safety and efficacy in proof-of-concept, randomized clinical trial of tanezumab for chronic prostatitis/chronic pelvic pain syndrome. Urology 2012;80:1105–10. [24] Pfizer Inc. Tanezumab Arthritis Advisory Committee briefing document. Available from: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeeting Materials/Drugs/ArthritisDrugsAdvisoryCommittee/UCM295205.pdf. [accessed 27.06.14]. [25] Quebec Task Force on Spinal Disorders. Scientific approach to the assessment and management of activity-related spinal disorders. A monograph for clinicians. Report of the Quebec Task Force on Spinal Disorders. Spine (Phila Pa 1976) 1987;12:S1–S59. [26] Roelofs PD, Deyo RA, Koes BW, Scholten RJ, van Tulder MW. Nonsteroidal antiinflammatory drugs for low back pain: an updated Cochrane review. Spine (Phila Pa 1976) 2008;33:1766–74. [27] Roland M, Morris R. A study of the natural history of low-back pain. Part II: development of guidelines for trials of treatment in primary care. Spine (Phila Pa 1976) 1983;8:145–50. [28] Rowbotham MC. What is a ‘‘clinically meaningful’’ reduction in pain? PAINÒ 2001;94:131–2. [29] Salaffi F, Stancati A, Silvestri CA, Ciapetti A, Grassi W. Minimal clinically important changes in chronic musculoskeletal pain intensity measured on a numerical rating scale. Eur J Pain 2004;8:283–91. [30] Schnitzer TJ, Lane NE, Birbara C, Smith MD, Simpson SL, Brown MT. Long-term open-label study of tanezumab for moderate to severe osteoarthritic knee pain. Osteoarthritis Cartilage 2011;19:639–46. [31] Shelton DL, Zeller J, Ho WH, Pons J, Rosenthal A. Nerve growth factor mediates hyperalgesia and cachexia in auto-immune arthritis. PAINÒ 2005;116:8–16. [32] Stengaard-Pedersen K, Ekesbo R, Karvonen AL, Lyster M. Celecoxib 200 mg q.d. is efficacious in the management of osteoarthritis of the knee or hip regardless of the time of dosing. Rheumatology 2004;43:592–5. [33] Watson JJ, Allen SJ, Dawbarn D. Targeting nerve growth factor in pain: what is the therapeutic potential? BioDrugs 2008;22:349–59. [34] Zahn PK, Subieta A, Park SS, Brennan TJ. Effect of blockade of nerve growth factor and tumor necrosis factor on pain behaviors after plantar incision. J Pain 2004;5:157–63.
PAIN 155 (2014) 1793–1801
www.elsevier.com/locate/pain
Long-term safety and effectiveness of tanezumab as treatment for chronic low back pain Joseph S. Gimbel a,⇑, Alan J. Kivitz b, Candace Bramson c, Mary Anne Nemeth c, David S. Keller c, Mark T. Brown c, Christine R. West c, Kenneth M. Verburg c a b c
Arizona Research Center, Phoenix, AZ, USA Altoona Center for Clinical Research, Duncansville, PA, USA Pfizer Inc, Groton, CT, USA
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
a r t i c l e
i n f o
Article history: Received 17 December 2013 Received in revised form 6 June 2014 Accepted 10 June 2014
Keywords: Effectiveness Low back pain Nerve growth factor Safety Tanezumab
a b s t r a c t A noncontrolled, randomized, multicenter study (NCT00924664) evaluated long-term safety and effectiveness of tanezumab in patients with chronic low back pain following a randomized placebo- and active-controlled parent study that evaluated analgesic efficacy. Patients were randomized to tanezumab 10 mg (n = 321) or 20 mg (n = 527) administered at 8-week intervals via 3 intravenous injections followed by 4 subcutaneous injections. Effectiveness analyses included change from parent study baseline in Brief Pain Inventory Short Form, Roland Morris Disability Questionnaire, and Patient’s Global Assessment of low back pain. Safety assessments included adverse event documentation, physical/neurological examinations, and laboratory tests. Mean treatment duration during the extension study was 194 and 202 days with tanezumab 10 and 20 mg, respectively. Both tanezumab doses provided similar and sustained improvements in all effectiveness outcomes. The most frequently reported adverse events were arthralgia, paresthesia, and hypoesthesia. Adverse events initially described as osteonecrosis were reported in 6 patients (tanezumab 10 mg, n = 2; tanezumab 20 mg, n = 4); 9 additional patients (tanezumab 10 mg, n = 7; tanezumab 20 mg, n = 2) underwent total joint replacement (TJR). A blinded, independent adjudication committee reviewed all 6 patients with reported osteonecrosis and 4 of the 9 patients undergoing TJR. Adjudication outcomes were osteonecrosis (n = 0), worsening osteoarthritis (n = 5; 1 rapidly progressive), and another diagnosis or indeterminate (n = 5). Tanezumab 10 mg had better tolerability than tanezumab 20 mg, and may represent an effective long-term treatment for chronic low back pain. Ó 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
1. Introduction Treatment of chronic low back pain remains a challenging clinical problem despite availability of numerous therapeutic interventions [5–7,26]. Low back pain is often a long-term condition, with up to one-third of patients reporting persistent pain of at least moderate intensity 1 year after an acute episode [7]. Therapeutic agents currently used in management of chronic low back pain include opioids and/or nonsteroidal antiinflammatory drugs (NSAIDs) despite a lack of completely effective pain relief in many patients and little-to-no evidence of long-term benefits [5,26]. In ⇑ Corresponding author. Address: Arizona Research Center, 2525 W. Greenway Road, Suite 114, Phoenix, AZ 85023, USA. Tel.: +1 602 863 6363. E-mail address: [email protected] (J.S. Gimbel).
addition, these agents are often poorly tolerated due to significant central nervous system, cardiovascular, and gastrointestinal side effects, especially with long-term use [2,3,5,7,9]. Thus, there remains an unmet need for novel pharmacological approaches and new analgesics to provide sustained relief of chronic low back pain. One approach to selecting targets for potential analgesic therapies has been identification of components of pain signaling cascades. The neurotrophin, nerve growth factor (NGF), has a key role in the developing nervous system where it mediates functional contacts of specific populations of sensory and sympathetic neurons with their targets [21]. In the adult, the primary function of NGF is that of a modulator of nociceptive neuronal activity [21]. NGF levels are elevated in several chronic pain conditions and are
http://dx.doi.org/10.1016/j.pain.2014.06.004 0304-3959/Ó 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
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associated with increased pain perception [33]. Inhibition of NGF decreases pain behavior in animal models of bone fracture [19], plantar incision [34], and arthritis [31], and reduces pain in patients with chronic pain conditions [4,12,20,22,23,30]. Tanezumab is a humanized monoclonal antibody that tightly binds NGF with high selectivity and specificity, thereby preventing NGF from interacting with the receptors, neurotrophic tyrosine kinase receptor type 1 (TrkA) and low-affinity NGF receptor (p75) [1,15]. In clinical studies of tanezumab, patients with osteoarthritis (OA) had significant and clinically meaningful improvements in pain, function, and global assessments; adverse events were generally mild to moderate in intensity [4,20,22,30]. Tanezumab also has demonstrated efficacy in patients with chronic low back pain [17,18]. In a Phase 2 double-blind, randomized clinical trial, a single 200 lg/kg intravenous (i.v.) dose of tanezumab was clinically and statistically superior to placebo and naproxen in patients with chronic low back pain [17]. In a subsequent Phase 2b double-blind, multi-dose, active- and placebo-controlled randomized clinical trial, tanezumab (10 mg or 20 mg i.v.) provided clinically significant analgesic efficacy vs both placebo and naproxen over 16 weeks of treatment [18]. In both studies, tanezumab significantly reduced pain and improved physical function and Patient’s Global Assessment (PGA) of low back pain [17,18]. Since chronic low back pain often requires long-term treatment, an open-label extension clinical trial was conducted to further assess tanezumab in this chronic pain condition using i.v. and subcutaneous (s.c.) fixed-dose regimens. The primary objective of this study was to evaluate long-term safety of tanezumab in patients with chronic low back pain. The secondary objective was to evaluate long-term effectiveness of tanezumab.
neurological, other pain, or psychological conditions; known history of rheumatoid arthritis, seronegative spondyloarthropathy, Paget’s disease of the spine, pelvis, or femur; fibromyalgia, and tumors or infections of the spinal cord. Key exclusion criteria for the extension study were screening failure in the parent study and withdrawal from the parent study for an adverse event or serious adverse event. 2.2. Study design All patients underwent a second randomization for the extension study to maintain blinding to tanezumab dose. Patients who received tanezumab 10 mg or tanezumab 20 mg in the parent double-blind study were re-randomized to the same dose, whereas patients who were randomly assigned to tanezumab 5 mg, placebo, or naproxen in the parent study were re-randomized to receive tanezumab 10 mg or tanezumab 20 mg in a 1:2 ratio. Patients received 3 i.v. injections of tanezumab 10 mg or 20 mg followed by up to 4 s.c. injections every 8 weeks (Fig. 1). U.S. Food and Drug Administration (FDA)-approved prescription analgesics, overthe-counter analgesics, or muscle relaxants were permitted as concomitant analgesic medications for chronic low back pain. Recruitment, enrollment, and study drug administration were discontinued in July 2010 following a partial clinical hold placed by the FDA on studies of chronic low back pain and other chronic pain conditions due to adverse events related to joint safety in tanezumab phase 3 OA studies. The intended treatment duration in this study was 64 weeks, but due to implementation of the partial clinical hold, too few patients remained in the study after week 24 to reliably estimate response to tanezumab beyond this time.
2. Methods
2.3. Effectiveness
This was a noncontrolled, randomized, dose-blinded, multicenter, parallel-group safety study (ClinicalTrials.gov identifier NCT00924664) conducted in patients with chronic low back pain. This study was an extension of a randomized, double-blind, placebo- and naproxen-controlled multiple-dose study of tanezumab (ClinicalTrials.gov identifier NCT00876187) [18]. The study was conducted in compliance with the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice guidelines. The protocol was reviewed and approved by institutional review boards at all study sites. Written informed consent was obtained from each patient before initiation of protocol-specified procedures.
Effectiveness was assessed as the change from baseline in Brief Pain Inventory Short Form (BPI-SF) score of average pain, Roland Morris Disability Questionnaire (RMDQ); PGA of low back pain, and the percentage of patients with P 30%, P 50%, P 70%, and P 90% reduction in BPI-SF score. BPI-SF was assessed on an 11-point numerical rating scale (range, 0 = no pain to 10 = pain as bad as you can imagine) [8]. RMDQ was assessed using a 25-point score (range, 0–24, with a lower score indicating better function) [27], and PGA of low back pain utilizes a 5-point scale (1 = very good, 2 = good, 3 = fair, 4 = poor, 5 = very poor) developed by Pharmacia (Pfizer Inc, New York, NY, USA) and adapted from assessments used in a variety of clinical trials of OA, rheumatoid arthritis, and chronic low back pain [18,32].
2.1. Study population 2.4. Safety For inclusion in the parent study, patients were required to have chronic low back pain with duration of P3 months, necessitating regular use of analgesic medication and classified as category 1 or 2 (primary location of low back pain between the 12th thoracic vertebra and the lower gluteal folds, with or without radiation into the posterior thigh) according to the Quebec Task Force on Spinal Disorders classification [25]; average low back pain intensity score while receiving current treatment of P4 (on an 11-point numerical rating scale), and PGA of low back pain of fair, poor, or very poor [18]. For the extension study, key inclusion criteria were treatment in the parent study, enrollment in the extension study at least 8 weeks but no longer than 12 weeks after last dose of study medication in the parent study and completion of the end of treatment visit or withdrawn for lack of efficacy in the parent study. Key exclusion criteria from the parent study were: history of lumbosacral radiculopathy within the past 2 years, vertebral fracture, major trauma, or back surgery in the past 6 months; significant cardiac,
Safety assessments included adverse event documentation (including severity and investigator’s opinion of relationship to study drug), vital signs, physical and neurological examinations, 12-lead electrocardiograms, injection site assessments, and laboratory tests. Adverse events reported for the extension study were those that started during this study (even if a separate event of the same adverse event term occurred in the parent study) or those that started during the parent study and worsened in this study. Severity of all adverse events and investigator’s opinion of the adverse event’s relationship to study drug were obtained and recorded. Any serious adverse event considered life threatening or resulting in death was reported immediately to the sponsor. Study investigators performed standardized neurological examinations at each clinic visit. Neurological examinations were scored using the Neurological Impairment Scale, a validated, standardized instrument for evaluation of signs of peripheral neuropathy [10].
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Parent study
Extension study
Placebo
Tanezumab 5 mg
Tanezumab 10 mg
Tanezumab 10 mg
Tanezumab 20 mg
Tanezumab 20 mg
Naproxen 500 mg BID
Week BL DB IV
8
16a
24
BL OL
8
16
24
32
40
48
IV
IV
IV
SC
SC
SC
SC
IV
56
64
Administration of study drug Fig. 1. Study design. BID, twice daily; BL, baseline; DB, double-blind; i.v., intravenous; OL, open-label (blinded to dose strength); SC, subcutaneous. aPreferred rollover time point to extension study.
Patients were referred to a neurologist (blinded to treatment arm) for further evaluation if any adverse event suggestive of a new or worsened peripheral neuropathy or any adverse event of abnormal peripheral sensation was reported, or if clinically significant changes were found upon neurological examination. After implementation of the clinical hold, a blinded, independent adjudication committee reviewed all adverse events initially reported as osteonecrosis, as well as reported total joint replacements (TJRs) of any causality if postbaseline radiographs were obtained and collected within approximately 9 months prior to TJR surgery. The adjudication committee reviewed radiographs and magnetic resonance images and source documentation, including progress notes; orthopedic consults; operative, radiology, and pathology reports; and pathology specimens (reviewed by an orthopedic pathologist who described findings to other committee members) [16,24]. Cases were classified as primary osteonecrosis, rapidly progressive OA, normal progression of OA, insufficient information to distinguish between rapid and normal progression of OA, other joint condition/diagnosis, or insufficient information to distinguish among primary osteonecrosis, worsening OA, or another diagnosis [16,24].
3. Results This study was conducted at 115 centers in the United States. Of the 1347 patients treated in the parent study, a total of 848 were randomized and treated in this extension study (Fig. 2). Patient demographics and baseline characteristics were comparable across treatments (Table 1). Mean combined treatment duration in the parent and extension studies were 270 and 259 days in the tanezumab 10-mg and 20-mg treatment groups, respectively. Before the study was terminated, the majority of patients reached week 24 of the extension study (tanezumab 10 mg: 224/ 321; 69.8%; tanezumab 20 mg: 358/527; 67.9%), of whom 155 (48.3%) patients in the tanezumab 10-mg group and 258 (49.0%) patients in the tanezumab 20-mg group had observed data for analysis at this time point (Fig. 2); only a small proportion (14/ 848, 1.7%) had visits beyond week 32. Most patients (52.9%) received 3 or more i.v. doses of tanezumab only or followed by 1 or more s.c. doses of tanezumab (28.3%, Table 1). The most frequent reason for discontinuation was study termination by the sponsor (529 patients [62.4%]; Fig. 2). 3.1. Effectiveness
2.5. Statistical analysis No minimum number of patients was required for evaluation of safety or effectiveness in the extension study. The maximum potential sample size of 427 in the tanezumab 10-mg group and 613 in the tanezumab 20-mg group (1040 patients over both treatments) would provide a 95% probability of seeing at least 1 patient with an adverse event, where the true ‘‘rare adverse event’’ rate was 0.29% or greater. Summary statistics (n, mean, SD, SEM, median, and range, or percentage response) were calculated for the effectiveness endpoints on the intent-to-treat population, which was defined as subjects who received P 1 study drug infusion and had P 1 evaluation postinfusion in the extension study. No statistical inferential tests were undertaken for the analysis of effectiveness in this study. Effectiveness results are presented through week 24 of the extension study. Safety was evaluated over the entire study.
Tanezumab treatment provided sustained improvements across all effectiveness endpoints. The decrease in the BPI-SF average pain from parent study baseline peaked at week 4 of the extension study and was generally similar regardless of previous treatment in the parent study in both tanezumab groups, (Fig. 3). Similar effectiveness was seen when considering only those patients treated with tanezumab in the parent and extension studies. This improvement in BPI-SF average pain was sustained throughout the study, since the mean change from baseline at week 24 was similar to week 4. Efficacy was comparable between the tanezumab 10-mg and 20-mg treatments; tanezumab 20-mg treatment provided only slightly greater reduction than tanezumab 10-mg treatment in BPI-SF average pain at all time points. Although all patients had improvement in mean BPI-SF average pain from baseline of the extension study, those who had received placebo, naproxen, or tanezumab 5 mg during the parent study had
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Screened, N = 851 Excluded, N = 2 Did not meet entrance criteria Total randomized, N = 849
Randomized to tanezumab 10 mg but not treated, n = 1
Randomized to and treated with tanezumab 10 mg, n = 321
Discontinuations from study, n (%) Adverse event, 0 (0.0) Lack of efficacy, 0 (0.0) No longer willing to participate in study, 3 (0.9) Lost to follow-up, 3 (0.9) Protocol violation, 0 (0.0) Withdrew due to pregnancy, 1 (0.3) Other, 1 (0.3) Study terminated by sponsor, 1 (0.3)
Patients evaluated at Week 4 of Extension Study, n = 312
Discontinuations from study, n (%) Adverse event, 18 (5.6) Lack of efficacy, 9 (2.8) No longer willing to participate in study, 28 (8.7) Lost to follow-up, 5 (1.6) Protocol violation, 1 (0.3) Withdrew due to pregnancy, 0 (0.0) Other, 14 (4.4) Study terminated by sponsor, 82 (25.5)
Patients evaluated at Week 24 of Extension Study, n = 155b
Discontinuations from study, n (%) Adverse event, 5 (1.6) Lack of efficacy, 1 (0.3) No longer willing to participate in study, 16 (5.0) Lost to follow-up, 2 (0.6) Protocol violation, 1 (0.3) Withdrew due to pregnancy, 0 (0.0) Other, 14 (4.4) Study terminated by sponsor, 116 (36.1)
Completed study n = 0
Randomized to and treated with tanezumab 20 mg, n = 527
Randomized to tanezumab 20 mg but not treated, n = 0
Discontinuations from study, n (%) Adverse event, 1 (0.3)a Lack of efficacy, 2 (0.4) No longer willing to participate in study, 7 (1.3) Lost to follow-up, 2 (0.4) Protocol violation, 0 (0.0) Withdrew due to pregnancy, 0 (0.0) Other, 2 (0.4) Study terminated by sponsor, 2 (0.4)
Patients evaluated at Week 4 of Extension Study, n = 511
Discontinuations from study, n (%) Adverse event, 34 (6.5)a Lack of efficacy, 12 (2.3) No longer willing to participate in study, 39 (7.4) Lost to follow-up, 9 (1.7) Protocol violation, 4 (0.8) Withdrew due to pregnancy, 1 (0.2) Other, 25 (4.7) Study terminated by sponsor, 129 (24.5)
Patients evaluated at Week 24 of Extension Study, n = 258b
Discontinuations from study, n (%) Adverse event, 6 (1.1) Lack of efficacy, 1 (0.2) No longer willing to participate in study, 25 (4.7) Lost to follow-up, 1 (0.2) Protocol violation, 1 (0.2) Withdrew due to pregnancy, 0 (0.0) Other, 25 (4.7) Study terminated by sponsor, 199 (37.8)
Completed study n = 0
Fig. 2. Patient disposition. aAdverse events include 2 patients who died during the study (these deaths were not considered related to study medication); bFour patients (n = 1, tanezumab 10 mg; n = 3 tanezumab 20 mg) with Week 24 data had missing Week 4 data, so the number of patients continuing in the study past Week 4 is larger than the number of patients with observed Week 4 data.
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J.S. Gimbel et al. / PAIN 155 (2014) 1793–1801 Table 1 Patient baseline and demographic characteristics. Tanezumab 10 mg n = 321
Tanezumab 20 mg n = 527
Gender, n (%) Female
167 (52.0)
277 (52.6)
Age, y Mean (range)
53.3 (18–90)
53.2 (22–88)
Race, n (%) White Black Asian Other Weight, mean (SD) kg Body mass index, mean (SD) kg/m2
265 (82.6) 40 (12.5) 5 (1.6) 11 (3.4) 85.7 (18.0) 29.5 (4.9)
436 (82.7) 72 (13.7) 6 (1.1) 13 (2.5) 87.1 (18.3) 29.7 (5.2)
Durationa since diagnosis of chronic low back pain, y Mean (range)
11.34 (0.30–55.9)
11.83 (0.28–63.8)
Primary etiologya, physician assessment, n (%) Degenerative joint disease/OA Injury/muscular strain Degenerative disc disease Other
113 (35.2) 114 (35.5) 91 (28.4) 3 (0.9)
233 (44.2) 148 (28.1) 134 (25.4) 12 (2.3)
Number of i.v. doses administered 1 2 3 4 5
59 93 169 0 0
102 145 276 3 1
Number of SC doses administered 1 2 3
71 8 1
111 42 7
Duration of treatment Mean, days (range)
193.8 (15–345)
202.3 (12–406)
OA, osteoarthritis; i.v., intravenous; SC, subcutaneous. a At parent study baseline.
the greatest improvements upon switching to 10 mg (Fig. 3B) or 20 mg tanezumab (Fig. 3C). In addition, few patients (25/848; 2.9%) discontinued due to lack of efficacy, further indicating that tanezumab treatment had persistent effectiveness. Sustained improvements in other effectiveness endpoints, including RMDQ and PGA, were also observed during the extension study, with the greatest improvement generally occurring at week 4 (data not shown). In addition, percentages of patients with P 30%, P 50%, P 70%, and P 90% reduction in BPI average pain remained high throughout the extension study. At week 24, the percentages of responders were similar, with tanezumab 10-mg and 20-mg treatment across all categories (Fig. 4). 3.2. Safety Overall incidence of adverse events and discontinuations due to an adverse event (all causalities) was higher with tanezumab 20 mg than with tanezumab 10 mg (Table 2). Paresthesia was the most frequent reason for discontinuation and occurred in 2 patients (0.6%) in the tanezumab 10-mg treatment group and 7 patients (1.3%) in the tanezumab 20-mg treatment group. Two patients died during the study and 1 patient died 4 days after withdrawing from the study (all had received tanezumab 20 mg). No death was considered related to the study drug. The first patient was an 85-year-old woman who died as a result of lung cancer.
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The second patient, a 78-year-old woman, died as a result of cardiac arrest. A third patient, an 84-year-old woman who discontinued the study on day 91 (no longer willing to participate), died from natural causes on study day 95. The percentage of patients reporting a serious adverse event was similar (Table 2). Serious adverse events were considered related to treatment in 5 patients (1.6%) in the tanezumab 10-mg group and in 5 patients (0.9%) in the tanezumab 20-mg group. The most frequently reported serious adverse event was OA (3 patients in each group), which met the criteria for a serious adverse event due to hospitalization for joint replacement surgery. Adverse events of abnormal peripheral sensation occurred at a higher incidence in the tanezumab 20-mg group (Table 3). Most (71.7%) adverse events of abnormal peripheral sensation resolved before last patient contact and most were mild to moderate in intensity. The majority of patients (89.2% and 91.5% in the tanezumab 10-mg and tanezumab 20-mg groups, respectively) had no new or worsened abnormalities in their final neurological examination (Table 4). Few patients had a clinically significant new or worsened abnormality at the last neurological examination (tanezumab 10 mg: 3.2%; tanezumab 20 mg: 1.7%). A total of 156 patients had adverse events of abnormal peripheral sensation or clinically significant new or worsened abnormality upon the neurological examination and were therefore referred for neurological consultation (Table 4). Altogether, 7.2% of patients were categorized by the consulting neurologist, with findings suggestive of a new or worsened peripheral neuropathy based on symptoms, clinically significant signs, or diagnostic tests at final neurological consultation. Adverse events initially described as osteonecrosis were reported by 6 patients (tanezumab 10 mg, n = 2 [0.6%]; tanezumab 20 mg, n = 4 [0.8%]; Fig. 5). Three of 6 patients with reported osteonecrosis had documented evidence of OA in the affected joint before enrolling in the parent study, 1 patient had a history of trauma in the affected joint, and the other 2 patients had insufficient information to determine whether OA was present in the affected joint at entry into the parent study. Four of the 6 patients with reported osteonecrosis underwent TJR. Nine additional patients (tanezumab 10 mg, n = 7 [2.2%]; tanezumab 20 mg, n = 2 [0.4%]) underwent TJR without osteonecrosis reported as an adverse event. Seven of these had history of OA, and 1 patient had history of knee pain; the remaining patient who underwent TJR did not have documented OA or prestudy X-rays. All 6 patients with reported osteonecrosis, and 4/9 patients undergoing TJR were evaluated by the adjudication committee. No patients were subsequently adjudicated as having primary osteonecrosis (Fig. 5). Instead, adjudication outcomes were worsening OA (n = 5), another diagnosis (n = 3), or lack of consensus and/or insufficient information to reach a conclusion (n = 2). Of the 5 patients adjudicated to worsening OA, 2 were adjudicated to normal progression of OA, 1 patient with a prior history of severe lateral knee OA in the affected joint was adjudicated to rapid progression of OA, and 2 patients had insufficient information to distinguish between rapid and normal OA progression. For the 3 patients adjudicated to another diagnosis, 1 had posttraumatic OA of the left ankle, 1 had posttraumatic fracture of the knee secondary to trauma, and 1 had a subchondral fracture of the lateral femoral condyle. Of the 15 patients with either investigatorreported osteonecrosis or TJR, 7 took NSAIDs at some time while they were treated with tanezumab in this study. The 1 patient adjudicated to rapid progression of OA had no history of concomitant NSAID use. Long-term tanezumab treatment was not associated with any meaningful changes in clinical laboratory values, vital signs, or electrocardiogram results.
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Fig. 3. Change from baseline in average Brief Pain Inventory Short Form score for all parent study patients who participated in extension study (A), patients receiving tanezumab 10 mg (B), or tanezumab 20 mg (C) in extension study by parent study treatment (ITT, observed data). BL, baseline; ITT, intent-to-treat. aGap between studies P 8 weeks and < 12 weeks. bPatients treated with either tanezumab 5 mg or 10 mg in parent study. cPatients treated with either tanezumab 5 mg or 20 mg in parent study.
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Fig. 4. Percentage of patients with P 30%, P 50%, P 70%, and P 90% reduction in Brief Pain Inventory average pain at week 24.
4. Discussion This randomized, parallel-group, multicenter study evaluated the long-term safety and effectiveness of tanezumab at doses of 10 mg and 20 mg in patients with chronic low back pain. The duration of chronic low back pain (nonspecific chronic low back pain with a duration averaging longer than 10 years), baseline pain scores, and functional impairment as measured by the RMDQ at entry in the parent study indicate this patient population had moderate-to-severe pain and disability despite daily treatment with an analgesic medication [18]. The most frequent reason for discontinuation was early study termination by the sponsor. Few patients who discontinued did so due to lack of efficacy, indicating a sustained analgesic effect of tanezumab. A decrease in the BPI-SF average pain from parent study baseline occurred during this study, with a peak at week 4. This improvement was sustained over 24 weeks of treatment in the extension study. Long-term effectiveness of tanezumab was Table 2 Incidence of adverse events, n (%).
Patients with adverse eventsa Patients with serious adverse events Patients discontinued due to adverse events
Tanezumab 10 mg n = 321
Tanezumab 20 mg n = 527
198 (61.7) 15 (4.7) 20 (6.2)
370 (70.2) 24 (4.6) 39 (7.4)
b
Adverse events occurring in P 3% in any group Arthralgia 41 (12.8) Paresthesia 31 (9.7) Hypoesthesia 23 (7.2) Pain in extremity 12 (3.7) Peripheral edema 11 (3.4) Headache 10 (3.1) Upper respiratory tract infection 11 (3.4) Musculoskeletal pain 14 (4.4) Diarrhea 6 (1.9) Myalgia 6 (1.9) Infusion site reaction 12 (3.7) Back pain 10 (3.1) Muscle strain 8 (2.5) Joint swelling 6 (1.9) Osteoarthritis 11 (3.4) Sinusitis 12 (3.7)
77 56 41 39 32 27 26 23 18 18 17 17 17 17 16 14
(14.6) (10.6) (7.8) (7.4) (6.1) (5.1) (4.9) (4.4) (3.4) (3.4) (3.2) (3.2) (3.2) (3.2) (3.0) (2.7)
a An adverse event was defined as one that started during this study (even if a separate event of the same adverse event term occurred in the parent study) or started during the parent study and worsened in this study. b Presentation order for adverse events based on incidence in the tanezumab 20-mg group.
supported by the categorical assessment of the BPI-SF average pain as measured by the percentage of patients with P 30%, P 50%, P 70%, or P 90% change from baseline. Clinically meaningful pain relief has been defined by others as a reduction in pain intensity of approximately 30% from baseline [28,29]. At week 24 in this study, more than 60% of patients had P 50% reduction in pain score, and thus, had clinically meaningful pain reduction. Similarly, sustained improvements were also observed for RMDQ and PGA of low back pain from week 4 through week 24 of the extension study. Across all effectiveness endpoints, no consistent benefit of 20 mg tanezumab over 10 mg tanezumab was noted. The adverse event profile was consistent with the parent study [18] and other long-term tanezumab studies [11,30]. The percentage of patients with a serious adverse event was similar in both groups, although these events were more frequently reported than in the parent study due to occurrence of serious adverse events initially reported as osteonecrosis or TJR in the extension study. Per study protocol, all patients reporting abnormal peripheral sensations, pain in extremity, or those with clinically significant neurological examination findings underwent examination by a neurologist. Rates of adverse events of peripheral polyneuropathies and neurological consultation categorizations of new or worsened peripheral neuropathies for the extension study were similar to those reported during the parent study [18], indicating that longer duration tanezumab treatment was not associated with additional peripheral neuropathy safety concerns. During the conduct of clinical studies of tanezumab and other NGF inhibitors in subjects with OA pain, a signal event initially described by investigators as osteonecrosis often leading to TJR raised concerns about joint-related safety of tanezumab and led to a partial clinical hold by the FDA on the entire NGF inhibitor class. Reports of osteonecrosis and other documented TJRs underwent careful and thorough investigation by an independent, expert adjudication committee [16,24]. No evidence was found to indicate that tanezumab is associated with an increased risk of osteonecrosis, a disease process quite distinct from osteoarthritis, although a
Table 3 Incidence of adverse events of abnormal peripheral sensation, n (%). Tanezumab 10 mg n = 321 Adverse events of abnormal peripheral sensationa,b Paresthesia 31 (9.7) Hypoesthesia 23 (7.2) Decreased vibratory sense 2 (0.6) Hyperesthesia 3 (0.9) Allodynia 0 Burning sensation 2 (0.6) Dysesthesia 1 (0.3) Neuropathy peripheral 1 (0.3) Sensory disturbance 4 (1.2) Hypoesthesia oral 0 Paresthesia oral 0 Neuralgia 0 Peripheral sensorimotor neuropathy 0 Polyneuropathy 0 Formication 1 (0.3)
Tanezumab 20 mg n = 527 56 (10.6) 41 (7.8) 14 (2.7) 11 (2.1) 11 (2.1) 8 (1.5) 7 (1.3) 7 (1.3) 2 (0.4) 1 (0.2) 1 (0.2) 1 (0.2) 1 (0.2) 1 (0.2) 0
a Adverse events of abnormal peripheral sensation included allodynia, axonal neuropathy, burning sensation, decreased vibratory sense, demyelinating polyneuropathy, dysesthesia, formication, hyperesthesia, hyperpathia, hypoesthesia, hypoesthesia facial, hypoesthesia oral, intercostal neuralgia, neuralgia, neuritis, neuropathy peripheral, paresthesia, paresthesia oral, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, polyneuropathy, polyneuropathy chronic, sensory disturbance, sensory loss, and thermohypoesthesia. b Presentation order for adverse events based on incidence in the tanezumab 20-mg group.
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Table 4 Summary of final neurological examinations and neurological consultations (intentto-treat population, observed data)a. Tanezumab 10 mg n = 321
Tanezumab 20 mg n = 527
Final neurological examination assessments, n (%) New or worsened abnormality Clinically significant Not clinically significant Total No new or worsened abnormality
10 (3.2) 24 (7.6) 34 (10.8) 282 (89.2)
9 (1.7) 35 (6.8) 44 (8.5) 471 (91.5)
Final neurological consultation categorization, n (%) Patients referred for consultation 46 (14.3)
110 (20.9)
Suggestive of new or worsened peripheral neuropathy, n (%) Total 19 (5.9) Based on symptoms only 4 (1.2) Based on clinically significant signs only 4 (1.2) Based on diagnostic tests 11 (3.4) Other neurological symptoms or signs 16 (5.0) No neurological symptoms or signs 11 (3.4)
42 (8.0) 8 (1.5) 7 (1.3) 27 (5.1) 41 (7.8) 27 (5.1)
a Neurological examinations were performed per protocol by study investigators. Neurological consultations were performed by neurologists following a neurological adverse event report or after significant neurological examination abnormalities were detected by investigators.
risk of rapidly progressive osteoarthritis was identified [23]. On March 12, 2012, the FDA Arthritis Advisory Committee reviewed these results, as well as those prepared by the FDA [13,14]. The
committee endorsed continued clinical development of the NGF inhibitor class of compounds, with additional measures to minimize the risk and further protect patient safety. On August 28, 2012, the FDA lifted the partial clinical hold on tanezumab related to joint safety. In this study, 6 patients reported adverse events initially classified as osteonecrosis, and 9 other patients underwent TJR related to OA. The adjudication committee reviewed all 6 of the patients reporting osteonecrosis and 4 of the 9 patients with TJR; none were adjudicated by the committee to primary osteonecrosis. One patient was adjudicated to rapidly progressive osteoarthritis. In conclusion, in patients with chronic low back pain, tanezumab i.v. and s.c. had a safety profile that was consistent with other clinical trials with tanezumab. Although both tanezumab 10 mg and 20 mg provided sustained effectiveness, tanezumab 10 mg had better tolerability. Tanezumab provided sustained pain relief, improvement in physical functioning, and improvement in global assessment of chronic low back pain in this long-term extension study. No new safety concerns were identified with long-term tanezumab use. Tanezumab may represent an effective long-term treatment for chronic low back pain. Conflict of interest statement Candace Bramson, Mary Anne Nemeth, David S. Keller, Mark T. Brown, Christine R. West, and Kenneth M. Verburg are employees of and hold stock options, restricted stock units, or stock in Pfizer Inc, and Alan Kivitz owns Pfizer stock.
Patients with TJR or investigatorreported AEs of ON, n = 15 Tanezumab 10 mg, n = 9 Tanezumab 20 mg, n = 6
Patients not adjudicated, n = 0
Patients with reported ON Tanezumab 10 mg, n = 2 Tanezumab 20 mg, n = 4
6/6 (100%)
Patients with TJR related to OA Tanezumab 10 mg, n = 7 Tanezumab 20 mg, n = 2
Patients not adjudicated, n = 5 X-rays unavailable, n = 3 Reported TJR after cutoff date, n = 2
4/9 (44%)
Patients adjudicated, n = 10 Tanezumab 10 mg, n (%) 5 (55.6) Tanezumab 20 mg, n (%) 5 (83.3)
Other diagnosis, n = 3 Subchondral fracture, knee, (tanezumab 20 mg), n = 1 Post-traumatic OA, ankle, (tanezumab 10 mg), n = 1 Post-traumatic fracture, knee, (tanezumab 20 mg), n = 1
Normal progression of OA, n = 2 Tanezumab 10 mg, n = 2 Tanezumab 20 mg, n = 0
Worsening OA, n = 5 Tanezumab 10 mg, n = 4 Tanezumab 20 mg, n = 1
Rapid progression of OA, n = 1 Tanezumab 10 mg, n = 0 Tanezumab 20 mg, n = 1
Lack of consensus or insufficient information to distinguish ON from worsening OA, n = 2 Tanezumab 10 mg, n = 0 Tanezumab 20 mg, n = 2
Insufficient information to determine rate of progression, n = 2 Tanezumab 10 mg, n = 2 Tanezumab 20 mg, n = 0
Fig. 5. Adjudication outcomes of joint safety events. OA, osteoarthritis; ON, osteonecrosis; TJR, total joint replacement.
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