Tanezumab for Chronic low Back Pain: A Long-Term, Randomized, Celecoxib-Controlled Japanese Phase III Safety Study

Figures & data

Figure 1. Study design.

Subcutaneous treatment was administered every 8 weeks and oral treatment was administered daily at a dosage of 200 mg/day (100 mg twice daily). Prior to receiving treatment at week 16, patients must have had a ≥30% reduction from baseline in LBPI score at week 16 and a ≥15% reduction from baseline in LBPI score at any week from week 1 to week 15 to continue the study.

LBPI: Low back pain intensity; SC: Subcutaneous.

Table 1. Concomitant medication protocols.

• Patients were required to discontinue all analgesics (except stable doses of muscle relaxants, pregabalin, gabapentin and antidepressants that were initiated ≥30 days prior to screening) for the treatment of CLBP until week 16

• Aspirin (>324 mg/day) and opioids were prohibited through week 64

• NSAID use (prescription and over the counter) was prohibited through week 64. During this time, patients reporting NSAID use due to insufficient relief of CLBP were withdrawn from the study. Patients reporting >10 days (aggregate total) of NSAID use for conditions other than CLBP in an 8-week SC dosing interval, and who reported further NSAID use after counseling, were also withdrawn from study medication and entered into the safety follow-up period

• Both systemic corticosteroids and corticosteroid injections into the back were prohibited through week 80

• Rescue medication (acetaminophen) was allowed up to 3 days/week at a dosage of ≤3000 mg/day from baseline to week 16. Rescue medication could be taken daily after week 16 up to a maximum of 3000 mg/day (weeks 16–64) or 4000 mg/day (after week 64)

CLBP: Chronic low back pain; NSAID: Nonsteroidal anti-inflammatory drug; SC: Subcutaneous.

Figure 2. Patient disposition.

The diagram shows the flow of patients throughout the trial. Data are number (%) of patients.

*Two patients were screened but withdrew consent prior to randomization.

^†If a patient withdrew due to efficacy reasons other than the specific criteria at week 16 (see Results section), the reason was classified as ‘insufficient clinical response’.

^‡Patients completed the study if they completed the safety follow-up period, regardless of whether they completed the treatment phase.

Table 2. Patient demographics and baseline characteristics.

Characteristic	Tanezumab 5 mg (n = 92)	Tanezumab 10 mg (n = 93)	Celecoxib 200 mg (n = 92)
Sex, n (%)   Male   Female	55 (59.8) 37 (40.2)	49 (52.7) 44 (47.3)	54 (58.7) 38 (41.3)
Asian race, n (%)	92 (100.0)	93 (100.0)	92 (100.0)
Age, years   Mean (range)	53.3 (22–79)	52.3 (21–78)	54.3 (19–81)
Mean (SD) duration since low back pain diagnosis, years	8.9 (8.8)	7.7 (9.1)	9.1 (10.5)
Mean (SD) BMI, kg/m^2	24.1 (3.9)	23.9 (4.2)	23.9 (3.6)
Mean (SD) baseline PainDetect score^†	6.79 (5.74)	6.71 (5.21)	7.36 (5.76)
PainDetect category, n (%)   ≤12   13–18   ≥19	80 (87.0) 5 (5.4) 7 (7.6)	79 (84.9) 10 (10.8) 4 (4.3)	78 (84.8) 8 (8.7) 6 (6.5)
Quebec Task Force, n (%)   Category 1: Pain without radiation   Category 2: Pain with radiation to extremity, proximally   Category 3 or greater	77 (83.7) 15 (16.3) 0	82 (88.2) 11 (11.8) 0	79 (85.9) 13 (14.1) 0
Primary etiology assessment, n (%)   Degenerative disc disease   Degenerative joint disease/OA   Injury/Muscle strain   Other	32 (34.8) 13 (14.1) 6 (6.5) 41 (44.6)	40 (43.0) 11 (11.8) 0 42 (45.2)	38 (41.3) 17 (18.5) 1 (1.1) 36 (39.1)
Mean (SD) baseline LBPI score^‡	6.74 (0.97)	6.82 (1.09)	6.72 (1.00)
Mean (SD) baseline RMDQ score^§	8.27 (5.02)	8.12 (4.86)	7.75 (4.95)
NSAID treatment prior to start of study, n (%)   Celecoxib   Loxoprofen^¶   Meloxicam	80 (87.0) 47 (51.1) 0	83 (89.2) 48 (51.6) 1 (1.1)	84 (91.3) 47 (51.1) 1 (1.1)

† PainDetect is a tool to screen for the prevalence of neuropathic pain components in CLBP patients, with scores ranging from -1 to 38; a score of ≤12 indicates that a neuropathic component is unlikely; scores ≥19 indicate a neuropathic component is likely.

‡ Scores range from 0 = no pain to 10 = worst possible pain.

§ Scores range from 0 to 24 with lower score indicating better function.

¶ Also includes the terms loxoprofen sodium and loxoprofen sodium dihydrate.

BMI: Body mass index; LBPI: Low back pain intensity; NSAID: Nonsteroidal anti-inflammatory drug; OA: Osteoarthritis; RMDQ: Roland Morris disability questionnaire; SD: Standard deviation.

Table 3. Summary of all-causality TEAEs through week 56 (treatment period).

Number (%) of patients	Tanezumab 5 mg (n = 92)	Tanezumab 10 mg (n = 93)	Celecoxib 200 mg (n = 92)
Any TEAE	58 (63.0)	51 (54.8)	62 (67.4)
Serious TEAE	4 (4.3)	9 (9.7)	2 (2.2)
Severe TEAE	3 (3.3)	2 (2.2)	1 (1.1)
Treatment discontinuation due to TEAE	3 (3.3)	5 (5.4)	4 (4.3)
Study discontinuation due to TEAE	1 (1.1)	1 (1.1)	0
Most common TEAEs^†   Nasopharyngitis   Back pain   Fall   Contusion   Arthralgia   Intervertebral disc protrusion   Headache   Hypoesthesia   Pain in extremity   Myalgia   Pyrexia   Diarrhea   Gastroenteritis   Musculoskeletal pain   Pneumonia   Hypertension	14 (15.2) 4 (4.3) 6 (6.5) 3 (3.3) 5 (5.4) 2 (2.2) 2 (2.2) 5 (5.4) 3 (3.3) 3 (3.3) 2 (2.2) 1 (1.1) 1 (1.1) 3 (3.3) 3 (3.3) 2 (2.2)	13 (14.0) 5 (5.4) 4 (4.3) 4 (4.3) 3 (3.2) 3 (3.2) 3 (3.2) 2 (2.2) 1 (1.1) 1 (1.1) 1 (1.1) 1 (1.1) 1 (1.1) 0 0 0	6 (6.5) 4 (4.3) 3 (3.3) 2 (2.2) 6 (6.5) 3 (3.3) 2 (2.2) 3 (3.3) 3 (3.3) 1 (1.1) 4 (4.3) 3 (3.3) 3 (3.3) 3 (3.3) 1 (1.1) 3 (3.3)

† Reported in ≥3% of patients in any treatment group.

TEAE: Treatment-emergent adverse event.

Table 4. Summary of TEAEs of abnormal peripheral sensation through week 56 (treatment period).

Number (%) of patients	Tanezumab 5 mg (n = 92)	Tanezumab 10 mg (n = 93)	Celecoxib 200 mg (n = 92)
Any TEAE	9 (9.8)	4 (4.3)	4 (4.3)
Treatment discontinuation due to TEAE	0	0	1 (1.1)
Specific TEAE^†   Hypoesthesia   Carpal tunnel syndrome   Dysesthesia   Neuralgia   Sciatica   Paresthesia	5 (5.4) 1 (1.1) 1 (1.1) 1 (1.1) 1 (1.1) 0	2 (2.2) 2 (2.2) 0 0 0 1 (1.1)	3 (3.3) 0 0 0 1 (1.1) 0

Terms included in this analysis were: allodynia; axonal neuropathy; burning sensation; carpal tunnel syndrome; decreased vibratory sense; demyelinating polyneuropathy; dysesthesia; formication; hyperesthesia; hyperpathia; hypoesthesia; hypoesthesia oral; intercostal neuralgia; neuralgia; neuritis; neuropathy peripheral; paresthesia; paresthesia oral; peripheral sensorimotor neuropathy; peripheral sensory neuropathy; polyneuropathy; polyneuropathy chronic; sciatica; sensory disturbance; sensory loss; tarsal tunnel syndrome; thermohypoesthesia.

† Patients could have more than one specific TEAE of abnormal peripheral sensation.

TEAE: Treatment-emergent adverse event.

Table 5. Summary of TEAEs of possible decreased sympathetic function through week 56 (treatment period).

Number (%) of patients	Tanezumab 5 mg (n = 92)	Tanezumab 10 mg (n = 93)	Celecoxib 200 mg (n = 92)
Any TEAE	3 (3.3)	4 (4.3)	7 (7.6)
Treatment discontinuation due to TEAE	0	0	1 (1.1)
Specific TEAE^†   Bradycardia   Diarrhea   Nausea   Abdominal discomfort   Orthostatic hypotension   Presyncope   Vomiting	2 (2.2) 1 (1.1) 1 (1.1) 0 0 0 0	0 1 (1.1) 1 (1.1) 0 2 (2.2) 0 0	1 (1.1) 3 (3.3) 0 1 (1.1) 1 (1.1) 1 (1.1) 1 (1.1)

Terms included in this analysis were: abdominal discomfort; anal incontinence; anhidrosis; blood pressure orthostatic decreased; bradycardia; diarrhea; dizziness postural; early satiety; ejaculation delayed; ejaculation disorder; ejaculation failure; heart rate decreased; hypertonic bladder; hypohidrosis; micturition urgency; nausea; nocturia; orthostatic hypotension; pollakiuria; presyncope; respiratory distress; respiratory failure; sinus bradycardia; syncope; urinary hesitation; urinary incontinence; vomiting.

† Patients could have more than one specific TEAE of possible decreased sympathetic function.

TEAE: Treatment-emergent adverse event.

Table 6. Summary of joint safety through week 80 (treatment + follow-up period).

Number (%) of patients	Tanezumab 5 mg (n = 92)	Tanezumab 10 mg (n = 93)	Celecoxib 200 mg (n = 92)
Analyzed by adjudication committee	2 (2.2)	2 (2.2)	1 (1.1)
Composite joint safety end point   RPOA^†    RPOA type 1    RPOA type 2   Subchondral insufficiency fracture   Primary osteonecrosis   Pathological fracture	1 (1.1) 1 (1.1) 1 (1.1) 0 0 0 0	2 (2.2) 1 (1.1) 0 1 (1.1) 1 (1.1) 0 0	0 0 0 0 0 0 0
Normal progression of OA	0	0	0
Other joint outcome^‡	1 (1.1)	0	1 (1.1)

† RPOA type 1 was defined as a significant loss of joint space width ≥2 mm within approximately 1 year, without gross structural failure. RPOA type 2 was defined as abnormal bone loss or destruction, including limited or total collapse of at least one subchondral surface, which is not normally present in conventional end-stage osteoarthritis [25].

‡ Other joint outcomes included pre-existing subchondral insufficiency fracture (tanezumab 5 mg) and pre-existing arthroplasty (celecoxib).

OA: Osteoarthritis; RPOA: Rapidly progressive osteoarthritis.

Figure 3. Change in low back pain intensity and Roland Morris disability questionnaire scores from baseline to week 56.

The graphs show LS mean change from baseline in (A) LBPI and (B) RMDQ scores throughout the trial. No formal statistical hypothesis testing was performed.

LBPI: Low back pain intensity; LS: Least squares; RMDQ: Roland Morris disability questionnaire; SE: Standard error.

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Data sharing statement

The authors certify that this manuscript reports original clinical trial data, NCT02725411. Upon request, and patient to certain criteria, conditions and exceptions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual de-identified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines and medical devices (1) for indications that have been approved in the US and/or EU or (2) in programs that have been terminated (i.e., development for all indications has been discontinued). Pfizer and Lilly will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The de-identified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer.