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A Dose-response Study of AMG 162 (Denosumab) in Patients with Rheumatoid Arthritis on Methotrexate (MTX) to Validate Inhibitory Effect on Bone Erosion (Phase II)

DRIVE

346

The FAS (340 subjects) were female subjects 78.2%, male subjects 21.8%, mean age (standard deviation) 54.5 (10.92) years, height 158.20 (7.261) cm, body weight 56.80 (10.658) kg, duration of RA 2.25 (1.326) years, weekly MTX dose 8.05 (2.007) mg, baseline RF positive 68.2%, baseline RF negative 31.8%, baseline use of corticosteroids 43.2%, no baseline use of corticosteroids 56.8%, presence of concurrent osteoporosis 16.8%, and absence of concurrent osteoporosis 83.2%. Subjects were stratified at randomization according to baseline RF positive/negative and baseline use of corticosteroids. Sex, age, and concurrent osteoporosis, which were not stratification factors, appeared to be unbalanced, and the proportion of female and elderly subjects tended to be high in the placebo group. No significant imbalance was noted between the treatment groups in other items.

A total of 350 subjects were randomized (placebo group: 88 subjects, denosumab 60 mg Q6M group: 87 subjects, Q3M group: 87 subjects, Q2M group: 88 subjects), and 346 subjects of them received the study drug (placebo group: 88 subjects, Q6M group: 86 subjects, Q3M group: 85 subjects, Q2M group: 87 subjects). A total of 35 subjects discontinued the study, and 311 subjects completed the study (placebo group: 82 subjects, Q6M group: 78 subjects, Q3M group: 72 subjects, Q2M group: 79 subjects).

The incidence of adverse events was 83.0% (73/88 subjects), 80.2% (69/86 subjects), 76.5% (65/85 subjects), and 94.3% (82/87 subjects) in the placebo, Q6M, Q3M, and Q2M groups, respectively. Of these events, the incidence of adverse events judged to be related to the study drug was 18.2% (16/88 subjects), 18.6% (16/86 subjects), 14.1% (12/85 subjects), and 20.7% (18/87 subjects), respectively. No fatal adverse events occurred. The incidence of serious adverse events was 10.2% (9/88 subjects), 4.7% (4/86 subjects), 7.1% (6/85 subjects), and 9.2% (8/87 subjects) in the placebo, Q6M, Q3M, and Q2M groups, respectively.

The arithmetic mean (standard deviation) of changes in bone erosion score from baseline at Month 12 (which was the primary endpoint) was 0.990 (2.6872), 0.269 (0.9800), 0.140 (0.5345), and 0.085 (1.5204) in the placebo, Q6M, Q3M, and Q2M groups, respectively. (Q6M group: P = 0.0082, Q3M group: P = 0.0036, Q2M group: P < 0.0001).

The bone erosion score was significantly lower in all AMG 162 groups than in the placebo group at Month 6. No differences were observed in the change in JSN score from baseline at Months 6 and 12 between any AMG 162 group and the placebo group. Administration of AMG 162 did not have any negative impact on the JSN score. The change in TSS from baseline at Month 12 was significantly smaller in all AMG 162 groups than in the placebo group. At Month 6, the change was significantly smaller in the Q2M group than in the placebo group. Results supporting the above data were obtained as to the progression of the bone erosion score, JSN score, and TSS. The percent change from baseline in the BMD of lumbar spine L1 to L4 and total hip showed a significant increase in all AMG 162 groups compared with that in the placebo group.

In a placebo-controlled study, AMG 162 60 mg was subcutaneously administered for 12 months in RA patients on MTX therapy. AMG 162 showed a significant inhibitory effect on progression of bone erosion compared with that of placebo, and the change in bone erosion score were the smallest in the Q2M group, followed by the Q3M and Q6M groups. In the safety assessment, AMG 162 60 mg was well tolerated in the Q6M, Q3M and Q2M regimens.

Nov. 19, 2015

https://ard.bmj.com/content/75/6/983.long

Yes

Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/ Supporting Documents: - Study Protocol - Statistical Analysis Plan - Clinical Study Report Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication. Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent. URL: https://vivli.org/ourmember/daiichi-sankyo/

DAIICHI SANKYO Co.,Ltd.

dsclinicaltrial@daiichisankyo.co.jp

DAIICHI SANKYO Co.,Ltd.

dsclinicaltrial@daiichisankyo.co.jp

completed

Oct. 29, 2010

Interventional

randomized, double-blind, placebo-controlled study

treatment purpose

2

-Ambulatory outpatients who are diagnosed with rheumatoid arthritis according to the American College of Rheumatology (ACR) criteria for rheumatoid arthritis classification (1987 revision)

-Functional class IV according by the ACR revised classification (1991)

Both

Rheumatoid Arthritis

investigational material(s)
Generic name etc : AMG 162
INN of investigational material : Denosumab
Therapeutic category code : 399 Agents affecting metabolism, n.e.c.
Dosage and Administration for Investigational material : AMG 162 60 mg administered subcutaneously - Every 6 months/ Every 3 months/ Every 2 months

control material(s)
Generic name etc : Placebo
INN of investigational material : -
Therapeutic category code : --- Other
Dosage and Administration for Investigational material : Subcutaneously for placebo

safety
efficacy
confirmatory
Erosion Score
modified Sharp

efficacy
pharmacokinetics
1:Total Sharp Score,Joint Space Narrowing score
2:Bone Mineral Density
3:Pharmacokinetics (Serum AMG 162 concentration)

1:modified Sharp
2:DXA

Sept. 21, 2010