SYNOPSIS
Name of Sponsor/Company

Daiichi Sankyo Co., Ltd.

Name of Finished Product

NARURAPID® TABLETS

Name of Active Ingredienthydromorphone hydrochloride (INN)

Title of Study

DS-7113b phase III study
A randomized double-blind comparison study with immediate
release (IR) oxycodone in opioid-naive patients with cancer pain

Investigators-Study Centre(s)50 sites

Publication (reference)
Studied Period

December 2013 – October 2014

Phase of Development

Phase 3

Objectives

To evaluate the efficacy and safety of DS-7113b IR tablet
additionally dosed in a randomized double-blind comparison study
with IR oxycodone in opioid-naive patients under cancer pain
management refractory to non-opioid analgesics.

Methodology

A multicenter, active controlled, randomized, double-blind,parallel-group study

Number of Patients (planned

Planned:180 subjectsand analyzed)

Analyzed: 172 subjects

Diagnosis and Main Criteria

Inclusion:

for Inclusion

・ Patients receiving non-opioid analgesics for cancer pain, whohave not been receiving opioid analgesics
・ Patients whose VAS is ≥ 35 mm and judged necessary to betreated with strong opioid analgesics
・ Patients with an ECOG Performance Status (PS) is ≤ 3, etc.
Exclusion:
・ Patients with serious hepatic, renal, or respiratory
disorder.
・ Patients with symptom(s)/finding(s) falling under thecontraindications or relative contraindications stated in thepackage insert for oxycodone hydrochloride powder andmorphine hydrochloride preparations, etc.

Test Product, Dose and Mode

Test product (batch number):of Administration, Batch

DS-7113b tablet 1 mg (D7113T1H12T05)

Number

DS-7113b tablet 2 mg (D7113T1H12T06)
DS-7113b tablet 4 mg (D7113T1H12T07)

Dosage and Administration:
As in the table below, subjects received a hydromorphone tablet ora placebo tablet orally four times daily for 5 days. The initial dosesof hydromorphone hydrochloride was 4 mg/day. When it wasjudged that a dose increase or reduce was necessary during theperiod of study drug administration, it was possible to increase orreduce the dose step by step.
Daily dose

Duration of Treatment

14 mg

28 mg

312 mg

416 mgTreatment period: 5 days
Post-treatment obsevation period: 1 day

Reference Therapy, Dose andReference Therapy (batch number):Mode

Oxycodone hydrochloride powder 2.5 mg (W3078)

ofAdministration,

Batch Number

Oxycodone hydrochloride powder 5 mg (W3107)
Dosage and Administration:
As in the table below, subjects received oxycodone hydrochloride
powder or placebo powder orally four times daily for 5 days. The
initial doses of oxycodone hydrochloride was 10 mg/day. When it
was judged that a dose increase or reduce was necessary during theperiod of study drug administration, it was possible to increase orreduce the dose step by step.
Daily dose

Criteria for Evaluation

110 mg

220 mg

340 mg

460 mgEfficacy: Change of VAS between pre-treatment and end oftreatment (Primary endpoint)
Safety: Adverse event, Clinical laboratory evaluation

Statistical Method

Primary endpoint:
Summary statistics were calculated for VAS scores at baseline, at
treatment completion/discontinuation and for the change in VAS
scores. Analysis of covariance (ANCOVA) was conducted using
the baseline VAS scores as a covariate to calculate the 95% CI

(two-sided) for a difference in the least squares mean in themagnitude of change in VAS scores between the hydromorphoneand oxycodone groups. P-values and least squares means for eachgroup were calculated.
Summary - Conclusion

The intergroup difference (95% CI) in the least squares meanfor the change in VAS scores at completion/discontinuation oftreatment was −3.4 mm (−9.8 to 3.1 mm). Given that theupper limit of the 95% CI was <10 mm, the non-inferioritylimit determined at the time of planning. Therefore, thenon-inferiority of hydromorphone relative to oxycodone wassuggested.

The incidence of adverse events was 83.0% in thehydromorphone group and 77.4% in the oxycodone group. No
significant intergroup differences of the incidence of adverse
event and serious adverse event were observed.

Therefore, the efficacy and safety of hydromorphone tablets arecomparable to those of oxycodone immediate-release formulation.
Date of Report

March 26, 2018