SYNOPSIS
Name of Sponsor/Company

Daiichi Sankyo Co., Ltd.

Name of Finished Product

NARUSUS® TABLETS

Name of Active Ingredienthydromorphone hydrochloride (INN)

Title of Study

DS-7113b extended-release (ER) tablet phase III study
Arandomized

double-blind

comparison

study

withextended-release oxycodone in opioid-naive patients with cancer
pain
Investigators-Study Centre(s)49 sites

Publication (reference)

J Pain Res. 2017 Aug 18;10:1953-1962
A randomized, double-blind study of hydromorphonehydrochloride extended-release tablets versus oxycodonehydrochloride extended-release tablets for cancer pain:
efficacy and safety in Japanese cancer patients (EXHEAL:a Phase III study of EXtended-release HydromorphonE forcAncer pain reLief)

Studied PeriodOctober 2014 – September 2015

Phase of Development

Phase 3

Objectives

To evaluate the efficacy and safety of DS-7113b ER tablet
additionally dosed in a randomized double-blind comparison study
with ER 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 (plannedPlanned:180 subjects

and analyzed)

Analyzed: 178 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 thecontraindications 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 ER tablet 2 mg（D7113T2H14M01 ）Number

DS-7113b ER tablet 6 mg（D7113T2H14M03 ）DS-7113b ER tablet 12 mg（D7113T2H14M05 ）DS-7113b ER tablet 24 mg（D7113T2H14M07 ）Dosage and Administration:
As in the table below, subjects received a hydromorphone ER
tablet or a placebo tablet orally once daily for 7 days. The initial
doses of hydromorphone hydrochloride was 4 mg/day. When itwas 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 doseDuration of Treatment

14 mg

28 mg

38 mg

412 mg

516 mg624 mgTreatment period: 7 days
Post-treatment observation period: 1 day

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

Oxycodone hydrochloride ER tablet 5 mg（3462）

ofBatch Number

Administration,Oxycodone hydrochloride ER tablet 10 mg（3456）
Oxycodone hydrochloride ER tablet 20 mg（3435）
Dosage and Administration:
As in the table below, subjects received oxycodone hydrochloride
ER tablet or placebo tablet orally once daily for 7 days. The initial
doses of oxycodone hydrochloride was 10 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
110 mgCriteria for Evaluation

220 mg

340 mg

460 mg

560 mg

680 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, attreatment 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 hydromorphone
and oxycodone groups VAS score, and ensured that the upper limit
did not exceed 10 mm, which was defined as the non-inferioritylimit. P-values and least squares means for each group werecalculated.

Summary - Conclusion

The intergroup difference (95% CI) in the least squares mean
for the change in VAS scores at completion/discontinuation oftreatment was −0.4 mm (−5.9 to 5.0 mm). Given that theupper limit of the 95% CI was <10 mm, the non-inferiority
limit determined at the time of planning. Therefore, thenon-inferiority of hydromorphone relative to oxycodone wassuggested.

The incidence of adverse events was 80.7% in thehydromorphone group and 83.7% in the oxycodone group,and no significant intergroup difference was observed.
However the incidence rates of nausea and vomiting werehigher in the hydromorphone group than in the oxycodone
group, tthe severity of nausea and vomiting was mild ormoderate in all these patients and approximately 70% was
mild of these patients. No significant intergroup differences of
the incidence of serious adverse event, severe adverse event
and adverse event leading to discontinuation of study
treatment were observed.

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

March 26, 2018