诺和诺德降糖药Ryzodeg达非劣效性终点

诺和诺德于12月3日在国际糖尿病联盟（IDF）世界糖尿病大会上公布了糖尿病药物Ryzodeg的BOOST项目INTENSIFY PREMIX I试验的数据。该项研究是一项为期26周、随机、对照开放标签、治疗至目标（treat-to-target）研究，在既往经每天一次或2次预混或自行混合胰岛素治疗的2型糖尿病患者中开展，将Rezodeg与双相门冬胰岛素30（biphasic insulin aspart 30）进行了疗效和安全性对比。研究中，Rezodeg和双相门冬胰岛素30均每天给药2次，并结合或无口服降糖药治疗。

研究结果表明，在整个试验期，与双相门冬胰岛素30相比，Ryzodeg取得了改善的血糖控制，并显著降低了总体和夜间低血糖发生率；在维持期（从第16周起），与双相门冬胰岛素30相比，Ryzodeg显著降低了严重低血糖发生率。该项研究达到了非劣效性的主要终点，并达到了空腹血糖（FPG）控制优越性的次要终点。

Ryzodeg是首个由2种不同的胰岛素类似物Tresiba（胰岛素degludec）和NovoRapid（门冬胰岛素，insulin aspart）组成的复合药物，2者以70%：30%的比例装入胰岛素笔，用于2型糖尿病患者的治疗。

Tresiba为每日一次的超长效基础胰岛素类似物，作用持续时间超过42小时，赋予了日常服药时间的灵活性，同时不影响疗效和低血糖风险。NovoRapid则是一种速效餐时（mealtime）胰岛素，可提供快速和餐后双重血糖控制。

关于Ryzodeg：

Ryzodeg是胰岛素degludec/门冬胰岛素（insulin aspart）的全球品牌名，由2种不同的胰岛素类似物Tresiba（胰岛素degludec）和诺和锐（NovoRapid，insulin aspart）以70%和30%的比例组成的复合药物。与双相门冬胰岛素30相比，Ryzodeg在主餐时每日给药2次，可成功降低HbA1c水平，同时低血糖发生率降低。目前，Ryzodeg已获日本、墨西哥、欧盟、挪威、冰岛、瑞士、萨尔瓦多、智力等国批准。

关于BOOST项目：

诺和诺德于20100年完成了IIIa期BOOST项目。该项目由6个临床试验组成，包含了支持Ryzodeg监管申请的主要数据。该项目在咨询过欧盟和美国的监管机构后设计开展。

英文原文：Ryzodeg? offers improved glycaemic control with significantly lower rates of hypoglycaemia compared to biphasic insulin aspart 30 in adults with type 2 diabetes1

Copenhagen, Denmark, 3 December 2013 – Data presented today at the World Diabetes Congress of the International Diabetes Federation (IDF) show that adults with type 2 diabetes achieved improved glycaemic control, significantly lower rates of overall and nocturnal confirmed hypoglycaemia for the full trial period, and a significantly lower rate of severe hypoglycaemia during the maintenance period (defined as week 16 onwards) with Ryzodeg? compared to biphasic insulin aspart 30, both administered twice-daily1.

Ryzodeg? is the first combination of two distinct insulin analogues, Tresiba? (insulin degludec), the once-daily basal insulin with an ultra-long duration of action, and the well-established mealtime insulin NovoRapid? (insulin aspart), in the ratio of 70% and 30%, in one pen for people with type 2 diabetes2-4.

"Type 2 diabetes is a progressive disease and many patients who are uncontrolled with basal insulin need to add mealtime insulin to achieve or maintain their glycaemic targets over time. As Ryzodeg? is a combination of two distinct insulins, a basal insulin with a long and steady action profile and a well-established mealtime insulin, it is a simple way for patients to add mealtime control with a reduced risk of overall and nocturnal confirmed, and severe hypoglycaemia," said lead investigator Gregory Fulcher, Royal North Shore Hospital, Sydney, Australia.

The multinational BOOST? INTENSIFY PREMIX I trial was a 26-week, randomised, controlled open-label, treat-to-target trial comparing the efficacy and safety of Ryzodeg? and biphasic insulin aspart 30, both administered twice-daily with or without oral antidiabetic drugs in adult patients with type 2 diabetes previously treated with premixed or self-mixed insulin either once- or twice-daily.

Overall study results include1:

Ryzodeg? achieved the primary endpoint of non-inferiority to biphasic insulin aspart 30 for mean change in HbA1c from baseline (estimated treatment difference [ETD] –0.03% points, 95% CI –0.18; 0.13).
Ryzodeg? achieved the secondary endpoint of superiority in lowering FPG compared with biphasic insulin aspart 30 (ETD –1.14 mmol/L, 95% CI –1.53; –0.76, p<0.001).
Final mean daily insulin dose was 11% lower for Ryzodeg? compared with biphasic insulin aspart 30 (1.08 U/kg versus 1.20 U/kg; estimated rate ratio [RR] 0.89, 95% CI 0.83; 0.96, p=0.002).
Significantly lower rates of overall confirmed (self-reported PG <3.1 mmol/L or severe episode requiring assistance) and nocturnal confirmed hypoglycaemia (onset 00.01–05.59 hours) for Ryzodeg? versus biphasic insulin aspart 30 were reported.
A 32% lower rate of overall confirmed hypoglycaemia (9.7 versus 14.0 episodes/patient/year, RR 0.68, 95%CI 0.52; 0.89, p=0.0049).
A 73% lower rate of nocturnal confirmed hypoglycaemia (0.7 versus 2.5 episodes/patient/year; RR 0.27, 95% CI 0.18; 0.41, p<0.0001).
A numerically lower rate of severe hypoglycaemia, although the difference was not significant (0.09 versus 0.25 episodes/patient/year, RR 0.50, 95% CI 0.19; 1.30, p=ns).
During the maintenance period (defined as week 16 onwards, a period when majority of patients achieve stable insulin dose and glycaemic control) significant differences were reported in rates of hypoglycaemia comparing Ryzodeg? with biphasic insulin aspart 30.
A 39% lower rate of overall confirmed hypoglycaemia (RR 0.61, 95% CI 0.45; 0.83, p=0.0015).
A 77% lower rate of nocturnal confirmed hypoglycaemia (RR 0.23, 95% CI 0.13; 0.41, p<0.0001).
An 89% lower rate of severe hypoglycaemia (RR 0.11, 95% CI 0.01; 0.91, p=0.04).
About Ryzodeg?
Ryzodeg? is the global brand name for insulin degludec/insulin aspart. It is a combination of two distinct insulin analogues, Tresiba? (insulin degludec) and NovoRapid? (insulin aspart) in the ratio of 70% and 30%. Ryzodeg? delivered twice-daily at main meals offers successful reductions in HbA1c2 with lower rates of hypoglycaemia versus biphasic insulin aspart 30 in people with type 2 diabetes5,6. Ryzodeg? has been approved in Japan, Mexico, EU, Norway, Iceland, Switzerland, El Salvador and Chile.

About the BOOST? programme
Novo Nordisk completed the phase 3a BOOST? programme in 2010. This programme consisted of six randomised, controlled, treat-to-target trials in more than 30 countries and comprised the majority of the data supporting the regulatory applications for Ryzodeg?. More than 2000 people were included in the development programme. The programme was designed after consultancy with regulatory agencies in Europe and USA.