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Trajenta
Linagliptin, 5 mg film coated tablet

Response Document
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

COMMENT CONCERNING STUDY 1218.63:

Study 1218.63 is an additional clinical study of Linagliptin as the therapy add-on to insulin
with or without oral anti diabetic combination in elderly patient (age > 70 years). Linagliptin
is superior compared to placebo in reduction baseline HbAlc and FPG until 24 weeks. In this
study, only 21% patient received insulin therapy.

Response:
The title of the Study 1218.63 is as follows: A Phase III randomised, double-blind, placebo-
controlled, parallel group, efficacy and safety study of linagliptin (5 mg), administered orally
once daily over 24 weeks in type 2 diabetic patients (age >70 years) with insufficient
glycaemic control (HbAl c >7.0%) despite metformin and/or sulphonylurea and/or insulin
therapy

This study was primarily a safety and efficacy study in elderly patients insufficiently treated
with background therapies metformin, sulphonylurea, insulin, alone or in combination.
1218.63 was not designed as a pivotal study for efficacy for the combination linagliptin and
insulin. However a pooled analysis of all elderly patients (n: 244) taking insulin background
from trials 1218.63 and 1218.36 was performed (EFF-3 of the submission document). The
analysis of the pooling showed significant and clinically relevant reduction in HbAlc after 24
weeks (-0.77%).
Table 4.10: 1
Sununaty of key efficacy data for the 3 efficacy groupings up to the
timepoint of the primary analysis
Efficacy study grouping 1 EFF-1 EFF-2 EFF-3
(pivotal study) (patients with severe (elderly patients
chronic renal impairment) aged ?70 years)
Placebo: 617 Placebo: 52 Placebo: 118
Number of patients Linagliptin: 618 Linagliptin: 52 Linagliptin: 126
Mean baseline HbAie. (%) 8.30 8.29 8.20
Change in HbAic. (*a) 2 -0.65 ** -0.43 " -0.77 **
(Primal)! endpoint)
Change in FPG. (mg/dL) 2 -11.2 ** -1.8 -19.4
Change in weight. (kg) 2 -0.3 -0.2 -0.1
The piimary endpoint was assessed after 24 weeks for EFF-1 and EFF-3. and after 12 weeks for EFF-2
2 Adjusted mean treatment difference - placebo) using ANCOVA at the timepoint of the primary
analysis (* P<0.05. ** 1,<0.0001)

Source data: [U11-2630. Tables 3.1.2.1. 3.3.2.1, 3.4.2.1 4.1.1.1. 4.1.2.1. 4.1.9.1. 4.3.1.1. 4.3.2.1. 4.3.6.1. 4.4.1.1. 4.4.2.1.
and 4.4.6.1]

REPONSE TO COMMENTS dated 23 June 2014