Amendment to Protocol Version 2.0 Changes made to protocol version 1.0 due to comments from EC 9/11-2016: • New section added to section 7.5, p. 39, information about biobank. • Information about ‘total blood loss volume’ – added to section 7.5.1, p. 39: (The calculated blood sampling volume per patient is approximately 40 mL in total).

Changes made to protocol version 2.0 due to comments from DMA 22/12-2016: • Definitions on Adverse reactions (ARs) and Suspected Unexpected Serious Adverse Reactions (SUSARs) are added to section 11.1, p. 46: 
 Changes made to protocol version 2.0 due to comments from DMA 22/12-2016: • Definitions on Adverse reactions (ARs) and Suspected Unexpected Serious Adverse Reactions (SUSARs) are added to section 11.1, p. 46: 
 Adverse reaction (AR): All noxious and unintended responses to an investigational medicinal product related to any dose should be considered adverse drug reactions. The phrase “responses to an investigational medicinal product” means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility – in essence, the relationship cannot be ruled out. Suspected Unexpected Serious Adverse Reaction (SUSAR):
A serious adverse event that has a suspected causal relationship with the investigational medicinal product and which is not consistent with the applicable investigator brochure. • Changes to Chapter 7 Methods and assessments: Changes to section 7.1 p. 28, Visit procedures: Change from: ’Each subject will attend two screening visits (V1 and V2) to determine eligibility for participation in the trial. Subjects fulfilling all of the inclusion criteria and none of the exclusion criteria will be randomised to one of the given treatments. Randomized subjects will be scheduled to attend a visit 3 where the trial product is dosed (V3) and a follow up visit (V4).’ Change to: ‘Each subject will attend two screening visits (V1 and V2) to determine eligibility for participation in the trial. Subjects fulfilling all of the inclusion criteria and none of the exclusion criteria will be randomised to one of the given treatments. Randomized subjects will be scheduled to attend a visit 3 where the trial product is dosed (V3) and a follow up visit (V4).’ .. etc

• Changes of Inclusion criteria, section 5.2 p. 22, due to lack of patients fulfilling the inclusion criteria: Deletion of the following inclusion criterion: 3. In treatment with metformin, but no other anti- diabetic drugs • Changes of Exclusion criteria, section 5.3 p. 22-24, due to lack of patients: Deletion of the following exclusion criteria: 2. A subject who has a supine blood pressure at screening (including those on anti-hypertensives), after resting for 5 min, outside the range of 90-140 mmHg systolic or 50-90 mmHg diastolic (excluding white-coat hypertension; therefore, if a repeated measurement on a second screening visit shows values within the range, the subject can be included in the trial). 3. A subject who is in pharmacological treatment of hypertension if the current treatment includes other than an ACE-inhibitor 8. A subject who smokes more than 5 cigarettes, or the equivalent, per day and is unable to refrain from smoking during the in-house periods as determined by the Investigator. 15. A subject who has proliferative retinopathy or maculopathy, and/or severe neuropathy, in particular autonomic neuropathy, as judged by the Investigator. Change of exclusion criterion 5 from: 5. A subject who has participated in any other trials involving investigational products within the 3 months preceding the start of dosing. Change of exclusion criterion 5 to: 5. A subject who has participated in any other trials involving investigational products within the 1 month preceding the start of dosing. • Changes of Visit exclusion criteria, section 5.3.1 p. 24-25, due to lack of patients: Deletion of the following visit exclusion criteria: 1. Strenuous exercise within 48 h prior to screening visit to end of follow up visit, as judged by the Investigator. 5. A subject who has used any new non-prescribed systemic medication or topical medication, ... etc

• Changes in Section 1.1 Objectives: Changed from: (1, 2 and 4 mg) Changed to: (1, 4 and 8 mg) • Changes in Section 1.5 Trial products: Changed from: • Placebo • XEN-D0501, 1 mg/tablet • XEN-D0501, 2 mg/tablet • XEN-D0501, 4 mg/tablet Changed to: • Placebo • XEN-D0501, 1 mg/tablet • XEN-D0501, 4 mg/tablet • XEN-D0501, 8 mg, 2 x 4mg/tablet Changes in Section 3.3 Objectives: Changed from: (1, 2 and 4 mg) Changed to: (1, 4 and 8 mg) Changes in Section 4.2.1 Treatment of subjects: Change from: 1. XEN-D0501, 1 mg p.o. (n=6) and placebo (n=2) 2. XEN-D0501, 2 mg p.o. (n=6) and placebo (n=2) 3. XEN-D0501, 4 mg p.o. (n=6) and placebo (n=2) Change to: 1. XEN-D0501, 1 mg p.o. (n=6) and placebo (n=2) 2. XEN-D0501, 4 mg p.o. (n=6) and placebo (n=2) 3. XEN-D0501, 8 mg p.o. (n=6) and placebo (n=2) Change from: Each subject will be randomised to a given treatment. Cohorts of 8 patients are run subsequently whereof 2 patients receive placebo and 6 patients receive XEN-D0501 beginning with the 1 mg dose followed by the 2 and 4 mg dose groups. Change to: Each subject will be randomised to a given treatment. Cohorts of 8 patients are run subsequently whereof 2 patients receive placebo and 6 patients receive XEN-D0501 beginning with the 1 mg dose followed by the 4 and 8 mg dose groups. • Changes in Section 8.1 Trial products: Changed from: • Placebo • XEN-D0501, 1 mg/tablet • XEN-D0501, 2 mg/tablet • XEN-D0501, 4 mg/tablet Changed to: • Placebo • XEN-D0501, 1 mg/tablet • XEN-D0501, 4 mg/tablet • XEN-D0501, 8 mg, 2 x 4mg/tablet