The reason for this substantial amendment was to change the primary efficacy endpoint of this trial from “…the change in 24-hour mean SBP from baseline to day 14…” to “…the change in daytime mean SBP from baseline to day 14…”. This was done based on a preliminary review of baseline ABPM recordings (after randomization of four subjects and screening of over three dozen patients), where it became apparent that the differences between the daytime and night-time SBPs were so great that they would compromise the statistical validity of the data if SBP24h was used as the endpoint, as well as a review of the literature. Inclusion criterion 3 was changed to “SBP24h > 135 mmHg at baseline (Day 0)” to “SBPday > 135 mmHg at baseline (Day 0)”. Similarly, exclusion criterion 2 was changed from “SBP24h < 135 mmHg at baseline (Day 0)” to “SBPday < 135 mmHg at baseline (Day 0)”. This was done for consistency with the above referenced endpoint revisions.

1. The reason for this substantial amendment was to revise exclusion criterion number 1 to specify that subjects are excluded from participating in the study if their resting systolic BP at Screening was > 179 mmHg (previously 169 mmHg). The required mean SBP as measured by ABPM during the baseline 24 hours remained < 169 mmHg. This change was made in response to initial recruitment results showing that a relatively large proportion of potential subjects were hypertensive at Screening but were subsequently found to be normotensive by ambulatory BP monitoring at baseline/randomization. No impact on the trial outcomes were anticipated by this change. 2. The reason for this modified Substantial Amendment was to address the concerns set out in the MHRA grounds for non-acceptance letter, dated 8th August 2014, for Substantial Amendment 2.0, Version 1.0 dated 7th July 2014. Inclusion criterion number 2 was revised, as requested, to specify that the patients eligible for this study are those that require chronic pharmacological therapy. Inclusion criterion number 3 was deleted, and is instead now part of inclusion criterion number 2. New wording is as follows: Inclusion Criteria 2. Newly diagnosed hypertension that requires chronic pharmacological therapy. Specifically, the subject must meet both of the following criteria: a. Resting systolic BP ≥ 140 mmHg and ≤179 mmHg (where resting is defined as supine for at least 10 minutes with minimal interaction) at Initial Screening Visit; b. SBPday > 135 mmHg at Baseline Visit (Day 0); To address the concerns of both the MHRA and the Investigators, the inclusion criterion was clarified as noted above. These changes were simply clarifications, and no impact on the trial outcomes were anticipated by these changes.

The reason for this amendment was to request that the maximum age for enrollment in this trial be increased from 65 to 75 years. This was done for multiple reasons. First, this change was requested by the study investigators to facilitate recruitment into the study. In addition, this age will be more reflective of the age of patients who will eventually receive this medication when and if it is approved for marketing. Having enrolled 56 patients and reviewed the blinded efficacy and safety data, including the ABPM data from these patients, it was clear that there had been no instances of clinically significant hypotension or hypertension among these patients. Thus, the data now justified a conclusion that it was safe to increase the enrollment age. It should further be noted that since patients were monitored while on the study, including have an ABPM for the initial 24 hours following initiation of therapy, if any patient were to develop symptomatic hypotension or hypertension, this should be quickly noted by the investigators. This change was not anticipated to impact the trial outcomes.

1.The Study Protocol exclusion criterion number 17 regarding a positive drug screen at Screening was amended. Specifically, the following exception was added: “A positive drug screen for opiates only (with all other drug tests negative) will not be a basis for exclusion if the subject took over-the-counter narcotics as indicated on the product label within 24 hours prior to the drug screen.” This exception was added to take into account that there are several over-the-counter narcotics available in the United Kingdom, and that the protocol does not specifically restrict these medications prior to enrollment. Thus, there was the potential to have to screen fail an otherwise eligible subject for taking a common over-the-counter medication. This change was not anticipated to impact the trial outcomes. 2. Appendix F of the Study Protocol was revised to replace the January 2013 product label for commercial amlodipine besylate [Norvasc® (amlodipine besylate) tablets] with the current label approved by FDA on March 23, 2015. The updated label included the following safety-related revisions: • Addition of a possible association between extrapyramidal disorder and amlodipine during post-marketing reporting. • Addition of clarithromycin as a strong inhibitor of CYP3A that may increase the plasma concentrations of amlodipine. • Addition of a possible drug interaction between tacrolimus and amlodipine (increase in tacrolimus exposure). None of the above findings were anticipated to pose a significant risk to the subjects in the ongoing trial due to how the study was designed (i.e., restricted eligibility/patient population, intensive safety monitoring, restricted concomitant medications, and relatively short exposure to amlodipine).