Valsartan ER Tablets EZRA Pharma dba Division of EZRA Innovations LLC PROTOCOL SYNOPSIS Protocol Number: TBD

Version 2.0

Investigational Product: Valsartan Extended Release Tablets, Diovan Tablets Active Ingredient: Valsartan, USP Study Title: A prospective, randomized, open label, blinded endpoint, crossover study to compare the safety, efficacy, and duration of action of Valsartan ER 160 mg once-daily to Diovan160 mg once-daily on patients with stage I and stage II hypertension. I Hypertension (HTN)

Study Phase:

Indicator under Investigation: Study Objective:

Primary Objective: Compare the reduction in mean 24 hour systolic BP in hypertensive patients treated with Valsartan ER 160 mg or with Diovan 160 mg as measured by Ambulatory Blood Pressure Monitoring (ABPM)

Secondary Objectives: Compare the reduction in mean daytime systolic and diastolic BP in hypertensive patients treated with Valsartan ER 160 mg or with Diovan 160 mg as measured by Ambulatory Blood Pressure Monitoring (ABPM). Compare the reduction in mean nighttime systolic and diastolic BP in hypertensive patients treated with Valsartan ER 160 mg or with Diovan 160 mg as measured by Ambulatory Blood Pressure Monitoring (ABPM).

Compare the mean reduction in systolic and diastolic BP measured during the final 4 hours of the dosing interval in hypertensive patients treated with Valsartan ER 160 mg or with Diovan 160 mg as measured by Ambulatory Blood Pressure Monitoring (ABPM). Compare the Pharmacokinetic (PK) profile of Valsartan ER 160 mg to Diovan 160 mg following an 8 hour fast. Compare the safety profile of Valsartan ER 160 mg to Diovan 160 mg.

Study Design:

In this prospective, randomized, open label, blinded endpoint study, hypertensive patients, either newly diagnosed or treated hypertensive patients, who have been weaned off all antihypertensive medications and who fulfill all inclusion/ exclusion criteria, will enter a 3 week single blind placebo washout period. Following the washout period, patients with a mean seated systolic BP of 150-mmHg and 180 mmHg and a mean seated Diastolic blood pressure of 110 mmHg will be eligible for the study. Eligible patients will be admitted to the PK unit (within 48 hours of the qualifying office BP). Following an 8 hour fast, patients will be attached to an ambulatory BP monitor and will be monitored for a period of at least 24 hours in the PK unit to establish a baseline BP. Patients with a mean daytime SBP (8am-4pm) of 130 mmHg and 180 mmHg and a mean daytime DBP of 110 mmHg will be randomized to either Valsartan ER 160 mg, PO, once-daily in the morning or to Diovan 160 mg, PO, once-daily in the morning. Patients randomized to Diovan 160 mg will be instructed to take their medication approximately 1 hour before their breakfast. Patients randomized to Valsartan ER 160 mg will be instructed to take their medication about 15 minutes after completing their breakfast. Patients will then be given their first dose of the study medication in the PK unit. Medication will be dispensed to the patients and they will be discharged from the PK unit and told to return to the clinic in 1 week for a BP check and a compliance assessment. At the clinic visit, patients will

have drug dispensed and told to return to into the PK unit for PK period 2 in 2 weeks. Following an 8-hour fast in the PK unit, patients will be dosed with their current medication at approximately 8am. Patients randomized to Diovan will 160mg will be dosed in the fasting state and patients randomized to Valsartan ER 160 mg will be dosed 15 minutes after a full breakfast. An Ambulatory BP monitor will be attached to the patient for 24 hours (BPs will be measured at 20 minute intervals) and PK measurements (0, , 1, 1 , 2, 3, 4, 5, 6, 7, 8 , 12, 16, 24 hours) will be performed. Following at least 24 hours of BP monitoring the ABPM will be removed. Following removal of the ABPM patients will be discharged from the PK unit. Patients will enter a 1 week single blind placebo washout period. After, the 1-week washout period patients will return for a clinic visit. Patients who were treated on Valsartan ER 160 mg will be crossed over to receive Diovan 160 mg and those who were treated on Diovan 160 mg will be crossed over to receive Valsartan ER 160 mg. Patients will be dosed in the clinic. Those on Diovan 160 mg will be dosed in the fasting state, and those on Valsartan ER 160 mg will be does after a full breakfast. Patients will be seen after 1 week in the clinic for a BP check and a compliance check. Patients will be instructed to return to the PK unit after a further 2 weeks for PK period 3. Following an 8-hour fast, patients will be attached to an ABPM unit and will be dosed with study medication at about 8 am. (Diovan 160mg patients in the fasting state and Valsartan ER 160mg patients 15 minutes after a full breakfast) 24 hour BP measurements will be obtained and PK measurements will be performed as in PK period 2. After completion of the 24-hour BP monitor, patients will exit the study and be treated at the discretion of the Principal Investigator (PI).

Study Duration:

The maximum duration of subject participation is approximately 10 weeks. The Screening period is 3 weeks and on each treatment regimen the period is 3 weeks with a 1 week washout between treatment periods. 1 US investigative site

Study Site and Location:

Planned Sample Size:

Approximately 30 subjects will enter active treatment

Subject Eligibility Criteria: Inclusion Criteria (Subjects must satisfy all of the following criteria to be included in the study): Males and Females 18 -75 years old. Patients must be willing and able to sign informed consent. Newly diagnosed hypertensive patients and treated hypertensive patients who have been off all antihypertensive medications for at least 3 weeks. Mean seated systolic BP of 150 mmHg and 180 mmHg and mean daytime systolic BP on ABPM of 135 mmHg. Mean DBP (office and ABPM) of 110 mmHg. Females of child bearing potential should be on adequate and acceptable contraception.

Exclusion Criteria (Subjects who meet any of the following criteria will be disqualified from entering the study): Subjects with Type I diabetes, or Type II diabetes requiring insulin. Subjects whose non-dominant arm is < 24 cm or > 42 cm in circumference (arm extended, upper arm midpoint circumference). Subjects with serious disorders which may limit the ability to evaluate the efficacy and safety of Valsartan 160 mg and Divoan 160 mg, including cardiovascular, renal (including the absence of one kidney), pulmonary, hepatic, gastrointestinal (including clinically significant malabsorption), endocrine/metabolic (with the exception of non-insulin, dependent Type II diabetes), hematologic / oncologic (including an active malignancy other than basal cell carcinoma), neuralogic and psychiatric diseases. Subjects with a history of myocardial infarction, angina, coronary angioplasty, bypass surgery or heart failure within the last 6 months. Subjects with a history of cerebrovascular accident or transient ischemic attack within the last 1 year.

Subjects with clinically significant cardiac conduction defects, including second or third degree AV block, left bundle branch block, sick sinus syndrome, atrial fibrillation, atrial flutter, an accessory bypass tract, or any arrhythmia requiring medication. Subjects with hemodynamically significant valvular disease. Subjects with secondary hypertensive of any etiology, such as renal disease, pheochromocytoma, or Cushings syndrome. Subjects with requirement for any of the medications indicated on the list of Excluded Medications. Subjects who have clinical laboratory values at screening which are designated by the Investigator as clinically significant. Subjects with a history of drug and alcohol abuse within the past two years. Subjects with a history of an allergic response to any ARBs. Subjects with a history of angioneurotic edema. Subjects who have participated in another investigational drug study within 28 days prior to signing the informed consent form, or who will participate in another drug study during the course of the trial. Subjects who work the night shift. Subjects who are involved in the study as research site personnel.

Dosage Form, Dose and All doses of this study medication will be taken orally as tablets Route of Administration: once daily in the morning. Patients being treated with Diovan 160 mg will be dosed 1 hour before breakfast. Patients being treated with Valsartan ER 160 mg will be dosed 15 minutes after breakfast.

Analysis of ABPM (Ambulatory Blood Pressure Monitoring) Data: Derivation of Values Multiple blood pressure monitoring values are planned be taken each hour (approximately every 20 minutes). It is possible that for some expected measurement times that the measurement is not possible. In that case the value will be missing for that measurement time. For each hour, the hourly mean will be calculated based on the observable measurements (i.e. if only 2 observable measurements were taken in a particular hour those 2 measurements would be used to derive the hourly mean). The ABPM measurements usually are taken for longer than 24 hours, but only the first 24 hours are used for the hourly mean calculations. If a subject has more than 5 missing hourly means or more than 3 consecutive missing hourly means then the ABPM measurement for that day is considered unusable for the analysis. In this case, either the ABPM measurement will need to be redone or that subject visit will be excluded from the analysis. For each post-baseline visit, the observed value and time-matched change from baseline will be derived for each hour (i.e. the 11th hour Baseline value will be subtracted from the 11th hour Period 1 value to obtain the 11th hour change from baseline for Period 1) for both systolic and diastolic blood pressure. If more than 5 missing hourly change from baselines or more than 3 consecutive missing changes from baseline then the change from baseline ABPM measurements for that day is considered unusable for the change from baseline analysis. The individual hourly means (not the individual BP measurements) or hourly time matched changes from Baseline will be averaged to obtain the daily, morning and evening means.

Analysis of Values An Analysis of Variance (ANOVA) model with Treatment, Sequence and Period will be used to determine significant differences. Subject will be a random effect in the model. The ANOVA model will be used to test for significant changes from Baseline and significant differences between treatments. Both the observed values (using Baseline, Period 1 and Period 2 values), and the changes from baseline

(using Period 1 change from Baseline and Period 2 change from Baseline) will be tested for entire day, morning and evening. If there are no significant differences (<.05) from baseline, then the differences between treatments will not be tested.

Analysis of Pharmacokinetic Data:

Analytical Assay Plasma concentrations of Valsartan will be measured by a validated analytical method using LC-MS/MS.

Pharmacokinetic Parameters Assessments

Throughout the report, summary statistics for continuous PK Parameters (including Cmax, tmax, t1/2, AUC0-24, and AUC0-inf) will include mean, geometric mean, standard deviation, coefficient of variation (CV%), median, minimum, and maximum; tmax will be summarized using median, minimum, and maximum values. The log-transformed AUC0-24, AUC0-inf, t1/2 and Cmax will be analyzed using a mixed effect linear model with effects for sequence, subject, period and treatment. The subject effect will be treated as a random effect. The 90% confidence intervals will be derived from this model and back-transformed into standard units. The pharmacokinetic analysis (i.e. PK Parameter derivation) will be conducted using model-independent methods as implemented in WinNonlin(r) (version 4.0 or later). Relative Bioavailability The relative mean Cmax, AUC0-t and AUC0-, of the Test to Reference formulation for Ln-transformed data will be calculated.

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Rationale: Cardiovascular disease remains the most common cause of death in the United States. Hypertension is the most important of the CV risk factors and occurs in approximately 75 million Americans. This number is estimated to increase dramatically over the next 10-15 years due to the aging population. Results of the epidemiologic data has shown that only about 50% of hypertensive patients are controlled to a BP level of less than 140 mmHg over 90 mmHg. Thus, in excess of 35 million American hypertension patients are uncontrolled and remain at significant risk for developing cardiovascular disease. For this reason, it is important to develop more effective and more convenient treatment for hypertension patients in an attempt to increase the number of patients achieving goal BP. It is well known that blood pressure has a reproducible circadian pattern over 24hours. BP is highest during the day, drops in the early evening, is lowest between 2-4am and then rapidly increases from the low nighttime values to the higher daytime values between 5am-12noon. It is during this rapid surge in blood pressure that the greatest number of cardiovascular events occurs. It would thus seem important that adequate BP control is maintained during this period. This has created a new problem in the management of hypertension. It has been shown that patient compliance is significantly better with once-a-day dosing than with twice daily dosing. So to improve patient compliance, antihypertensive drugs with longer half-lives have been developed in an attempt to achieve adequate BP control over the entire dosing interval with once-a-day dosing. However, ambulatory BP monitoring has shown that several of the once-a-day agents dosed in the morning, do not provide 24-hour efficacy and lose BP control during the last few hours of the dosing interval, which coincides with the early morning surge in BP and the time when effective BP control seems to be important. In an attempt to overcome this problem, studies in which drugs are dosed at night have been performed, but these have shown that the drugs tend to peak when BP is physiologically at its lowest levels, which may also be associated with other problems such as acute ischemic optic neuropathy. Clearly this is not an optimal solution. Developing once-a-day antihypertensive agents with true 24-hour efficacy becomes more important to enhance patient compliance and maintain BP control. Angiotensin receptor blockers (ARBs) have proven to be an important treatment in the management of hypertension. Among the ARBs, Diovan has been the most commonly used of the ARBs. It is effective and well tolerated both as monotherapy and in combination with diuretic and calcium channel blockers. However, there have been some concerns over the duration of action of Diovan, particularly at lower doses, and whether is provides true 24-hour BP control. In this study we will be comparing a new formulation, Valsartan ER to Diovan. Valsartan ER utilizes a delivery system, which achieves gastric

retention by utilizing a swelling and floating system; this delivery system results in a continuous trickling of solubilized drug across the absorption site. Pharmacokinetic studies have demonstrated that patients treated with Valsartan ER have significantly higher plasma levels of drug between 6 and 24 hours compared to Diovan. It is anticipated that these differences in plasma drug levels will result in greater efficacy and a longer duration of action compared to Diovan without compromising the side effect profile. Greater efficacy is likely to result in an increase in the percentage of patients achieving recommended BP control, and the longer half life of the drug will result in better BP control during the important last 4-6 hours of the dosing interval making this a true once-a-day agent. All patients will have 24-hour ambulatory BP monitoring in order to compare the efficacy and duration of action when treated with Diovan and Valsartan ER in a crossover study design. The availability of more effective, true, once-a-day agents will provide a very important addition to our armamentarium of antihypertensive agents and will be helpful in obtaining greater control rates in hypertensive patients. Although an 80mg and 160mg dose will be pursued by EZRA Pharma, the intended starting dose will be 160mg. Previous studies with Diovan have shown 160mg is more effective then 80mg- however, there is no difference in the side effect profile. Since lower blood pressures seem to be associated with the reduction in CVD, a safe 160mg dose, which is more effective than the 80mg dose would be preferable. The 80mg dose would be used for patients with stimulated renin angiotensin systems, such as that which occurs in volume depleted elderly patients.