Safety And Tolerability Of Subcutaneous MANP In Difficult To Control/Resistant Hypertensive Subjects

Study Overview
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Brief Summary
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A randomized, double-blind, placebo-controlled multiple ascending dose study in hypertensive subjects on stable doses of at least three hypertensive drugs for at least 6 weeks prior to Screening. The study will consist of screening, PK-unit admittance, and safety follow up periods. Subjects will be randomized at a 6:2 ratio of either MANP or placebo and will be stratified by race in each dosage cohort. The entire first Cohort will be given the lowest dosage with subsequent cohorts progressing sequentially to the higher doses depending on safety and tolerability of the previous cohort. Endpoints not related to the safety reviews will be analyzed after the last patient last visit (LPLV).

Official Title
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A Phase 1B, Multiple Ascending Dose Trial Examining The Safety And Tolerability Of Subcutaneous MANP In Difficult To Control/Resistant Hypertensive Subjects

Conditions
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Resistant Hypertension, Difficult to Control Hypertension

Intervention / Treatment
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* Drug: MANP
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: DTC/RH diagnosed with clinic SBP ≥140 mmHg or DBP ≥ 90 mmHg (or SBP ≥ 130 mmHg or DBP ≥ 80 mmHg for diabetics) while on at least three standard-of-care antihypertensive medications (which must include a diuretic). MDRD eGFR ≥ 30 mL/min. Men and women between the ages of 18 - 80. BMI within the range of 18-40 kg/m2. Women of childbearing potential must not be pregnant and agree to avoid becoming pregnant while receiving study treatment and for 14 days after the last study visit. Exclusion Criteria: HbA1c ≥ 8% at Screening. Use of other investigational drugs within 30 days of screening or foreseen use during the study. Inability to comply with study requirements as judged by the Investigator. Pregnant and/or breastfeeding. Any disease or condition (medical or surgical) which, in the opinion of the investigator, might compromise the hematologic, cardiovascular, pulmonary, renal, gastrointestinal, hepatic, or central nervous system; or other conditions that may interfere with the absorption, distribution, metabolism or excretion of study drug, or would place the subject at increased risk.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo Comparator<br>Subjects randomized to the placebo arm, will receive a single subcutaneous injection each morning daily. Intervention: Placebo | Drug: Placebo<br>* Placebo Comparator<br>|
| Experimental: MANP<br>Subjects randomized to the experimental arm, will receive a single subcutaneous injection each morning daily. (multiple ascending dose cohorts) Intervention: Drug: MANP | Drug: MANP<br>* Novel designer peptide to represent a pGC-A/cGMP therapeutic<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events | Number and percent of participants with one or more Treatment Emergent Adverse Events (TEAEs) or any serious adverse events (SAEs). | through study completion, an average of 2 months. | 
| Blood Pressure | Change in SBP and DBP | From baseline to Days 1-6, Day 12, and 21. | 
| Hematology Hematocrit | Change in Percent Hematocrit | From baseline to Day 21. | 
| Physical Examination: Body Parts | Change in investigator assessment of the condition of body parts (head, throat, abdomen, and extremities) | From baseline to Day 21 | 
| ECG: QT interval | Change in 12-Lead ECG QT Interval | From baseline to Days 1-6 and Day 21. | 
| Temperature | Change in Temperature | From baseline to Days 1-6, Day 12, and 21. | 
| Pulse Rate | Change in Pulse Rate | From baseline to Days 1-6, Day 12, and 21. | 
| Hematology: Hemoglobin | Change in g/dL Hemoglobin | From baseline to Day 21 | 
| Hematology: Mean Corpuscular Hemoglobin | Change in the mean corpuscular hemoglobin. | From baseline to Day 21 | 
| Hematology: Platelets | Change in platelet count | From baseline to Day 21 | 
| Hematology: RBC distribution | Change in red blood cell distribution width | From baseline to Day 21 | 
| Hematology: RBC | Change in red blood cell count | From baseline to Day 21 | 
| Hematology: WBC | Change in white blood cell count | From baseline to Day 21 | 
| Chemistry: Sodium | Change in Sodium concentration. | From baseline to Day 21 | 
| Chemistry: Potassium | Change in Potassium concentration. | From baseline to Day 21 | 
| Chemistry: Chloride | Change in Chloride concentration | From baseline to Day 21 | 
| Chemistry: Bicarbonate | Change in Bicarbonate concentration | From baseline to Day 21 | 
| Chemistry: Alanine aminotransferase | Change in ALT (IU/L) | From baseline to Day 21 | 
| Chemistry: Aspartate aminotransferase | Change in AST (IU/L) | From baseline to Day 21 | 
| Chemistry: Alkaline phosphatase | Change in Alkaline phosphatase (IU/L) | From baseline to Day 21 | 
| Chemistry: Bilirubin | Change in Total bilirubin (mg/dL) | From baseline to Day 21 | 
| Chemistry: Blood urea nitrogen | Change in BUN (mg/dL) | From baseline to Day 21 | 
| Chemistry: Creatinine | Change in Creatinine (mg/dL) | From baseline to Day 21 | 
| Chemistry: Glucose | Change in Glucose (mg/dL) | From baseline to Day 21 | 
| Chemistry: HbA1c | Change in percent HbA1c | From baseline to Day 21 | 
| Physical Examination: Organs | Change in investigator assessment of the condition of organs (skin, eyes, ears, nose, thyroid, lungs, liver, spleen, and lymph nodes) | From baseline to Day 21 | 
| Abbreviated Neurological Examination | Change in investigator assessment of neurological condition | From baseline to Day 21 | 
| ECG: QTc interval | Change in 12-Lead ECG QTc (Fridericia's) Interval | From baseline to Days 1-6 and Day 21 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiac Metrics: Blood pressures | Change in SBP and DBP | From Baseline for Day 1-6 | 
| Serum creatinine | Change in Serum creatinine | From Baseline for Day 1-6 | 
| MANP | Change in amount of Plasma MANP both in plasma. | From baseline for Day 1 & Day 5 | 
| Immune Response | Change in amount of anti-MANP and anti-ANP | From baseline for Day 1, Day 5, Day 12, & Day 21 | 
| Metabolics | Change in amount of non-esterified insulin and glucose. | From baseline for Day 1 & Day 5 | 
| eGFR, | Change in eGFR, | From Baseline for Day 1-6 | 
| Urine flow rate | Change in urine flow rate | From Baseline for Day 1-6 | 
| Urinary Sodium Excretion | Change in amount of urinary sodium excretion | From Baseline for Day 1-6 | 
| cGMP | Change in amount of cGMP both in plasma and urine | from baseline for Day 1 & Day 5 | 
| Aldosterone | Change in amount of aldosterone both in plasma and urine | from baseline for Day 1 & Day 5 | 
| Cardiac Metrics: | Heart Rate | From Baseline for Day 1-6 |