Safety Study of RMJH-111b to Treat Essential Hypertension

A Phase 1/2, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety and Tolerability of RMJH-111b in Adult Subjects With Essential Hypertension

The purpose of this study was to evaluate the safety of RMJH-111b, including how well it is tolerated, and the effect of RMJH-111b on blood pressure in subjects with hypertension. The study also measured the amount of magnesium in the blood and urine before and after RMJH-111b administration to evaluate what the body does to RMJH-111b (pharmacokinetics).

This was a phase 1/2, single center, randomized, double-blind, placebo-controlled study to assess the safety and tolerability of RMJH-111b in adult subjects with essential hypertension. Assessments of pharmacokinetics and efficacy were secondary objectives. RMJ Holdings LLC (doing business as RMJH Rx) is developing RMJH-111b (magnesium citrate, tribasic anhydrous) soft gelatin capsules for the treatment of essential hypertension. The rationale for developing RMJH-111b for essential hypertension is based on reported calcium channel blocker and vasodilator effects of magnesium cation (Mg++). Given this hypothesized mechanism of action, RMJH-111b may not be effective for subjects with other causes or forms of hypertension, and thus the diagnosis of essential hypertension was a key inclusion criterion for this trial. In order to avoid confounding the results of the trial, subjects who were already taking anti-hypertensive medications to manage their hypertension were taken off of those medications and underwent a 7-day washout period. Subjects that met the specified blood pressure criteria after the washout [systolic blood pressure (SBP) ≥ 150 and ≤ 200 mmHg and diastolic blood pressure (DBP) ≥ 95 and ≤ 115 mmHg] received placebo orally twice a day (bid) for a 3-day run-in period (Days 1-3). Subjects that were recently diagnosed or previously diagnosed and off treatment for > 1 week before starting the study and who met the blood pressure criteria proceeded directly to the 3-day run-in period (i.e., without the 7-day washout period). During the 3-day run-in period, the subjects remained in the clinical research unit (CRU) on a low salt (2.5 g/24 hours) diet. Subjects that remained eligible after the run-in period were randomized to receive either 440 mg of RMJH-111b or placebo orally bid (i.e., total daily dose of 880 and 0 mg elemental magnesium, respectively) for a 7-day treatment period (Days 4-10). A total of 21 subjects randomized 15:6 to RMJH-111b or placebo was planned. Subjects were randomized on either June 10th or 23rd of 2016. Based on the screen failure rate of the 1st cohort, the number of subjects needed for the 2nd cohort was projected. The actual number of subjects eligible for randomization at the end of the run-in period in the 2nd cohort exceeded the projection by 1 and all eligible subjects were randomized. Thus, the actual number of subjects randomized was 22, with 16 subjects in the RMJH-111b group and 6 subjects in the placebo group (i.e., 16:6 rather than 15:6). Subjects remained in the CRU on a low salt (2.5 g/24 hours) diet for the entire 7-day treatment period and through the 24-hour post treatment assessments (Day 11). Subjects returned to the clinic 8 days (±3 days) after the last dose of Study Drug (active or placebo) for their Final Study Visit. Protocol-specified reasons for discontinuing a subject from the study included, but were not limited to: 1) subject's blood pressure was too elevated for them to safely continue in the study (subjects who experienced SBP >200 mmHg or DBP >115 mmHg had to have these measurements repeated approximately 1 hour later, and if the SBP or DBP remained elevated, the subject was to be removed from the study and treated accordingly), 2) subject experienced a sharp drop in blood pressure (SBP < 110 mmHg or DBP < 60 mmHg); 3) subject's patellar reflex (knee jerk) disappeared, and 4) subject's total serum magnesium levels increased to ≥ 5 mg/dL (twice the upper limit of normal). As a conservative measure for this first trial of RMJH-111b, the criterion regarding drop in blood pressure did not require any associated clinical symptoms. For the pivotal trial, RMJH Rx will incorporate orthostatic hypotension monitoring and refine the discontinuation criterion regarding drop in blood pressure to allow for continued Study Drug treatment in the absence of clinical symptoms, so as to avoid unnecessarily removing a subject that is experiencing therapeutic benefit. All measurements used for the safety assessments in this study are widely used, and generally recognized as reliable, accurate, and relevant. Further, they included standard parameters used in the evaluation of drugs with the potential for anti-hypertensive and magnesium toxicity effects. Because blood pressure varies at daytime compared to nighttime, mean daytime (8 AM to 4 PM), nighttime (10 PM to 6 AM), and 24-hour ambulatory blood pressure monitor (ABPM) parameters were used to assess the efficacy effects of RMJH-111b on blood pressure in this trial. While 24-hour ambulatory blood pressure monitoring is considered as a more precise method for the evaluation of drug effects on blood pressure than clinic visit (seated) blood pressures, this trial also included efficacy evaluations of seated SBP and DBP parameters for informational purposes and in particular to facilitate the design of the larger pivotal trial where ABPM monitoring will not be practical. The pharmacokinetic (PK) evaluation of magnesium is complicated by pre-existing endogenous levels of magnesium, other ingested sources of magnesium (daily diet and supplements; supplements with total daily dose of magnesium ≤ 150 mg were allowed in this study), and the tight regulation of magnesium in the body (magnesium homeostasis) with relatively high levels of magnesium in bones and soft tissues compared to approximately 1% in the blood. Thus, the total serum magnesium exposure was anticipated to be minimally effected with RMJH-111b intake, but evidence of urinary magnesium excretion coupled with maintained total serum magnesium exposure was expected to provide an indication of intake rather than magnesium wasting.

essential hypertension, hypertension, high blood pressure, cardiovascular disease, RMJH-111b, magnesium, magnesium citrate, calcium channel blocker, vasodilator, antihypertensive, anti-hypertensive

This study was a double-blind, placebo-controlled study. The Investigational Site pharmacist was not blinded and was responsible for dispensing the appropriate study drug based upon the randomization schedule and ensuring that the remaining Investigational Site personnel were blinded to the drug. Total serum magnesium was used to monitor for magnesium toxicity and subjects with levels ≥ 5 mg/dL were to be discontinued. Thus, there was the potential for these measurements to unblind the Principal Investigator. Due to the pre-existing endogenous levels of total serum magnesium and urine magnesium and the relatively large variability in values between subjects, review of these numbers would not necessarily have suggested one treatment arm over the other. To minimize the impact of such potential unblinding on the ABPM endpoints, a centralized ABPM reader was used and the reader was blinded to the total serum magnesium and urine magnesium values.

Four (4) RMJH-111b (magnesium citrate, tribasic anhydrous) soft gelatin capsules (110 mg elemental magnesium/capsule) orally bid for 7 days

Safety and Tolerability of RMJH-111b Compared to Placebo Based on Treatment Emergent Adverse Events (TEAEs)

Safety & tolerability were primarily assessed based on the incidence of reported TEAEs by system organ class & preferred term, as well as by categories: TEAE, severe TEAE, serious TEAE, drug-related TEAE, drug-related severe TEAE, drug-related serious TEAE, TEAE leading to discontinuation, & TEAE with outcome of death. Drug-related TEAEs were defined as TEAEs assigned a Study Drug (active or placebo) relationship of "adverse reaction" or "suspected adverse reaction". TEAEs were coded using the Medical Dictionary for Regulatory Activities, version 19.0. The severity of TEAEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. TEAEs were defined as any adverse event that started or increased in severity after the first randomized dose of Study Drug on Day 4 through the Final Study Visit (8 +/-3 days after last randomized dose).

Safety and Tolerability of RMJH-111b Compared to Placebo Based on Change in 24-hour Urinary Magnesium Excretion

Change in the mean value of 24-hour urinary magnesium excretion from baseline (Day 3 to pre-dose Day 4) to end of treatment (Day 10 to Day 11). Mean values that are negative represent a decrease in that value from baseline, whereas values that are positive represent an increase.

Changes in the mean values for seated SBP & DBP from baseline (pre-dose Day 4) to end of treatment (Day 11). Mean values that are negative represent a decrease in that value from baseline, whereas values that are positive represent an increase.

Change in mean body weight from baseline (Day 1) to end of treatment (Day 11). The weight measurements were made using a calibrated scale with the subject wearing light clothes and no shoes. Mean values that are negative represent a decrease in that value from baseline, whereas values that are positive represent an increase.

Safety and Tolerability of RMJH-111b Compared to Placebo Based on Change in 12-lead ECG Ventricular Rate (3 Hours After 1st Dose)

Change in mean 12-lead ECG ventricular rate from baseline (Screening or Day 1) to 3 hours after the first randomized dose (Day 4). Mean values that are negative represent a decrease in that value from baseline, whereas values that are positive represent an increase. The ECG assessments were recorded after the subject was resting at least 5 minutes in the supine position in a quiet environment.

Safety and Tolerability of RMJH-111b Compared to Placebo Based on Change in 12-lead ECG Ventricular Rate (After Last Dose)

Change in mean 12-lead ECG ventricular rate from baseline (Screening or Day 1) to after the last randomized dose (Day 11). Mean values that are negative represent a decrease in that value from baseline, whereas values that are positive represent an increase. The ECG assessments were recorded after the subject was resting at least 5 minutes in the supine position in a quiet environment.

Safety and Tolerability of RMJH-111b Compared to Placebo Based on Change in 12-lead ECG Intervals (3 Hours After 1st Dose)

Change in mean 12-lead ECG intervals (RR interval, PR interval, QRS interval, QT interval, corrected QT interval based on Fridericia formula) from baseline (Screening or Day 1) to 3 hours after the first randomized dose (Day 4). Mean values that are negative represent a decrease in that value from baseline, whereas values that are positive represent an increase. The ECG assessments were recorded after the subject was resting at least 5 minutes in the supine position in a quiet environment.

Safety and Tolerability of RMJH-111b Compared to Placebo Based on Change in 12-lead ECG Intervals (After Last Dose)

Change in mean 12-lead ECG intervals (RR interval, PR interval, QRS interval, QT interval, corrected QT interval based on Fridericia formula) from baseline (Screening or Day 1) to after the last randomized dose (Day 11). Mean values that are negative represent a decrease in that value from baseline, whereas values that are positive represent an increase. The ECG assessments were recorded after the subject was resting at least 5 minutes in the supine position in a quiet environment.

Safety and Tolerability of RMJH-111b Compared to Placebo Based on Change in 12-lead ECG Diagnosis (3 Hours After 1st Dose)

Change in 12-lead ECG diagnosis [i.e., normal to abnormal not clinically significant (NCS); normal to abnormal clinically significant (CS); abnormal NCS to abnormal CS; remained abnormal NCS; remained normal] from baseline (Screening or Day 1) to 3 hours after the first randomized dose (Day 4). The ECG was recorded after the subject was resting at least 5 minutes in the supine position in a quiet environment.

Safety and Tolerability of RMJH-111b Compared to Placebo Based on Change in 12-lead ECG Diagnosis (After Last Dose)

Change in 12-lead ECG diagnosis [i.e., normal to abnormal not clinically significant (NCS); normal to abnormal clinically significant (CS); abnormal NCS to abnormal CS; remained abnormal NCS; remained normal] from baseline (Screening or Day 1) to after the last randomized dose (Day 11). The ECG was recorded after the subject was resting at least 5 minutes in the supine position in a quiet environment.

Changes in patellar reflex score from baseline (pre-dose Day 4) to interim time points during the randomized treatment period (prior to each morning dose on Days 5 through 10) and to post-dose time points (Day 11 & Day 18 ± 3 days). The scoring values included 0, 1+, 2+, 3+, and 4+, where 2+ means normal patellar reflex and lower scores indicate a worsened outcome (1+ means reflex present only with reinforcement and 0 means loss of reflex). The patellar reflex assessment was made with the subject in the seated position, with legs hanging freely from the exam table. Loss of patellar reflex is an early sign of magnesium toxicity, and thus the test serves as an assessment for functional magnesium status. A clinical indication of a safe magnesium dosage regimen included the presence of the patellar reflex (knee jerk).

Pharmacokinetics of Total Serum Magnesium After Single and Repeated Oral Administrations of RMJH-111b Compared to Placebo Based on AUC

Venous blood samples were collected within 1 hour prior to & 0.5, 1, 2, 3, 6, & 12 hours following the morning dose of Study Drug on Days 3 (run-in placebo) and 4, & within 1 hour prior to & 0.5, 1, 2, 3, 6, 12, & 24 hours following the morning dose of Study Drug on Day 10. Blood samples were processed to serum & assayed for total serum magnesium by a central laboratory. The LLOQ was 0.06 mEq/L. Individual PK parameters for Days 4 & 10 were to be calculated using corrected concentration-time curves (with individual's baseline assessments of endogenous total serum magnesium at Day 3 subtracted); however, due to small numerical values after correction, the planned PK parameters could not be derived. The analyses were reattempted using the observed values (that include the endogenous levels of magnesium), which allowed AUC0-24 to be derived.

Pharmacokinetics of Total Serum Magnesium After Single and Repeated Oral Administrations of RMJH-111b Compared to Placebo Based on Trough Concentration Ratio

Venous blood samples were collected within 1 hour prior to the morning dose of Study Drug (active or placebo) on Days 4, 5, 6, 7, 8, 9, and 10. Blood samples were processed to serum & assayed for total serum magnesium by a central laboratory (LLOQ = 0.06 mEq/L). Ratios of the individual total serum magnesium trough concentrations at Days 5, 6, 7, 8, 9, and 10 relative to baseline (pre-dose Day 4) were calculated. Observed concentrations (including the endogenous levels of magnesium) were used for this purpose.

Pharmacokinetics of Urine Magnesium After Single and Repeated Oral Administrations of RMJH-111b Compared to Placebo Based on 24-hour Urinary Excretion

Urinary excretion of magnesium was assessed over three 24-hour periods. The first urine collection started immediately after the morning dose of run-in placebo on Day 3, and the second and third collections started immediately after the morning dose of Study Drug on Days 4 and 10, respectively. Observed 24-hour urinary magnesium excretion values at Days 3, 4, and 10 (i.e., without subtraction of the Day 3 values to correct for the individual's baseline assessment of endogenous urinary magnesium excretion) were used for comparisons with the total serum magnesium data (as only the observed serum values allowed for PK parameter derivation).

Efficacy of RMJH-111b Compared to Placebo Based on Change From Baseline in SBPday After 7 Days of Treatment

SBPday = mean daytime (8 AM to 4 PM) ABPM SBP. Note, mean values of change that are negative represent a decrease in that value from baseline, whereas values that are positive represent an increase. SBPday was measured twice during the subject's stay at the CRU: baseline measurements were collected from Day 3 to pre-dose Day 4 & post-dose measurements were collected from Day 10 to Day 11. An Investigational Site staff member placed the cuff on the subject's non-dominant arm & connected the ABPM at approximately 7 AM (± 60 minutes) on Days 3 & 10. A pre-dose ABPM reading was recorded immediately prior to the morning dose of run-in period placebo on Day 3 & the morning dose of treatment period Study Drug (active or placebo) on Day 10. The ABPM was started again immediately after dosing. The ABPM was removed at approximately 8 AM (± 60 minutes) on Days 4 and 11, respectively, but no sooner than 24 hours after the continuous monitoring was initiated.

Efficacy of RMJH-111b Compared to Placebo Based on Change From Baseline in SBPnight After 7 Days of Treatment

SBPnight = mean daytime (10 PM to 6 AM) ABPM SBP. Note, mean values of change that are negative represent a decrease in that value from baseline, whereas values that are positive represent an increase. SBPnight was measured twice during the subject's stay at the CRU: baseline measurements were collected from Day 3 to pre-dose Day 4 & post-dose measurements were collected from Day 10 to Day 11. An Investigational Site staff member placed the cuff on the subject's non-dominant arm & connected the ABPM at approximately 7 AM (± 60 minutes) on Days 3 & 10. A pre-dose ABPM reading was recorded immediately prior to the morning dose of run-in period placebo on Day 3 & the morning dose of treatment period Study Drug (active or placebo) on Day 10. The ABPM was started again immediately after dosing. The ABPM was removed at approximately 8 AM (± 60 minutes) on Days 4 and 11, respectively, but no sooner than 24 hours after the continuous monitoring was initiated.

Efficacy of RMJH-111b Compared to Placebo Based on Change From Baseline in SBP24hr After 7 Days of Treatment

SBP24hr = mean 24-hour ABPM SBP. Note, mean values of change that are negative represent a decrease in that value from baseline, whereas values that are positive represent an increase. SBP24hr was measured twice during the subject's stay at the CRU: baseline measurements were collected from Day 3 to pre-dose Day 4 & post-dose measurements were collected from Day 10 to Day 11. An Investigational Site staff member placed the cuff on the subject's non-dominant arm & connected the ABPM at approximately 7 AM (± 60 minutes) on Days 3 & 10. A pre-dose ABPM reading was recorded immediately prior to the morning dose of run-in period placebo on Day 3 & the morning dose of treatment period Study Drug (active or placebo) on Day 10. The ABPM was started again immediately after dosing. The ABPM was removed at approximately 8 AM (± 60 minutes) on Days 4 and 11, respectively, but no sooner than 24 hours after the continuous monitoring was initiated.

Efficacy of RMJH-111b Compared to Placebo Based on Change From Baseline in DBPday After 7 Days of Treatment

DBPday = mean daytime (8 AM to 4 PM) ABPM DBP. Note, mean values of change that are negative represent a decrease in that value from baseline, whereas values that are positive represent an increase. DBPday was measured twice during the subject's stay at the CRU: baseline measurements were collected from Day 3 to pre-dose Day 4 & post-dose measurements were collected from Day 10 to Day 11. An Investigational Site staff member placed the cuff on the subject's non-dominant arm & connected the ABPM at approximately 7 AM (± 60 minutes) on Days 3 & 10. A pre-dose ABPM reading was recorded immediately prior to the morning dose of run-in period placebo on Day 3 & the morning dose of treatment period Study Drug (active or placebo) on Day 10. The ABPM was started again immediately after dosing. The ABPM was removed at approximately 8 AM (± 60 minutes) on Days 4 and 11, respectively, but no sooner than 24 hours after the continuous monitoring was initiated.

Efficacy of RMJH-111b Compared to Placebo Based on Change From Baseline in DBPnight After 7 Days of Treatment

DBPnight = mean nighttime (10 PM to 6 AM) ABPM DBP. Note, mean values of change that are negative represent a decrease in that value from baseline, whereas values that are positive represent an increase. DBPnight was measured twice during the subject's stay at the CRU: baseline measurements were collected from Day 3 to pre-dose Day 4 & post-dose measurements were collected from Day 10 to Day 11. An Investigational Site staff member placed the cuff on the subject's non-dominant arm & connected the ABPM at approximately 7 AM (± 60 minutes) on Days 3 & 10. A pre-dose ABPM reading was recorded immediately prior to the morning dose of run-in period placebo on Day 3 & the morning dose of treatment period Study Drug (active or placebo) on Day 10. The ABPM was started again immediately after dosing. The ABPM was removed at approximately 8 AM (± 60 minutes) on Days 4 and 11, respectively, but no sooner than 24 hours after the continuous monitoring was initiated.

Efficacy of RMJH-111b Compared to Placebo Based on Change From Baseline in DBP24hr After 7 Days of Treatment

DBP24hr = mean 24-hour ABPM DBP. Note, mean values of change that are negative represent a decrease in that value from baseline, whereas values that are positive represent an increase. DBP24hr was measured twice during the subject's stay at the CRU: baseline measurements were collected from Day 3 to pre-dose Day 4 & post-dose measurements were collected from Day 10 to Day 11. An Investigational Site staff member placed the cuff on the subject's non-dominant arm & connected the ABPM at approximately 7 AM (± 60 minutes) on Days 3 & 10. A pre-dose ABPM reading was recorded immediately prior to the morning dose of run-in period placebo on Day 3 & the morning dose of treatment period Study Drug (active or placebo) on Day 10. The ABPM was started again immediately after dosing. The ABPM was removed at approximately 8 AM (± 60 minutes) on Days 4 and 11, respectively, but no sooner than 24 hours after the continuous monitoring was initiated.

Efficacy of RMJH-111b Compared to Placebo Based on Change From Baseline in Seated SBP After 7 Days of Treatment

Change from baseline (pre-dose Day 4) in seated SBP after 7 days of treatment (Day 11) with RMJH-111b compared to placebo was a secondary efficacy variable (i.e., seated SBP served dual functions as safety and efficacy variables, with the safety population used for the safety analyses described in outcome 3 and the efficacy population used for the efficacy analyses described here). Note, mean values that are negative represent a decrease in that value from baseline, whereas values that are positive represent an increase.

Efficacy of RMJH-111b Compared to Placebo Based on Change From Baseline in Seated DBP After 7 Days of Treatment

Change from baseline (pre-dose Day 4) in seated DBP after 7 days of treatment (Day 11) with RMJH-111b compared to placebo was a secondary efficacy variable (i.e., seated DBP served dual functions as safety and efficacy variables, with the safety population used for the safety analyses described in outcome 3 and the efficacy population used for the efficacy analyses described here). Note, mean values that are negative represent a decrease in that value from baseline, whereas values that are positive represent an increase.

Inclusion Criteria: Male or female, 18-80 years old Diagnosed with essential hypertension SBP ≥ 150 & ≤ 200 mmHg & DBP ≥ 95 and ≤ 115 mmHg after resting for 5 minutes in the seated position at Day 1 & baseline (pre-dose Day 4) Both males & women of child bearing potential (WCBP) agree to use adequate contraceptive methods while on study Willing and able to sign informed consent form (ICF) Suitable for participation in the study in the opinion of the Investigator Exclusion Criteria: History of myocardial infarction, congestive heart failure, or stroke within 6 months of Screening, or evidence of greater than 1st degree heart block or myocardial damage History of chronic hepatitis Uncontrolled diabetes (hemoglobin A1C ≥ 6.5%) at Screening or Day 1 Glomerular filtration rate < 60 mL/min at Screening or Day 1 Serum hypo- or hyper-natremia (≤ 133 & ≥145 meq/L) at Screening or Day 1 Low serum potassium (≤ 3.3 meq/L) at Screening or Day 1 Low total serum magnesium (≤ 1.3 mg/dL) or total serum magnesium greater than the upper limit of normal (2.5 mg/dL) at Screening or Day 1 Serum uric acid > 6.5 mg/dL for females or >7.5 mg/dL for males at Screening or Day 1 Absence of patellar reflex (knee jerk) at Day 1-3, or pre-dose Day 4 Evidence of clinically significant findings at Screening, during the run-in period (Days 1-3), or at baseline (pre-dose Day 4) which, in the opinion of the Investigator would pose a safety risk or interfere with appropriate interpretation of safety data Malignancy within 5 years of the Screening Visit (with the exception of basal cell and squamous cell skin carcinoma) Major surgery within four weeks prior to Screening Presence of a malabsorption syndrome possibly affecting drug absorption (e.g., Crohn's disease or chronic pancreatitis) Presence of irritable bowel syndrome, ulcerative colitis, or chronic diarrhea History of psychotic disorder History of alcoholism or drug addiction or current alcohol or drug use that, in the opinion of the Investigator, will interfere with the subject's ability to comply with the dosing schedule & study evaluations History of any illicit drug use within one year prior to Screening Positive drug screen at Screening or at Day 1, except subjects on prescription drugs that in the opinion of the Investigator will not influence the outcome of the study Positive breathalyzer test for blood alcohol content at Screening or at Day 1 Consumption of more than five cups of caffeinated beverages per day Current treatment or treatment within 30 days prior to the first dose of Study Drug (active or placebo; Day 4) with another investigational drug, or current enrollment in another clinical trial Current treatment or treatment within 10 days prior to the first dose of Study Drug (active or placebo; Day 4) with any anti-hypertension medication (other than Study Drug during the treatment period) Current treatment or treatment within 30 days prior to the first dose of Study Drug (active or placebo; Day 4) with magnesium-containing antacids or laxatives, dietary supplement(s) where the total daily dose of magnesium is greater than 150 mg, central nervous system depressants, neuromuscular blocking agents, or cardiac glycosides, lithium-containing drugs, bisphosphonates, sodium polystyrene sulfonate, or tetracycline/quinolone antibiotics, anti-tumor necrosis factor-alpha drugs, or phytotherapeutic/herbal/ plant derived preparations Known hypersensitivity to magnesium Known hypersensitivity to the inactive ingredients in the Study Drug (placebo and active) Positive pregnancy test at Screening or at Day 1, or lactating Arm circumference greater than 42 centimeters