0 mg elemental magnesium/capsule

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.

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.

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.

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.

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.

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).

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.

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).

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.

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.

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.

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.

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.

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.

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.

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.

Total of all reporting groups

Baseline height was measured at the Screening visit using a calibrated stadiometer with the subject wearing no shoes.

Baseline weight was measured after the washout period and before the first placebo run-in dose (i.e., on Day 1) using a calibrated scale with the subject wearing light clothes and no shoes.

Baseline heart rate was measured after the run-in period and prior to the first randomized dose (i.e., pre-dose Day 4). The measurement was made after the subject was sitting for at least 5 minutes in a quiet environment and prior to the blood sample collection for baseline total serum magnesium.

Baseline respiration rate was measured after the run-in period and prior to the first randomized dose (i.e., pre-dose Day 4). The measurement was made after the subject was sitting for at least 5 minutes in a quiet environment and prior to the blood sample collection for baseline total serum magnesium.

Baseline temperature was measured after the run-in period and prior to the first randomized dose (i.e., pre-dose Day 4).

Baseline seated SBP was measured after the run-in period and prior to the first randomized dose (i.e., pre-dose Day 4). The measurement was made after the subject was sitting for at least 5 minutes in a quiet environment and prior to the blood sample collection for baseline total serum magnesium. The recorded seated SBP value was the mean of two measurements taken 2 minutes apart and using the dominant arm.

Baseline seated DBP was measured after the run-in period and prior to the first randomized dose (i.e., pre-dose Day 4). The measurement was made after the subject was sitting for at least 5 minutes in a quiet environment and prior to the blood sample collection for baseline total serum magnesium. The recorded seated DBP value was the mean of two measurements taken 2 minutes apart and using the dominant arm.

Baseline SBPday [mean daytime (8 AM to 4 PM) ABPM SBP] was measured after the run-in period & prior to the 1st randomized dose (Day 3 to pre-dose Day 4). An Investigational Site member placed the cuff on the subject's non-dominant arm & connected the ABPM at approximately 7 AM (± 60 minutes) on Day 3. A pre-dose ABPM reading was recorded immediately prior to the morning dose of run-in period placebo (Day 3). The ABPM was started again immediately after dosing, and was removed at approximately 8 AM (± 60 minutes) on Day 4, but no sooner than 24 hours after the monitoring was initiated.

Baseline SBPnight [mean nighttime (10 PM to 6 AM) ABPM SBP] was measured after the run-in period & prior to the 1st randomized dose (Day 3 to pre-dose Day 4). An Investigational Site member placed the cuff on the subject's non-dominant arm & connected the ABPM at approximately 7 AM (± 60 minutes) on Day 3. A pre-dose ABPM reading was recorded immediately prior to the morning dose of run-in period placebo (Day 3). The ABPM was started again immediately after dosing, and was removed at approximately 8 AM (± 60 minutes) on Day 4, but no sooner than 24 hours after the monitoring was initiated.

Baseline SBP24hr (mean 24-hour ABPM SBP) was measured after the run-in period & prior to the 1st randomized dose (Day 3 to pre-dose Day 4). An Investigational Site member placed the cuff on the subject's non-dominant arm & connected the ABPM at approximately 7 AM (± 60 minutes) on Day 3. A pre-dose ABPM reading was recorded immediately prior to the morning dose of run-in period placebo (Day 3). The ABPM was started again immediately after dosing, and was removed at approximately 8 AM (± 60 minutes) on Day 4, but no sooner than 24 hours after the monitoring was initiated.

Baseline DBPday [mean daytime (8 AM to 4 PM) ABPM DBP] was measured after the run-in period & prior to the 1st randomized dose (Day 3 to pre-dose Day 4). An Investigational Site member placed the cuff on the subject's non-dominant arm & connected the ABPM at approximately 7 AM (± 60 minutes) on Day 3. A pre-dose ABPM reading was recorded immediately prior to the morning dose of run-in period placebo (Day 3). The ABPM was started again immediately after dosing, and was removed at approximately 8 AM (± 60 minutes) on Day 4, but no sooner than 24 hours after the monitoring was initiated.

Baseline DBPnight [mean nighttime (10 PM to 6 AM) ABPM DBP] was measured after the run-in period & prior to the 1st randomized dose (Day 3 to pre-dose Day 4). An Investigational Site member placed the cuff on the subject's non-dominant arm & connected the ABPM at approximately 7 AM (± 60 minutes) on Day 3. A pre-dose ABPM reading was recorded immediately prior to the morning dose of run-in period placebo (Day 3). The ABPM was started again immediately after dosing, and was removed at approximately 8 AM (± 60 minutes) on Day 4, but no sooner than 24 hours after the monitoring was initiated.

Baseline DBP24hr (mean 24-hour ABPM DBP) was measured after the run-in period & prior to the 1st randomized dose (Day 3 to pre-dose Day 4). An Investigational Site member placed the cuff on the subject's non-dominant arm & connected the ABPM at approximately 7 AM (± 60 minutes) on Day 3. A pre-dose ABPM reading was recorded immediately prior to the morning dose of run-in period placebo (Day 3). The ABPM was started again immediately after dosing, and was removed at approximately 8 AM (± 60 minutes) on Day 4, but no sooner than 24 hours after the monitoring was initiated.

Venous blood samples were collected within 1 hour prior to & 0.5, 1, 2, 3, 6, & 12 hours following the morning dose of run-in placebo on Day 3 & within 1 hour prior to the 1st randomized dose on Day 4. Blood samples were processed to serum & assayed for total serum magnesium by a central laboratory [lower limit of quantitation (LLOQ) = 0.06 mEq/L]. Individual concentration-time curves were plotted & area under the serum concentration-time curve from time zero to 24 hours post-dose (AUC0-24) values were derived. This value represents the subject's endogenous levels of total serum magnesium.

A venous blood sample was collected within 1 hour prior to the first randomized dose (pre-dose Day 4). The blood sample was processed to serum & assayed for total serum magnesium by a central laboratory (LLOQ = 0.06 mEq/L). This value represents the subject's baseline concentration of endogenous total serum magnesium.

Baseline urinary excretion of magnesium was assessed over a 24-hour period, starting immediately after the morning dose of run-in placebo on Day 3 and ending prior to the first randomized dose (i.e., Day 3 - pre-dose Day 4). This value represents the subject's baseline endogenous urinary magnesium excretion.

Baseline 12-lead electrocardiogram (ECG) ventricular rate was measured at Screening or Day 1. The ECG assessments were recorded after the subject was resting at least 5 minutes in the supine position in a quiet environment.

Baseline 12-lead ECG intervals (RR interval, PR interval, QRS interval, QT interval, corrected QT interval based on Fridericia formula) were measured at Screening or Day 1. The ECG assessments were recorded after the subject was resting at least 5 minutes in the supine position in a quiet environment.

Baseline 12-lead ECG diagnosis [normal; abnormal but not clinically significant (NCS); abnormal and clinically significant (CS)] was assessed at Screening or Day 1. The ECG was recorded after the subject was resting at least 5 minutes in the supine position in a quiet environment.

Baseline patellar reflex score was measured at pre-dose Day 4. 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.

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.

Safety population = all randomized subjects who received at least 1 dose of Study Drug. 1 subject in RMJH-111b arm was discontinued on Day 9 due to protocol-specified criterion [SBP<110 mmHg; the SBPs (102-109 mmHg) were not associated with clinical symptoms & were not assigned as TEAEs] & is therefore missing Day 10-11 assessment (i.e., n=15).

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.

Safety population = all randomized subjects who received at least 1 dose of Study Drug. 1 subject in RMJH-111b arm was discontinued on Day 9 due to protocol-specified criterion [SBP<110 mmHg; the SBPs (102-109 mmHg) were not associated with clinical symptoms & were not assigned as TEAEs] & is therefore missing Day 11 assessments (i.e., n=15).

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 population = all randomized subjects who received at least 1 dose of Study Drug. 1 subject in RMJH-111b arm was discontinued on Day 9 due to protocol-specified criterion [SBP<110 mmHg; the SBPs (102-109 mmHg) were not associated with clinical symptoms & were not assigned as TEAEs] & is therefore missing Day 11 assessment (i.e., n=15).

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 population = all randomized subjects who received at least 1 dose of Study Drug

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 population = all randomized subjects who received at least 1 dose of Study Drug. 1 subject in RMJH-111b arm was discontinued on Day 9 due to protocol-specified criterion [SBP<110 mmHg; the SBPs (102-109 mmHg) were not associated with clinical symptoms & were not assigned as TEAEs] & is therefore missing Day 11 assessment (i.e., n=15).

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 population = all randomized subjects who received at least 1 dose of Study Drug

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 population = all randomized subjects who received at least 1 dose of Study Drug. 1 subject in RMJH-111b arm was discontinued on Day 9 due to protocol-specified criterion [SBP<110 mmHg; the SBPs (102-109 mmHg) were not associated with clinical symptoms & were not assigned as TEAEs] & is therefore missing Day 11 assessment (i.e., n=15).

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 population = all randomized subjects who received at least 1 dose of Study Drug

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.

Safety population = all randomized subjects who received at least 1 dose of Study Drug. 1 subject in RMJH-111b arm was discontinued on Day 9 due to protocol-specified criterion [SBP<110 mmHg; the SBPs (102-109 mmHg) were not associated with clinical symptoms & were not assigned as TEAEs] & is therefore missing Day 11 assessment (i.e., n=15).

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).

Safety population = all randomized subjects who received at least 1 dose of Study Drug. 1 RMJH-111b subject was discontinued on Day 9 due to protocol requirement [SBP<110 mmHg; SBPs (102-109 mmHg) not associated with clinical symptoms & not assigned as TEAEs] & lacked Day 10-11 assessments (i.e., n=15). Subject was at 2+ for Day 4-9 & Final Visit.

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.

PK population = all randomized subjects who received at least 1 dose of Study Drug with valid data for at least 1 pre- & post-dose assessment. 1 subject in RMJH-111b arm was missing PK assessments beyond Day 8, & thus is only included in the analyses for Days 3 & 4 and not for Day 10 (i.e., n = 16 for Days 3 & 4, but n = 15 for Day 10).

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.

PK population = all randomized subjects who received at least 1 dose of Study Drug with valid data for at least 1 pre- & post-dose assessment. 1 subject in RMJH-111b arm was missing PK assessments beyond Day 8, & thus is only included in the analyses for Days 5-8 and not for Days 9-10 (i.e., n = 16 for Days 5-8, but n = 15 for Days 9-10).

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).

PK population = all randomized subjects who received at least 1 dose of Study Drug with valid data for at least 1 pre- & post-dose assessment. 1 subject in RMJH-111b arm was missing PK assessments beyond Day 8, & thus is only included in the analyses for Days 3 & 4 and not for Day 10 (i.e., n = 16 for Days 3 and 4, but n = 15 for Day 10).

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 population = all randomized subjects who completed 7 days of treatment & the Day 3-Day 4 and Day 10-Day 11 ABPM assessments. 1 subject in RMJH-111b arm was discontinued on Day 9 due to meeting protocol-specified criterion (SBP < 110 mmHg). The SBPs (102-109 mmHg) were not associated with clinical symptoms & were not assigned as TEAEs.

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 population = all randomized subjects who completed 7 days of treatment & the Day 3-Day 4 and Day 10-Day 11 ABPM assessments. 1 subject in RMJH-111b arm was discontinued on Day 9 due to meeting protocol-specified criterion (SBP < 110 mmHg). The SBPs (102-109 mmHg) were not associated with clinical symptoms & were not assigned as TEAEs.

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 population = all randomized subjects who completed 7 days of treatment & the Day 3-Day 4 and Day 10-Day 11 ABPM assessments. 1 subject in RMJH-111b arm was discontinued on Day 9 due to meeting protocol-specified criterion (SBP < 110 mmHg). The SBPs (102-109 mmHg) were not associated with clinical symptoms & were not assigned as TEAEs.

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 population = all randomized subjects who completed 7 days of treatment & the Day 3-Day 4 and Day 10-Day 11 ABPM assessments. 1 subject in RMJH-111b arm was discontinued on Day 9 due to meeting protocol-specified criterion (SBP < 110 mmHg). The SBPs (102-109 mmHg) were not associated with clinical symptoms & were not assigned as TEAEs.

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 population = all randomized subjects who completed 7 days of treatment & the Day 3-Day 4 and Day 10-Day 11 ABPM assessments. 1 subject in RMJH-111b arm was discontinued on Day 9 due to meeting protocol-specified criterion (SBP < 110 mmHg). The SBPs (102-109 mmHg) were not associated with clinical symptoms & were not assigned as TEAEs.

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 population = all randomized subjects who completed 7 days of treatment & the Day 3-Day 4 and Day 10-Day 11 ABPM assessments. 1 subject in RMJH-111b arm was discontinued on Day 9 due to meeting protocol-specified criterion (SBP < 110 mmHg). The SBPs (102-109 mmHg) were not associated with clinical symptoms & were not assigned as TEAEs.

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 population = all randomized subjects who completed 7 days of treatment & pre-dose Day 4 & Day 11 assessments. 1 subject in RMJH-111b arm was discontinued on Day 9 for meeting protocol-specified criterion [SBP<110 mmHg; SBPs (102-109 mmHg) were not associated with clinical symptoms & not assigned as TEAEs] & is therefore excluded.

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.

Efficacy population = all randomized subjects who completed 7 days of treatment & pre-dose Day 4 & Day 11 assessments. 1 subject in RMJH-111b arm was discontinued on Day 9 for meeting protocol-specified criterion [SBP<110 mmHg; SBPs (102-109 mmHg) were not associated with clinical symptoms & not assigned as TEAEs] & is therefore excluded.

Four (4) placebo soft gelatin capsules (0 mg elemental magnesium/capsule) orally bid for 7 days

continuous moderate

single event or intermittent mild

intermittent mild

intermittent mild

intermittent mild