Essential HypertensionPhase 1/2NCT02822222
Safety Study of RMJH-111b to Treat Essential Hypertension
A Phase 1/2 study testing Magnesium citrate, tribasic anhydrous soft gelatin capsule in people with Essential Hypertension, run by RMJ Holdings, LLC at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Essential Hypertension
- What is being tested?
- Magnesium citrate, tribasic anhydrous soft gelatin capsule
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 22 participants
- Where
- 1 siteUnited States
- Study dates
- 10 Jun 2016to 7 Jul 2016
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 27Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Orange County Research Center
Tustin, California, 92780
About this study
Official title: 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).
Read the detailed description
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.
- Conditions
- Essential Hypertension
- Being tested
- Magnesium citrate, tribasic anhydrous soft gelatin capsule, Placebo soft gelatin capsule
- Keywords
- essential hypertension, hypertension, high blood pressure, cardiovascular disease, RMJH-111b, magnesium, magnesium citrate, calcium channel blocker, vasodilator, antihypertensive, anti-hypertensive
- Medical subject headings
- Essential Hypertension, Hypertension, Cardiovascular Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Magnesium citrate, tribasic anhydrous soft gelatin capsuleDrug
Also called RMJH-111b
110 mg elemental magnesium/capsule
Placebo soft gelatin capsuleDrug
Also called Placebo
0 mg elemental magnesium/capsule
| Study group | Role | What they receive |
|---|---|---|
| RMJH-111b | Experimental | Four (4) RMJH-111b (magnesium citrate, tribasic anhydrous) soft gelatin capsules (110 mg elemental magnesium/capsule) orally bid for 7 days Receives: Drug: Magnesium citrate, tribasic anhydrous soft gelatin capsule |
| Placebo | Placebo comparator | Four (4) placebo soft gelatin capsules (0 mg elemental magnesium/capsule) orally bid for 7 days Receives: Drug: Placebo soft gelatin capsule |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 14 days +/- 3 days
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.
Measured: 8 days
Safety and Tolerability of RMJH-111b Compared to Placebo Based on Change in Seated SBP and DBP
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.
Measured: 7 days
Safety and Tolerability of RMJH-111b Compared to Placebo Based on Change in Body Weight
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.
Measured: 10 days
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.
Measured: Up to 6 days
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.
Measured: Up to 13 days
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.
Measured: Up to 6 days
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.
Measured: Up to 13 days
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.
Measured: Up to 6 days
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.
Measured: Up to 13 days
Safety and Tolerability of RMJH-111b Compared to Placebo Based on Change in Patellar Reflex Score
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).
Measured: 14 days +/- 3 days
Secondary outcomes (11)
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.
Measured: 8 days
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.
Measured: 6 days
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).
Measured: 8 days
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.
Measured: 8 days
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.
Measured: 8 days
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.
Measured: 8 days
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.
Measured: 8 days
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.
Measured: 8 days
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.
Measured: 8 days
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.
Measured: 7 days
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.
Measured: 7 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Jul 2016 (estimated)
- Study start10 Jun 2016
- Primary completion7 Jul 2016
- Study completion7 Jul 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Essential HypertensionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 22 participants (actual)
Sponsor and investigators
- Lead sponsor
- RMJ Holdings, LLC
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Joel M Neutel, MD, Principal investigator, Orange County Research Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02822222
- Sponsor's protocol ID
- RMJH-111b-002
- Status last verified
- Sep 2020
- First submitted
- 28 Jun 2016
- Last updated
- 23 Sep 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 23 Sep 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT02822222
- Acronym / sponsor ID
- RMJH-111b-002
- Conditions
- Essential Hypertension
- Keywords
- essential hypertension, hypertension, high blood pressure, cardiovascular disease, RMJH-111b, magnesium, magnesium citrate, calcium channel blocker
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 22 participants (actual)
- Lead sponsor
- RMJ Holdings, LLCIndustry (pharma, biotech, devices)
- Study start
- 10 Jun 2016 (actual)
- Primary completion
- 7 Jul 2016 (actual)
- Study completion
- 7 Jul 2016 (actual)
- First posted
- 4 Jul 2016 (estimated)
- Results
- Posted 23 Sep 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| RMJH-111b | Experimental | Drug: Magnesium citrate, tribasic anhydrous soft gelatin capsuleFour (4) RMJH-111b (magnesium citrate, tribasic anhydrous) soft gelatin capsules (110 mg elemental magnesium/capsule) orally bid for 7 days |
| Placebo | Placebo comparator | Drug: Placebo soft gelatin capsuleFour (4) placebo soft gelatin capsules (0 mg elemental magnesium/capsule) orally bid for 7 days |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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)
Key exclusion criteria (27 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Magnesium citrate, tribasic anhydrous soft gelatin capsuleAlso: RMJH-111b110 mg elemental magnesium/capsule | Drug | RMJH-111b |
| Placebo soft gelatin capsuleAlso: Placebo0 mg elemental magnesium/capsule | Drug | Placebo |
Primary outcome
Safety and Tolerability of RMJH-111b Compared to Placebo Based on Treatment Emergent Adverse Events (TEAEs)
Time frame: 14 days +/- 3 days
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
Time frame: 8 days
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 and Tolerability of RMJH-111b Compared to Placebo Based on Change in Seated SBP and DBP
Time frame: 7 days
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 and Tolerability of RMJH-111b Compared to Placebo Based on Change in Body Weight
Time frame: 10 days
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)
Time frame: Up to 6 days
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)
Time frame: Up to 13 days
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)
Time frame: Up to 6 days
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)
Time frame: Up to 13 days
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)
Time frame: Up to 6 days
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)
Time frame: Up to 13 days
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 and Tolerability of RMJH-111b Compared to Placebo Based on Change in Patellar Reflex Score
Time frame: 14 days +/- 3 days
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).
11 secondary outcomes
Pharmacokinetics of Total Serum Magnesium After Single and Repeated Oral Administrations of RMJH-111b Compared to Placebo Based on AUC
Time frame: 8 days
Pharmacokinetics of Total Serum Magnesium After Single and Repeated Oral Administrations of RMJH-111b Compared to Placebo Based on Trough Concentration Ratio
Time frame: 6 days
Pharmacokinetics of Urine Magnesium After Single and Repeated Oral Administrations of RMJH-111b Compared to Placebo Based on 24-hour Urinary Excretion
Time frame: 8 days
Efficacy of RMJH-111b Compared to Placebo Based on Change From Baseline in SBPday After 7 Days of Treatment
Time frame: 8 days
Efficacy of RMJH-111b Compared to Placebo Based on Change From Baseline in SBPnight After 7 Days of Treatment
Time frame: 8 days
Efficacy of RMJH-111b Compared to Placebo Based on Change From Baseline in SBP24hr After 7 Days of Treatment
Time frame: 8 days
Efficacy of RMJH-111b Compared to Placebo Based on Change From Baseline in DBPday After 7 Days of Treatment
Time frame: 8 days
Efficacy of RMJH-111b Compared to Placebo Based on Change From Baseline in DBPnight After 7 Days of Treatment
Time frame: 8 days
Efficacy of RMJH-111b Compared to Placebo Based on Change From Baseline in DBP24hr After 7 Days of Treatment
Time frame: 8 days
Efficacy of RMJH-111b Compared to Placebo Based on Change From Baseline in Seated SBP After 7 Days of Treatment
Time frame: 7 days
Efficacy of RMJH-111b Compared to Placebo Based on Change From Baseline in Seated DBP After 7 Days of Treatment
Time frame: 7 days
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Sep 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Joel M Neutel, MD principal investigator
Orange County Research Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Magnesium citrate, tribasic anhydrous soft gelatin capsule in people with Essential Hypertension, run by RMJ Holdings, LLC at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 27 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 23 Sep 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 23 Sep 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Safety and Tolerability of RMJH-111b Compared to Placebo Based on Treatment Emergent Adverse Events (TEAEs) (time frame: 14 days +/- 3 days). The study lists 11 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Sep 2020.