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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 22
- 试验地点
- 1
- 主要终点
- Safety and Tolerability of RMJH-111b Compared to Placebo Based on Change in 24-hour Urinary Magnesium Excretion
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
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.
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
RMJH-111b
Four (4) RMJH-111b (magnesium citrate, tribasic anhydrous) soft gelatin capsules (110 mg elemental magnesium/capsule) orally bid for 7 days
干预措施: Magnesium citrate, tribasic anhydrous soft gelatin capsule (Drug)
Placebo
Four (4) placebo soft gelatin capsules (0 mg elemental magnesium/capsule) orally bid for 7 days
干预措施: Placebo soft gelatin capsule (Drug)
结局指标
主要结局
Safety and Tolerability of RMJH-111b Compared to Placebo Based on Change in 24-hour Urinary Magnesium Excretion
时间窗: 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 Treatment Emergent Adverse Events (TEAEs)
时间窗: 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 Body Weight
时间窗: 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 Intervals (3 Hours After 1st Dose)
时间窗: 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 Ventricular Rate (After Last Dose)
时间窗: 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 Diagnosis (After Last Dose)
时间窗: 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 12-lead ECG Intervals (After Last Dose)
时间窗: 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 Seated SBP and DBP
时间窗: 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 12-lead ECG Ventricular Rate (3 Hours After 1st Dose)
时间窗: 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 Diagnosis (3 Hours After 1st Dose)
时间窗: 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 Patellar Reflex Score
时间窗: 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).
次要结局
- Pharmacokinetics of Total Serum Magnesium After Single and Repeated Oral Administrations of RMJH-111b Compared to Placebo Based on AUC(8 days)
- Pharmacokinetics of Total Serum Magnesium After Single and Repeated Oral Administrations of RMJH-111b Compared to Placebo Based on Trough Concentration Ratio(6 days)
- Efficacy of RMJH-111b Compared to Placebo Based on Change From Baseline in SBP24hr After 7 Days of Treatment(8 days)
- Efficacy of RMJH-111b Compared to Placebo Based on Change From Baseline in Seated DBP After 7 Days of Treatment(7 days)
- Efficacy of RMJH-111b Compared to Placebo Based on Change From Baseline in SBPday After 7 Days of Treatment(8 days)
- Efficacy of RMJH-111b Compared to Placebo Based on Change From Baseline in SBPnight After 7 Days of Treatment(8 days)
- Pharmacokinetics of Urine Magnesium After Single and Repeated Oral Administrations of RMJH-111b Compared to Placebo Based on 24-hour Urinary Excretion(8 days)
- Efficacy of RMJH-111b Compared to Placebo Based on Change From Baseline in DBPnight After 7 Days of Treatment(8 days)
- Efficacy of RMJH-111b Compared to Placebo Based on Change From Baseline in DBPday After 7 Days of Treatment(8 days)
- Efficacy of RMJH-111b Compared to Placebo Based on Change From Baseline in DBP24hr After 7 Days of Treatment(8 days)
- Efficacy of RMJH-111b Compared to Placebo Based on Change From Baseline in Seated SBP After 7 Days of Treatment(7 days)