Safety Study of RMJH-111b to Treat Essential Hypertension

NCT02822222 | Completed Phase 1 Results FDA Drug

• 1 other identifier: RMJH-111b-002
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

Brief 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. 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).

Conditions

Essential Hypertension

Keywords

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

Outcome Measures

Primary Outcomes (11)

• 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).

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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).

  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

  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

• 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 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

Study Arms (2)

RMJH-111b

EXPERIMENTAL

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

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

Drug: Placebo soft gelatin capsule

Interventions

Magnesium citrate, tribasic anhydrous soft gelatin capsule DRUG

110 mg elemental magnesium/capsule

Also known as: RMJH-111b

RMJH-111b

Placebo soft gelatin capsule DRUG

0 mg elemental magnesium/capsule

Also known as: Placebo

Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• RMJ Holdings, LLC: lead

Study Sites (1)

Orange County Research Center

Tustin, California, 92780, United States

Location

MeSH Terms

Conditions

Essential Hypertension; Hypertension; Cardiovascular Diseases

Interventions

magnesium citrate

Condition Hierarchy (Ancestors)

Vascular Diseases

Limitations and Caveats

See Detailed Description under Study Description section of record for study design rationale and limits with regards to PK analysis of serum magnesium.

Results Point of Contact

• Title: Russell Jaffe, M.D., Chief Executive Officer
• Organization: RMJ Holdings LLC d/b/a RMJH Rx

rjaffe@rmjholdings.com

(703) 840-4440

Study Officials

• Joel M Neutel, MD

  Orange County Research Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 28, 2016
• First Posted: July 4, 2016
• Study Start: June 10, 2016
• Primary Completion: July 7, 2016
• Study Completion: July 7, 2016
• Last Updated: September 23, 2020
• Results First Posted: September 23, 2020

Record last verified: 2020-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)