Efficacy and tolerability of two formulations of ramipril in Korean adults with mild to moderate essential hypertension: an 8-week, multicenter, prospective, randomized, open-label, parallel-group noninferiority trial.
OBJECTIVE
This study was designed to compare the efficacy and tolerability of a new generic formulation of ramipril (test) and the branded formulation of ramipril (reference) to satisfy regulatory requirements for marketing of the generic product for use in Korean patients with mild to moderate hypertension.


METHODS
This was an 8-week, multicenter, prospective, randomized, open-label, parallel-group non-inferiority trial in adult patients (age > 18 years) with mild to moderate essential hypertension (sitting dia-stolic blood pressure [SiDBP] 90-109 mm Hg). After a 2-week washout of previous antihypertensive medications, eligible patients were randomized to receive either ramipril 5 mg/d in the morning (low-dose group: baseline SiDBP 90-99 mm Hg) or ramipril 10 mg/d (high-dose group: baseline SiDBP 100-109 mm Hg) for the first 4 weeks. If SiDBP was > or = 90 mm Hg after 4 weeks of treatment, the dose was increased to 10 mg/d for the remaining 4 weeks in the low-dose group, and hydrochlorothiazide 12.5 mg was added to the regimen for the remaining 4 weeks in the high-dose group. The primary end point was the change in SiDBP from baseline to week 8. Secondary end points included a noninferiority analysis of the test and reference formulations with respect to the change in mean sitting systolic blood pressure (SiSBP) from baseline to week 8; SiDBP and SiSBP response rates (proportion of patients achieving an SiDBP < 90 mm Hg and SiSBP < 140 mm Hg, respectively) at 8 weeks; and changes from baseline in SiSBP, pulse wave velocity (PWV), exercise capacity, left-ventricular diastolic function (LVDF), and levels of brain natriuretic peptide (BNP) and high-sensitivity C-reactive protein (hs-CRP). Laboratory and clinical adverse events (AEs) were monitored at each study visit (4 and 8 weeks).


RESULTS
The modified intent-to-treat population consisted of 89 patients (45 test, 44 reference; 60 men, 29 women; mean age, 49.7 years; mean weight, 69.9 kg). At week 8, mean (SD) SiSBP and SiDBP were significantly decreased from baseline in both groups (test: from 145.0 [9.7]/98.1 [5.3] mm Hg to 132.2 [11.1]/ 91.8 [7.1] mm Hg [P < 0.001]; reference: from 145.1 [11.4]/98.0 [5.7] mm Hg to 134.0 [14.6]/92.5 [7.9] mm Hg [P < 0.001]). The changes in blood pressure at week 8 did not differ significantly between the test and reference groups or between the low- and highdose groups in a subgroup analysis. Blood pressure response rates at 8 weeks did not differ significantly between the groups receiving the test and reference formulations (SiDBP: 26.7% and 31.8%, respectively; SiSBP: 37.8% and 40.9%). In addition, there were no significant between-group differences in the change in PWV (-63.8 and -38.7 cm/sec), LVDF at rest or after exercise, or levels of BNP or hs-CRP. The incidence of AEs was 64.4% in the test formulation group and 68.2% in the reference group formulation (P = NS). The most common AE in both groups was cough (10/45 [22.2%] and 10/44 [22.7%]).


CONCLUSIONS
There were no significant differences in the efficacy and tolerability of the test and reference formulations of ramipril in these Korean adults with mild to moderate hypertension. The new generic formulation was noninferior to the reference formulation in terms of the change in SiDBP at week 8.
Kim
Sang-Hyun
SH
Department of Internal Medicine, Seoul Metropolitan Boramae Hospital, Seoul, Republic of Korea.
Chung
Woo-Young
WY
Zo
Joo-Hee
JH
Kim
Myung-A
MA
Chang
Hyuk-Jae
HJ
Cho
Young-Seok
YS
Youn
Tae-Jin
TJ
Chae
In-Ho
IH
Choi
Dong-Joo
DJ
Gwak
Jae-Jin
JJ
Lee
Hae-Young
HY
Park
Jin-Sik
JS
Kang
Hyun-Jae
HJ
Kim
Young-Jin
YJ
Kim
Hyo-Soo
HS
D000959:Antihypertensive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D002097:C-Reactive Protein / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D016568:Drugs, Generic / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D006852:Hydrochlorothiazide / Q000627:therapeutic use; D006973:Hypertension / Q000188:drug therapy*; D007723:Korea; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000097:blood / Q000187:drug effects; D011446:Prospective Studies; D017257:Ramipril / Q000009:adverse effects / Q000737:chemistry* / Q000145:classification / Q000627:therapeutic use*; D012720:Severity of Illness Index; D016896:Treatment Outcome; D016277:Ventricular Function, Left / Q000187:drug effects
D000959:Antihypertensive Agents; D016568:Drugs, Generic; D006852:Hydrochlorothiazide; D020097:Natriuretic Peptide, Brain; D002097:C-Reactive Protein; D017257:Ramipril