A Prospective Randomized, Double-Blind, Multi-Center, Phase III Clinical Trial Evaluating the Efficacy and Safety of Olmesartan/Amlodipine plus Rosuvastatin Combination Treatment in Patients with Concomitant Hypertension and Dyslipidemia: A LEISURE Study

Background: This study was a multicenter, randomized, double-blinded, placebo-controlled phase III clinical trial to investigate the efficacy and safety of an olmesartan/amlodipine single pill plus rosuvastatin combination treatment for patients with concomitant hypertension and dyslipidemia. Methods: Patients with both hypertension and dyslipidemia aged 20–80 were enrolled from 36 tertiary hospitals in Korea from January 2017 to April 2018. Patients were randomized to three groups in a 1:1:0.5 ratio, olmesartan/amlodipine single pill plus rosuvastatin (olme/amlo/rosu) or olmesartan plus rosuvastatin (olme/rosu) or olmesartan/amlodipine single pill (olme/amlo) combination. The primary endpoints were change of sitting systolic blood pressure (sitSBP) from baseline in the olme/amlo/rosu vs. olme/rosu groups and the percentage change of low-density lipoprotein cholesterol (LDL-C) from baseline in the olme/amlo/rosu vs. olme/amlo groups after 8 weeks of treatment. Results: A total of 265 patients were randomized, 106 to olme/amlo/rosu, 106 to olme/rosu and 53 to olme/amlo groups. Baseline characteristics among the three groups did not differ. The mean sitSBP change was significantly larger in the olme/amlo/rosu group with −24.30 ± 12.62 mmHg (from 153.58 ± 10.90 to 129.28 ± 13.58) as compared to the olme/rosu group, −9.72 ± 16.27 mmHg (from 153.71 ± 11.10 to 144.00 ± 18.44 mmHg). The difference in change of sitSBP between the two groups was −14.62± 1.98 mmHg with significance (95% CI −18.51 to −10.73, p < 0.0001). The mean LDL-C reduced significantly in the olme/amlo/rosu group, −52.31 ± 16.63% (from 154.52 ± 30.84 to 72.72 ± 26.08 mg/dL) as compared to the olme/amlo group with no change, −2.98 ± 16.16% (from 160.42 ± 32.05 to 153.81 ± 31.57 mg/dL). Significant difference in change was found in LDL-C between the two groups with −50.10 ± 2.73% (95% CI −55.49 to −44.71, p < 0.0001). Total adverse drug reaction rates were 10.48%, 5.66% and 3.7% in the olme/amlo/rosu, olme/rosu and olme/amlo groups, respectively with no statistical significance among the three groups. Serious adverse drug reactions did not occur. Conclusions: Olmesartan/amlodipine single pill plus rosuvastatin combination treatment for patients with both hypertension and dyslipidemia is effective and safe as compared to either olmesartan plus rosuvastatin or olmesartan plus amlodipine treatment.


Introduction
Single pill combination (SPC) of two or more antihypertensive drugs has shown promising results in improving drug compliance, lowering blood pressure and potentially providing better clinical outcomes [1][2][3][4].
There have been many clinical trials to evaluate the efficacy and safety of the SPC of 2-3 classes of antihypertensive or dyslipidemia drug [5][6][7]. Moreover, SPCs with both antihypertensive and anti-dyslipidemia drugs have been developed and tested [4,[8][9][10][11]. Most of these studies showed promising efficacy and safety data as compared to monotherapy or equivalent doses of separate pill combinations. Reflecting these results, recent guidelines regarding hypertension management specifically indicated the use of single-pill combinations for the simple purpose of improving drug adherence [12]. The concept of single pill, or fixed dose combination, or poly-pill has broadened its scope beyond hypertension or dyslipidemia treatment. A recent clinical trial assessing the separate small dose combination of four classes of cardiovascular drugs suggests promising use of the poly-pill in reducing cardiovascular disease [10,13]. The performance of this kind of clinical trial suggests the popularity and promising future directions for the poly=pill or SPC in treating hypertension and cardiovascular disease. Patients with hypertension had high probability of dyslipidemia and vice versa. Therefore, concomitant prescription of antihypertensive and anti-dyslipidemia drugs is not rare and this will increase in the future as the elderly and co-morbid population grows. Accordingly, the SPC of different kinds of antihypertensive and anti-dyslipidemia drugs is needed in the context of compliance improvement and for better clinical outcome. Moreover, reflecting the recommendation of recent hypertension treatment guidelines regarding the initial two-drug combination for blood pressure management, even in stage I hypertensive patients, a three-drug combination with two antihypertensive drugs and one anti-dyslipidemia drug for patients with combined risk of hypertension and dyslipidemia is a reasonable strategy and needs to be tested [12]. We tested a well-known drugs combination, olmesartan and amlodipine as antihypertensive medication, and rosuvastatin as an anti-dyslipidemia drug. Olmesartan showed signs of harm by a greater occurrence rate of fatal cardiovascular events in a large scale prospective clinical, even if it showed promising results in reducing microalbuminuria [14]. However, other clinical trials showed safety and benefits in preventing cardiovascular events [15,16]. Furthermore, olmesartan is one of the most widely used antihypertensive drugs in Korea and globally [17].
We performed a prospective multi-center randomized double blinded placebo-controlled phase III clinical trial to assess an SPC drug composed of olmesartan/amlodipine plus a separate dose of rosuvastatin to examine its efficacy and safety in controlling blood pressure and serum lipid level. The final study purpose was to develop a triple SPC with these three drugs.

Purpose
This multicenter double blind phase III clinical trial was performed from January 2017 to April 2018 in 36 tertiary hospitals in Korea. The study purpose was to test the blood pressure (BP) lowering and low-density lipoprotein cholesterol (LDL-C) reducing effect of olmesartan/amlodipine plus a separate dose of rosuvastatin as compared to olmesartan plus rosuvastatin or olmesartan plus amlodipine.
The trial protocol was approved by the institutional review board at Seoul National University Bundang Hospital (IRB No. B-1610-368-002) and Hallym University Sacred Heart Hospital (IRB No. 2016-S072). All patients provided written informed consent at the time of enrolment and randomization. This study was performed under the standards specified in the International Council for Harmonization Guidelines for Good Clinical Practice and the principles of the Declaration of Helsinki. This trial was registered at ClinicalTrials.gov, with Identifier NCT03009487.

Patients
Patients aged 20-80 who had concomitant hypertension and dyslipidemia participated in this study. The patients had to have been prescribed both anti-hypertensive and antidyslipidemic drugs or meet the diagnosis criteria for hypertension and dyslipidemia (Supplementary Tables S1 and S2).

Study Procedures
After screening for eligibility (visit 1) and before randomization (visit 2), if subjects already took these medications, they stopped both antihypertensive and anti-dyslipidemia medications including fenofibrate, and took only olmesartan at 40 mg per day combined with therapeutic life style changes after patients agreed and provided informed consent at study entrance for 6 weeks of washout period ( Figure 1). mg/amlodipine 10 mg plus placebo of olmesartan 40 mg plus placebo of rosuvastatin 20 mg.

Study Procedures
After screening for eligibility (visit 1) and before randomization (visit 2), if subjects already took these medications, they stopped both antihypertensive and antidyslipidemia medications including fenofibrate, and took only olmesartan at 40 mg per day combined with therapeutic life style changes after patients agreed and provided informed consent at study entrance for 6 weeks of washout period ( Figure 1). Their sitSBP ought to have been within 140 to 180 mmHg at randomization time point (visit 2) and their lipid profile ought to have met the criteria (visit 2) ( Figure 1, Supplementary Tables S1 and S2). The BP was measured at the arm, with higher BP taken. After checking the BP and lipid profile at visit 2, patients were randomly assigned to three groups consecutively, study drug group (olme/amlo/rosu), olme/rosu and olme/amlo groups, with 1:1:0.5 ratio and with PROC plan in SAS system V9.3. by an independent statistician who do not know the study performance. We allocated half the number of patients to the/amlo group as compared to the other groups because of an ethical issue; those in the olme/amlo group did not receive anti-dyslipidemia drugs.
After being randomized to each group, patient received investigational drugs for 8 weeks and were followed up for safety and efficacy at 4 and 8 weeks of treatment ( Figure  2). Their sitSBP ought to have been within 140 to 180 mmHg at randomization time point (visit 2) and their lipid profile ought to have met the criteria (visit 2) ( Figure 1, Supplementary Tables S1 and S2). The BP was measured at the arm, with higher BP taken. After checking the BP and lipid profile at visit 2, patients were randomly assigned to three groups consecutively, study drug group (olme/amlo/rosu), olme/rosu and olme/amlo groups, with 1:1:0.5 ratio and with PROC plan in SAS system V9.3. by an independent statistician who do not know the study performance. We allocated half the number of patients to the/amlo group as compared to the other groups because of an ethical issue; those in the olme/amlo group did not receive anti-dyslipidemia drugs.
After being randomized to each group, patient received investigational drugs for 8 weeks and were followed up for safety and efficacy at 4 and 8 weeks of treatment ( Figure 2). Drug compliance was estimated by checking the remaining drugs at visit 2 and calculating real intake dose/planned dose. Drug compliance was estimated by checking the remaining drugs at visit 2 and calculating real intake dose/planned dose.

Sample Size Estimation and Statistical Analysis
For sample size estimation in the aspect of sitSBP change, the sitSBP change was −21.53 mmHg in amlo group and −13.30 in non-amlo group, with maximal standard deviation of 16.58 mmHg.
Thus, 86 patients in each group were required to allow for 2.5% alpha and 10% beta error.
For samples size estimation in the aspect of LDL-C change, we referred to relevant references and found minimal −48.0% LDL-C difference between rosuvastatin and norosuvastatin groups. We assumed maximal standard deviation as 11.1% and we hypothesized as follows; Thus, null hypothesis was Thus, two patients in each group were required to allow for 2.5% alpha and 10% beta error.
Combining the above two calculations, final study population was 86 in each group. Considering 15% lost to follow-up, 102 patients in the olme/amlo/rosu and olme/rosu groups and 51 in the olme/amlo group were required with 1:1:0.5 ratio.
The efficacy was evaluated mainly with a full analysis set (FAS) along with a Perprotocol Set (PPS) and safety was tested with a safety set (SS). In dealing with the missing values for the efficacy analysis, we used Last Observation Carried Forward (LOCF) methods for adjustment, and for safety analysis we used original data, with missing for without LOCF. Categorical variables were presented with numbers and percentages and compared using the Pearson's chi-square test or Fisher's exact test. Continuous variables with normal distribution were presented as the mean ± standard deviation and compared using the paired sample t-test, or one sample t-test or Wilcoxon singed rank test for intra-group comparison. To test the inter-group differences for continuous variables, ANCOVA test was performed. p value of <0.05 was considered to be significant. Statistical analysis was carried out using SAS version 9.4.

Endpoints
Primary endpoints were sitSBP change from baseline at 8 week treatment in olme/amlo/ rosu vs. olme/rosu group and percentage change of LDL-C from baseline in olme/amlo/rosu vs. olme/amlo group. The differences from baseline between two groups in sitSBP and LDL-C were also compared (study drug group vs. each of two comparator groups).

Subgroup Analysis
We stratified the patients according to age (65 years old over or not), sex and chronic kidney disease. Same findings were detected in all subgroups, more reduced sitSBP in olme/amlo/rosu group as compared to olme/rosu group and more lowered LDL-C in olme/amlo/rosu group as compared to olme/amlo group (Supplementary Table S5).

Discussion
Our study demonstrated the efficacy of the triple combination of olm/amlo/rosu on BP and LDL-C lowering, as well as safety, compared to olme/rosu or olme/amlo dual combination. Treatment with olme/amlo/rosu significantly reduced SBP by 24 mmHg and LDL-C by 52% compared to olme/rosu or olme/amlo. The attainment rates of target BP and LDL-C at 8 weeks were both 85%. Our data confirmed the efficacy of the triple combination of antihypertensive and anti-dyslipidemia drugs. In the safety profile, the olme/amlo/rosu combination shows similar results with the other two groups.
As the co-morbid and elderly population is growing more and more, the need for medication tends to increase. As such, drug compliance is likely to getting poorer as the number of pills increases. Recent studies have repeatedly provided evidence of the relationship of poor compliance and poor control of BP and LDL-C [18,19]. Poor compliance could be associated finally with poor clinical outcomes [20]. Therefore recent guidelines on hypertension management suggested single pill combination drugs to enhance drug compliance [12,21].
Our study had value in reflecting current the prevailing metabolic syndrome and testing the potential of a combination of different classes of drug, anti-hypertension and anti-dyslipidemia. These two diseases are frequently encountered in daily practice and are major components of metabolic syndrome. The drugs used in our study for BP lowering were olmesartan and amlodipine. Amlodipine is widely used in Korea as well as globally with myriad clinical data on improving clinical outcomes, as well as BP lowering, from large scale randomized clinical trials [17,21].
On the other hand, olmesartan is controversial regarding cardiovascular safety, because a ROADMAP trial showed more frequent development of fatal cardiovascular event in olmesartan users, 0.7% (15/2232) vs. 0.1% (3/2215), despite it improved primary endpoint of microalbuminuria. However, in that study, cardiovascular event was the secondary endpoint and the events rate was very small, 0.7% (15/2232) vs. 0.1% (3/2215) [14]. Moreover, the event was attributed to cardiovascular death among patients with preexisting coronary heart disease (2% [11/564] vs. 0.2% [1/540]). Considering our study population had simple hypertension and dyslipidemia (Table 1, only two patients have coronary heart disease) and the target patient group for this triple combination treatment was those with combined risks of simple hypertension and dyslipidemia rather than those with established coronary artery disease, olmesartan can be a good option for controlling hypertension. Other clinical studies performed after the ROADMAP trial and retrospective studies argue that the harm caused by olmesartan was not so robust and reported data for better cardiovascular outcome with that drug [15,16,22]. Noticeably, in a recent trial comparing BP target in elderly patients, one of the study drugs was olmesartan and this study showed reduced cardiovascular events in olmesartan users, so the previous concern can be diminished [16]. This drug also has potential for reducing albuminuria, improving renal function, improving left ventricular hypertrophy and halting coronary plaque progression [14,23,24].
The statin used in our study was rosuvastatin, and this also is associated with numerous data on improving hard clinical endpoints, especially in primary prevention of cardiovascular disease, as well as efficacy in lowering LDL-C [25,26]. Because rosuvastatin also has the property of delaying plaque regression, the combination of rosuvastatin with olmesartan could have potential in reducing or at least halting coronary plaque progression [27].
This combination of angiotensin receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEIs) and calcium channel blockers (CCBs) is first recommended as combination in major guidelines and is the most widely used combination in Korea and globally [17,21]. Thus there is a rationale for the two antihypertensive drugs with olmesartan and amlodipine in our trial. The combination of olmesartan/amlodipine was reported to be superior to perindopril/amlodipine in central BP reduction in a randomized, double blind trial [28]. When we consider that central BP lowering could play a role in improving outcomes, this result also supports the combination of olmesartan and amlodipine. In addition to this combination, we added rosuvastatin as a separate pill. This triple combination as SPC provided good safety and efficacy data and pharmacokinetic profile [29].
When we compare our results with other similar studies, the efficacy in attaining the BP target in our study was 85% which is equivalent to the olmesartan plus amlodipine plus hydrochlorothiazide triple combination of antihypertensive drugs, for which control rate was 83% from a large scale retrospective observational study [30]. In the safety profile, all adverse events occurred at 8.46% in that study, which was similar to our 7.17% [30].
The magnitude of reduction of LDL-C in olme/amlo/rosu arm (−52.41%) in our study, was very similar to that of the previous study (−52.3%) assessing the efficacy of olmesartan/rosuvastatin SPC reduction [11]. These results coincide well with previous studies, similar to ours in study design and drug used. Our results clearly demonstrated efficacy and safety and provide the rationale for developing a triple combination of olmesartan/amlodipine/rosuvastatin for treatment of hypertension and dyslipidemia.
Although this phase III trial was performed to develop the triple SPC drug for ease of drug compliance, the result is meaningful because it can provide physicians with efficacy and safety data for this SPC of antihypertensive and anti-dyslipidemia drugs and can help to treat patients with combined risks.

Limitations
Our study has limitations. Firstly, a larger study population would be better to assess the primary end-point of sitSBP and LDL-C reduction and target level attainment after 8 weeks with three subset groups. Secondly, a larger population in olme/amlo could balance each group's population and can give more concrete data, despite the ethical issue that the olme/amlo group do not receive anti-dyslipidemia drugs.

Conclusions
A triple combination of olmesartan/amlodipine/rosuvastatin treatment is safe and effective in reducing blood pressure and LDL-C. This combination will help to improve drug compliance in patients with co-morbidity. Future studies investigating whether this combination could increase the adherence rate and improve clinical outcomes are warranted.
Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/xxx/s1, Table S1. Inclusion criteria. Table S2. Pre-visit 2 inclusion criteria for dyslipidemia according to cardiovascular risk. Table S3. Final patients included. Table S4. Lipid levels other than LDL-C in 3 groups after 8week treatment. Table S5. Subgroup analysis.