Stage 2 Hypertension
Conditions
Keywords
Hypertension, aliskiren and valsartan
Brief summary
To evaluate the efficacy and safety of the valsartan/aliskiren combination compared to valsartan alone in patients with Stage 2 hypertension.
Interventions
DRUGValsartan/aliskiren
Valsartan/aliskiren (160/150mg) for 2 weeks followed by forced titration to valsartan/aliskiren (320/300mg) for the remaining 6 weeks
DRUGValsartan
Valsartan (160mg) for 2 weeks followed by forced titration to Valsartan (320mg) for the remaining 6 weeks
Sponsors
Novartis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients who are eligible and able to participate in the study, and who give written informed consent before any assessment is performed. * Men or women 18 years and older. * Patients with Stage 2 systolic hypertension; defined as having a MSSBP ≥160 mmHg and \<180 mmHg at Visit 5 (randomization).
Exclusion criteria
* Use of aliskiren or participation in a clinical trial that had aliskiren as treatment within 30 days of Visit 1. * Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (\>5 mIU/ml). * Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they meet the following definition of post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels \>40 mIU/m or 6 weeks post surgical bilateral oophorectomy with or without hysterectomy OR are using one or more of the following acceptable methods of contraception: surgical sterilization (e.g., bilateral tubal ligation), hormonal contraception (implantable, patch, oral), and double-barrier methods. Reliable contraception should be maintained throughout the study and for 7 days after study drug discontinuation. * Severe hypertension (an office cuff MSDBP ≥110 mmHg and/or MSSBP ≥180 mmHg). * Refractory hypertension, defined as unresponsive to triple drug therapy at the maximum dose of each drug, one of which must be a diuretic, and not at blood pressure goal (140/90 mmHg). * Patients treated with more than 3 antihypertensive medications (each component of a combination drug counts individually). * History or evidence of a secondary form of hypertension.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Sitting Systolic Blood Pressure (MSSBP) at Week 8 | Baseline to Week 8 | To compare the change from baseline in MSSBP after 8 weeks of treatment with a valsartan and aliskiren treatment regimen (160/150 mg, 320/300 mg) versus a valsartan treatment regimen (160 mg, 320 mg) in patients with Stage 2 Hypertension. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Achieving Blood Pressure Control (Defined as Patients Achieving a MSSBP <140 mmHg and MSDBP <90 mmHg) at Week 8 | At Week 8 | To evaluate the percentage of patients achieving blood pressure control (defined as patients achieving a MSSBP \<140 mmHg and MSDBP \<90 mmHg) at week 8 following treatment with a valsartan and aliskiren treatment regimen (160/150 mg, 320/300 mg) versus a valsartan treatment regimen (160 mg, 320 mg) in patients with Stage 2 Hypertension. |
| Change From Baseline in Mean Sitting Diastolic Blood Pressure (MSDBP) at Week 8 | Baseline to Week 8 | To compare the change in MSDBP after 8 weeks of treatment with a valsartan and aliskiren treatment regimen (160/150 mg, 320/300 mg) versus a valsartan (160 mg, 320 mg) treatment regimen in patients with Stage 2 Hypertension. |
| Percentage of Responders (Defined as Patients With MSSBP <140 mmHg or a Decrease From Baseline ≥20 mmHg) at Week 8 | At Week 8 | To compare the percentage of responders (defined as patients with MSSBP \<140 mmHg or a decrease from baseline ≥20 mmHg) at week 8 following treatment with a valsartan and aliskiren treatment regimen (160/150 mg, 320/300 mg) versus a valsartan treatment regimen (160 mg, 320 mg) in patients with Stage 2 Hypertension. |
| Mean Change From Baseline in Plasma Renin Activity (PRA) at Week 8 | Baseline to Week 8 | To assess the change from baseline in PRA after 8 weeks of treatment with a valsartan and aliskiren treatment regimen (160/150 mg, 320/300 mg) versus a valsartan treatment regimen (160 mg, 320 mg) in patients with Stage 2 Hypertension. |
| Mean Change From Baseline in Plasma Renin Concentration (PRC) at Week 8 | Baseline to Week 8 | To assess the change from baseline in PRC after 8 weeks of treatment with a valsartan and aliskiren treatment regimen (160/150 mg, 320/300 mg) versus a valsartan treatment regimen (160 mg, 320 mg) in patients with Stage 2 Hypertension. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Ambulatory Systolic Blood Pressure (MASBP). | Baseline to week 8 | To evaluate 24-hour ambulatory systolic blood pressure measurements in a subset of patients after 8 weeks of treatment with the combination of valsartan and aliskiren versus valsartan monotherapy in patients with stage 2 hypertension. |
| Change From Baseline in Mean Ambulatory Diastolic Blood Pressure (MADBP) | Baseline to week 8 | To evaluate 24-hour ambulatory diastolic blood pressure measurements in a subset of patients after 8 weeks of treatment with the combination of valsartan and aliskiren versus valsartan monotherapy in patients with stage 2 hypertension. |
| Longitudinal Repeated Measure Analysis for Change in MSSBP From Baseline Through Week 8 | Baseline through week 8 | To evaluate the change from baseline in MSSBP (mmHg) after 8 weeks; primary efficacy variable (ITT population) using Longitudinal analysis (A repeated measures analysis where assessments over time are considered , as opposed to looking at a single point in time.) |
| Completers Analysis for Change From Baseline in MSSBP at Week 8 | Baseline to week 8 | To evaluate the change from baseline in MSSBP (mmHg) at Week 8; primary efficacy variable at primary time point in ITT population - patients who completed the double-blind treatment period. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Valsartan/Aliskiren For the first 2 weeks patients received Valsartan/aliskiren (160/150mg). For the remaining 6 weeks, all patients received Valsartan/aliskiren 320/300mg (forced titration). | 232 |
| Valsartan For the first 2 weeks patients received Valsartan 160 mg. For the remaining 6 weeks, all patients received Valsartan 320 mg (forced titration). | 219 |
| Total | 451 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative Problems | 0 | 1 |
| Overall Study | Adverse Event | 18 | 10 |
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Patient withdrew consent | 8 | 6 |
| Overall Study | Protocol deviation | 0 | 2 |
| Overall Study | Unsatisfactory therapeutic effect | 3 | 3 |
Baseline characteristics
| Characteristic | Valsartan/Aliskiren | Valsartan | Total |
|---|---|---|---|
| Age Continuous | 57.5 years STANDARD_DEVIATION 11.1 | 56.7 years STANDARD_DEVIATION 11 | 57.1 years STANDARD_DEVIATION 11 |
| Sex: Female, Male Female | 107 Participants | 116 Participants | 223 Participants |
| Sex: Female, Male Male | 125 Participants | 103 Participants | 228 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 14 / 232 | 15 / 219 |
| serious Total, serious adverse events | 5 / 232 | 3 / 219 |
Outcome results
Primary
Change From Baseline in Mean Sitting Systolic Blood Pressure (MSSBP) at Week 8
To compare the change from baseline in MSSBP after 8 weeks of treatment with a valsartan and aliskiren treatment regimen (160/150 mg, 320/300 mg) versus a valsartan treatment regimen (160 mg, 320 mg) in patients with Stage 2 Hypertension.
Time frame: Baseline to Week 8
Population: Intent-to-treat (ITT) population consisted of all randomized patients who received at least 1 dose of study drug and had valid baseline and 1 valid post-baseline assessment of an efficacy variable. The last-observation-carried-forward (LOCF) method was used for replacing the missing values of the post-baseline assessments for ITT analysis at wk 8.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Valsartan/Aliskiren | Change From Baseline in Mean Sitting Systolic Blood Pressure (MSSBP) at Week 8 | Baseline | 164.8 mm Hg | Standard Deviation 4.54 |
| Valsartan/Aliskiren | Change From Baseline in Mean Sitting Systolic Blood Pressure (MSSBP) at Week 8 | Week 8 | 142.3 mm Hg | Standard Deviation 17.01 |
| Valsartan/Aliskiren | Change From Baseline in Mean Sitting Systolic Blood Pressure (MSSBP) at Week 8 | Change from Baseline to Week 8 | -22.5 mm Hg | Standard Deviation 16.04 |
| Valsartan | Change From Baseline in Mean Sitting Systolic Blood Pressure (MSSBP) at Week 8 | Baseline | 166.2 mm Hg | Standard Deviation 5.23 |
| Valsartan | Change From Baseline in Mean Sitting Systolic Blood Pressure (MSSBP) at Week 8 | Week 8 | 145.6 mm Hg | Standard Deviation 17.55 |
| Valsartan | Change From Baseline in Mean Sitting Systolic Blood Pressure (MSSBP) at Week 8 | Change from Baseline to Week 8 | -20.6 mm Hg | Standard Deviation 16.25 |
p-value: 0.29595% CI: [-4.61, 1.4]ANCOVA
Secondary
Change From Baseline in Mean Sitting Diastolic Blood Pressure (MSDBP) at Week 8
To compare the change in MSDBP after 8 weeks of treatment with a valsartan and aliskiren treatment regimen (160/150 mg, 320/300 mg) versus a valsartan (160 mg, 320 mg) treatment regimen in patients with Stage 2 Hypertension.
Time frame: Baseline to Week 8
Population: Intent-to-treat (ITT) population consisted of all randomized patients who received at least 1 dose of study drug and had valid baseline and 1 valid post-baseline assessment of an efficacy variable. The last-observation-carried-forward (LOCF) method was used for replacing the missing values of the post-baseline assessments for ITT analysis at wk 8.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Valsartan/Aliskiren | Change From Baseline in Mean Sitting Diastolic Blood Pressure (MSDBP) at Week 8 | Baseline | 93.9 mm Hg | Standard Deviation 8.22 |
| Valsartan/Aliskiren | Change From Baseline in Mean Sitting Diastolic Blood Pressure (MSDBP) at Week 8 | Week 8 | 85.7 mm Hg | Standard Deviation 10.94 |
| Valsartan/Aliskiren | Change From Baseline in Mean Sitting Diastolic Blood Pressure (MSDBP) at Week 8 | Change from Baseline to Week 8 | -8.2 mm Hg | Standard Deviation 9.77 |
| Valsartan | Change From Baseline in Mean Sitting Diastolic Blood Pressure (MSDBP) at Week 8 | Baseline | 94.8 mm Hg | Standard Deviation 8.68 |
| Valsartan | Change From Baseline in Mean Sitting Diastolic Blood Pressure (MSDBP) at Week 8 | Week 8 | 86.4 mm Hg | Standard Deviation 10.34 |
| Valsartan | Change From Baseline in Mean Sitting Diastolic Blood Pressure (MSDBP) at Week 8 | Change from Baseline to Week 8 | -8.3 mm Hg | Standard Deviation 9.49 |
p-value: 0.7995% CI: [-1.93, 1.47]ANCOVA
Secondary
Mean Change From Baseline in Plasma Renin Activity (PRA) at Week 8
To assess the change from baseline in PRA after 8 weeks of treatment with a valsartan and aliskiren treatment regimen (160/150 mg, 320/300 mg) versus a valsartan treatment regimen (160 mg, 320 mg) in patients with Stage 2 Hypertension.
Time frame: Baseline to Week 8
Population: The intent-to-treat (ITT) population consisted of all randomized patients who received at least one dose of study medication and had valid baseline and at least one valid post-baseline assessment of an efficacy variable.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Valsartan/Aliskiren | Mean Change From Baseline in Plasma Renin Activity (PRA) at Week 8 | Baseline | 0.992 ng/mL/h | Standard Deviation 1.29 |
| Valsartan/Aliskiren | Mean Change From Baseline in Plasma Renin Activity (PRA) at Week 8 | Week 8 | 0.436 ng/mL/h | Standard Deviation 0.659 |
| Valsartan/Aliskiren | Mean Change From Baseline in Plasma Renin Activity (PRA) at Week 8 | Change from Baseline to Week 8 | -0.540 ng/mL/h | Standard Deviation 1.285 |
| Valsartan | Mean Change From Baseline in Plasma Renin Activity (PRA) at Week 8 | Baseline | 0.831 ng/mL/h | Standard Deviation 0.854 |
| Valsartan | Mean Change From Baseline in Plasma Renin Activity (PRA) at Week 8 | Week 8 | 2.450 ng/mL/h | Standard Deviation 3.73 |
| Valsartan | Mean Change From Baseline in Plasma Renin Activity (PRA) at Week 8 | Change from Baseline to Week 8 | 1.577 ng/mL/h | Standard Deviation 3.528 |
Secondary
Mean Change From Baseline in Plasma Renin Concentration (PRC) at Week 8
To assess the change from baseline in PRC after 8 weeks of treatment with a valsartan and aliskiren treatment regimen (160/150 mg, 320/300 mg) versus a valsartan treatment regimen (160 mg, 320 mg) in patients with Stage 2 Hypertension.
Time frame: Baseline to Week 8
Population: The intent-to-treat (ITT) population consisted of all randomized patients who received at least one dose of study medication and had valid baseline and at least one valid post-baseline assessment of an efficacy variable.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Valsartan/Aliskiren | Mean Change From Baseline in Plasma Renin Concentration (PRC) at Week 8 | Baseline | 8.286 ng/L | Standard Deviation 10.893 |
| Valsartan/Aliskiren | Mean Change From Baseline in Plasma Renin Concentration (PRC) at Week 8 | Week 8 | 142.833 ng/L | Standard Deviation 293.228 |
| Valsartan/Aliskiren | Mean Change From Baseline in Plasma Renin Concentration (PRC) at Week 8 | Change from Baseline to Week 8 | 135.515 ng/L | Standard Deviation 296.758 |
| Valsartan | Mean Change From Baseline in Plasma Renin Concentration (PRC) at Week 8 | Baseline | 8.065 ng/L | Standard Deviation 14.932 |
| Valsartan | Mean Change From Baseline in Plasma Renin Concentration (PRC) at Week 8 | Week 8 | 20.089 ng/L | Standard Deviation 31.771 |
| Valsartan | Mean Change From Baseline in Plasma Renin Concentration (PRC) at Week 8 | Change from Baseline to Week 8 | 11.988 ng/L | Standard Deviation 32.679 |
Secondary
Percentage of Patients Achieving Blood Pressure Control (Defined as Patients Achieving a MSSBP <140 mmHg and MSDBP <90 mmHg) at Week 8
To evaluate the percentage of patients achieving blood pressure control (defined as patients achieving a MSSBP \<140 mmHg and MSDBP \<90 mmHg) at week 8 following treatment with a valsartan and aliskiren treatment regimen (160/150 mg, 320/300 mg) versus a valsartan treatment regimen (160 mg, 320 mg) in patients with Stage 2 Hypertension.
Time frame: At Week 8
Population: The intent-to-treat (ITT) population consisted of all randomized patients who received at least one dose of study medication and had valid baseline and at least one valid post-baseline assessment of an efficacy variable.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Valsartan/Aliskiren | Percentage of Patients Achieving Blood Pressure Control (Defined as Patients Achieving a MSSBP <140 mmHg and MSDBP <90 mmHg) at Week 8 | 44.3 percentage of patients |
| Valsartan | Percentage of Patients Achieving Blood Pressure Control (Defined as Patients Achieving a MSSBP <140 mmHg and MSDBP <90 mmHg) at Week 8 | 36.2 percentage of patients |
p-value: 0.10195% CI: [-1.56, 17.67]Cochran-Mantel-Haenszel
Secondary
Percentage of Responders (Defined as Patients With MSSBP <140 mmHg or a Decrease From Baseline ≥20 mmHg) at Week 8
To compare the percentage of responders (defined as patients with MSSBP \<140 mmHg or a decrease from baseline ≥20 mmHg) at week 8 following treatment with a valsartan and aliskiren treatment regimen (160/150 mg, 320/300 mg) versus a valsartan treatment regimen (160 mg, 320 mg) in patients with Stage 2 Hypertension.
Time frame: At Week 8
Population: The intent-to-treat (ITT) population consisted of all randomized patients who received at least one dose of study medication and had valid baseline and at least one valid post-baseline assessment of an efficacy variable.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Valsartan/Aliskiren | Percentage of Responders (Defined as Patients With MSSBP <140 mmHg or a Decrease From Baseline ≥20 mmHg) at Week 8 | 64.7 percentage of responders |
| Valsartan | Percentage of Responders (Defined as Patients With MSSBP <140 mmHg or a Decrease From Baseline ≥20 mmHg) at Week 8 | 53.1 percentage of responders |
p-value: 0.01895% CI: [2, 21.33]Cochran-Mantel-Haenszel
Other Pre-specified
Change From Baseline in Mean Ambulatory Diastolic Blood Pressure (MADBP)
To evaluate 24-hour ambulatory diastolic blood pressure measurements in a subset of patients after 8 weeks of treatment with the combination of valsartan and aliskiren versus valsartan monotherapy in patients with stage 2 hypertension.
Time frame: Baseline to week 8
Population: Patients who were willing to participate in the ABPM substudy and who met the study inclusion and exclusion criteria for randomization.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Valsartan/Aliskiren | Change From Baseline in Mean Ambulatory Diastolic Blood Pressure (MADBP) | Week 8 | 78.2 mm Hg | Standard Deviation 9.44 |
| Valsartan/Aliskiren | Change From Baseline in Mean Ambulatory Diastolic Blood Pressure (MADBP) | Baseline | 87.9 mm Hg | Standard Deviation 7.28 |
| Valsartan/Aliskiren | Change From Baseline in Mean Ambulatory Diastolic Blood Pressure (MADBP) | Change from Baseline to Week 8 | -9.7 mm Hg | Standard Deviation 7.02 |
| Valsartan | Change From Baseline in Mean Ambulatory Diastolic Blood Pressure (MADBP) | Week 8 | 81.7 mm Hg | Standard Deviation 10.11 |
| Valsartan | Change From Baseline in Mean Ambulatory Diastolic Blood Pressure (MADBP) | Baseline | 85.7 mm Hg | Standard Deviation 9.26 |
| Valsartan | Change From Baseline in Mean Ambulatory Diastolic Blood Pressure (MADBP) | Change from Baseline to Week 8 | -4.0 mm Hg | Standard Deviation 8.09 |
p-value: 0.00695% CI: [-8.37, -1.42]ANCOVA
Other Pre-specified
Change From Baseline in Mean Ambulatory Systolic Blood Pressure (MASBP).
To evaluate 24-hour ambulatory systolic blood pressure measurements in a subset of patients after 8 weeks of treatment with the combination of valsartan and aliskiren versus valsartan monotherapy in patients with stage 2 hypertension.
Time frame: Baseline to week 8
Population: Patients who were willing to participate in the Ambulatory Blood Pressure Monitoring (ABPM) substudy and who met the study inclusion and exclusion criteria for randomization.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Valsartan/Aliskiren | Change From Baseline in Mean Ambulatory Systolic Blood Pressure (MASBP). | Baseline | 146.1 mm Hg | Standard Deviation 9.14 |
| Valsartan/Aliskiren | Change From Baseline in Mean Ambulatory Systolic Blood Pressure (MASBP). | Week 8 | 130.3 mm Hg | Standard Deviation 13.41 |
| Valsartan/Aliskiren | Change From Baseline in Mean Ambulatory Systolic Blood Pressure (MASBP). | Change from Baseline to Week 8 | -15.8 mm Hg | Standard Deviation 11.42 |
| Valsartan | Change From Baseline in Mean Ambulatory Systolic Blood Pressure (MASBP). | Baseline | 143.5 mm Hg | Standard Deviation 14.1 |
| Valsartan | Change From Baseline in Mean Ambulatory Systolic Blood Pressure (MASBP). | Week 8 | 137.6 mm Hg | Standard Deviation 17.11 |
| Valsartan | Change From Baseline in Mean Ambulatory Systolic Blood Pressure (MASBP). | Change from Baseline to Week 8 | -6.0 mm Hg | Standard Deviation 13.34 |
p-value: 0.00495% CI: [-14.38, -2.93]ANCOVA
Other Pre-specified
Completers Analysis for Change From Baseline in MSSBP at Week 8
To evaluate the change from baseline in MSSBP (mmHg) at Week 8; primary efficacy variable at primary time point in ITT population - patients who completed the double-blind treatment period.
Time frame: Baseline to week 8
Population: The analysis included ITT patients who completed the double-blind treatment period \[those patients with a final observation at week 8, also known as observed cases (OC)\]. This analysis differed from the ITT-LOCF analysis, in that it did not include patients who discontinued from the trial prematurely.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Valsartan/Aliskiren | Completers Analysis for Change From Baseline in MSSBP at Week 8 | Baseline | 164.8 mm Hg | Standard Deviation 4.54 |
| Valsartan/Aliskiren | Completers Analysis for Change From Baseline in MSSBP at Week 8 | Week 8 | 140.9 mm Hg | Standard Deviation 15.74 |
| Valsartan/Aliskiren | Completers Analysis for Change From Baseline in MSSBP at Week 8 | Change from Baseline to Week 8 | -24.0 mm Hg | Standard Deviation 14.7 |
| Valsartan | Completers Analysis for Change From Baseline in MSSBP at Week 8 | Baseline | 166.2 mm Hg | Standard Deviation 5.23 |
| Valsartan | Completers Analysis for Change From Baseline in MSSBP at Week 8 | Week 8 | 145.9 mm Hg | Standard Deviation 16.89 |
| Valsartan | Completers Analysis for Change From Baseline in MSSBP at Week 8 | Change from Baseline to Week 8 | -20.3 mm Hg | Standard Deviation 15.49 |
p-value: 0.02895% CI: [-6.34, -0.37]ANCOVA
Other Pre-specified
Longitudinal Repeated Measure Analysis for Change in MSSBP From Baseline Through Week 8
To evaluate the change from baseline in MSSBP (mmHg) after 8 weeks; primary efficacy variable (ITT population) using Longitudinal analysis (A repeated measures analysis where assessments over time are considered , as opposed to looking at a single point in time.)
Time frame: Baseline through week 8
Population: The intent-to-treat (ITT) population consisted of all randomized patients who received at least one dose of study medication and had valid baseline and at least one valid post-baseline assessment of an efficacy variable.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Valsartan/Aliskiren | Longitudinal Repeated Measure Analysis for Change in MSSBP From Baseline Through Week 8 | -23.2 mm Hg | Standard Error 1.04 |
| Valsartan | Longitudinal Repeated Measure Analysis for Change in MSSBP From Baseline Through Week 8 | -20.1 mm Hg | Standard Error 1.08 |
p-value: 0.0495% CI: [-6.02, -0.14]GENMOD