Contraception
Conditions
Keywords
Contraception, NuvaRing
Brief summary
This is a study to assess the effectiveness of NuvaRing® (SCH 900702) for the prevention of pregnancy in fertile Chinese women. The acceptability and safety of NuvaRing® will also be assessed and compared with that of Yasmin.
Detailed description
The purpose of this study is to assess the contraceptive efficacy of NuvaRing in fertile Chinese women; to assess vaginal bleeding pattern (cycle control), general safety, and acceptability of NuvaRing; and to evaluate the NuvaRing's effect on dysmenorrhea.
Interventions
DRUGENG 120 µg + EE 15 µg intravaginal ring
13 cycles of ENG-EE (NuvaRing) vaginal ring use. Each cycle 28 days, with a 21-day active treatment period followed by 7-day ring-free period. One ring per cycle, each ring containing 11.7 mg ENG and 2.7 mg EE, and releasing on average 120 mcg/day of ENG and 15 mcg/day of EE.
DRUGDRSP 3 mg + EE 30 µg
13 cycles of DRSP-EE tablet use. Each cycle 28 days, with a 21-day active treatment period followed by a 7-day tablet-free period. Participants received total of 21 tablets per cycle, each tablet contained 3 mg DRSP and 30 μg EE.
Sponsors
Organon and Co
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
Key Inclusion Criteria: * Sexually active Chinese women, at risk for pregnancy and not planning to use condoms during trial medication use * Women in need for contraception and willing to use a hormonal contraceptive method for 13 cycles * Body mass index ≥18 and ≤29 kg/m\^2 Key
Exclusion criteria
* Contraindications for contraceptive steroids * Abnormal cervical smear corresponding to indeterminate changes at screening * Clinically relevant abnormal laboratory result at screening as judged by the investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pearl Index, by Treatment Group | Up to 1 year | Primary Efficacy Outcome measure for this study was contraceptive efficacy, or the prevention of in-treatment pregnancy. The total incidence of in-treatment pregnancies was expressed as the Pearl Index, which is defined as the number of in-treatment pregnancies per 100 woman-years of exposure (one woman-year defined as a period of 365.25 days). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Intermenstrual (Breakthrough) Bleeding/Spotting, by Cycle | Up to 1 year | Participants kept diaries to record vaginal bleeding events. They were asked to record, on a daily basis, whether they experienced vaginal bleeding, which included BLEEDING or SPOTTING, at any time during a cycle other than normal menstruation while in the study. (This is also known as breakthough bleeding.) Vaginal bleeding that required \>=2 pads/tampons per day was classified as BLEEDING. Vaginal bleeding that required \<=1 pad/tampon per day was classified as SPOTTING. |
| Percentage of Participants With Absence of Withdrawal Bleeding, by Cycle | Up to 1 year | Participants kept diaries to record vaginal bleeding events. They were asked to record, on a daily basis, whether vaginal bleeding was present. Absence of withdrawal bleeding was defined as no bleeding/spotting during the expected bleeding period. |
Participant flow
Pre-assignment details
Of the 983 participants randomized, 946 received treatment and 37 discontinued prior to receiving treatment.
Participants by arm
| Arm | Count |
|---|---|
| ENG-EE (NuvaRing) Participants were to complete 13 cycles of etonogestrel (ENG) and ethinylestradiol (EE) use. Each cycle was 28 days, with a 21-day active treatment period followed by a 7-day ring-free period. Participants used one ring per cycle. Each ring contained 11.7 mg ENG and 2.7 mg EE, and released on average 120 mcg/day of ENG and 15 mcg/day of EE. | 714 |
| DRSP-EE Participants were to complete 13 cycles of drospirenone (DRSP) and ethinylestradiol (EE) use. Each cycle was 28 days, with a 21-day active treatment period followed by a 7-day tablet-free period. Participants received a total of 21 tablets of DRSP-EE per cycle. Each tablet contained 3 mg DRSP and 30 μg EE. | 232 |
| Total | 946 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative | 3 | 0 |
| Overall Study | Adverse Event | 60 | 22 |
| Overall Study | Did not meet protocol eligibility | 1 | 0 |
| Overall Study | Did not wish to continue | 17 | 0 |
| Overall Study | Discontinued prior to treatment | 24 | 13 |
| Overall Study | Lost to Follow-up | 14 | 9 |
| Overall Study | Non-compliance with protocol | 13 | 4 |
| Overall Study | Pregnancy | 9 | 4 |
| Overall Study | Pregnancy wish | 0 | 2 |
| Overall Study | Withdrew Consent | 9 | 9 |
Baseline characteristics
| Characteristic | ENG-EE (NuvaRing) | DRSP-EE | Total |
|---|---|---|---|
| Age, Continuous | 31.8 Years STANDARD_DEVIATION 4 | 31.2 Years STANDARD_DEVIATION 3.9 | 31.7 Years STANDARD_DEVIATION 4 |
| Sex: Female, Male Female | 714 Participants | 232 Participants | 946 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 714 | 0 / 232 |
| serious Total, serious adverse events | 2 / 714 | 4 / 232 |
Outcome results
Primary
Pearl Index, by Treatment Group
Primary Efficacy Outcome measure for this study was contraceptive efficacy, or the prevention of in-treatment pregnancy. The total incidence of in-treatment pregnancies was expressed as the Pearl Index, which is defined as the number of in-treatment pregnancies per 100 woman-years of exposure (one woman-year defined as a period of 365.25 days).
Time frame: Up to 1 year
Population: Restricted Intent-to-Treat (R-ITT) Group, which consisted of all participants from the Intent-to-Treat (ITT) Group who had at least one cycle at risk (no condom use and confirmed intercourse).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| ENG-EE (NuvaRing) | Pearl Index, by Treatment Group | 1.92 Pregnancies per 100 woman-years |
| DRSP-EE | Pearl Index, by Treatment Group | 3.12 Pregnancies per 100 woman-years |
Comparison: Differences between the two treatment groups (ENG-EE vs. DRSP-EE) were explored using an exact 95% CI for the Ratio of the two Pearl Indices based on the Poisson distribution.p-value: 0.53195% CI: [0.19, 2.29]Poisson distribution method
Secondary
Percentage of Participants With Absence of Withdrawal Bleeding, by Cycle
Participants kept diaries to record vaginal bleeding events. They were asked to record, on a daily basis, whether vaginal bleeding was present. Absence of withdrawal bleeding was defined as no bleeding/spotting during the expected bleeding period.
Time frame: Up to 1 year
Population: ITT Group, which consisted of all randomized participants who used at least one ring/pill.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ENG-EE (NuvaRing) | Percentage of Participants With Absence of Withdrawal Bleeding, by Cycle | Cycle 3 (n=577,196) | 5.2 Percentage of participants |
| ENG-EE (NuvaRing) | Percentage of Participants With Absence of Withdrawal Bleeding, by Cycle | Cycle 8 (n=583,188) | 5.0 Percentage of participants |
| ENG-EE (NuvaRing) | Percentage of Participants With Absence of Withdrawal Bleeding, by Cycle | Cycle 5 (n=590,187) | 5.4 Percentage of participants |
| ENG-EE (NuvaRing) | Percentage of Participants With Absence of Withdrawal Bleeding, by Cycle | Cycle 9 (n=575,187) | 4.3 Percentage of participants |
| ENG-EE (NuvaRing) | Percentage of Participants With Absence of Withdrawal Bleeding, by Cycle | Cycle 2 (n=602,195) | 4.8 Percentage of participants |
| ENG-EE (NuvaRing) | Percentage of Participants With Absence of Withdrawal Bleeding, by Cycle | Cycle 10 (n=571,183) | 3.7 Percentage of participants |
| ENG-EE (NuvaRing) | Percentage of Participants With Absence of Withdrawal Bleeding, by Cycle | Cycle 6 (n=588,185) | 5.8 Percentage of participants |
| ENG-EE (NuvaRing) | Percentage of Participants With Absence of Withdrawal Bleeding, by Cycle | Cycle 11 (n=576,177) | 3.0 Percentage of participants |
| ENG-EE (NuvaRing) | Percentage of Participants With Absence of Withdrawal Bleeding, by Cycle | Cycle 4 (n=586,194) | 4.1 Percentage of participants |
| ENG-EE (NuvaRing) | Percentage of Participants With Absence of Withdrawal Bleeding, by Cycle | Cycle 12 (n=568,176) | 4.0 Percentage of participants |
| ENG-EE (NuvaRing) | Percentage of Participants With Absence of Withdrawal Bleeding, by Cycle | Cycle 7 (n=581,186) | 3.4 Percentage of participants |
| ENG-EE (NuvaRing) | Percentage of Participants With Absence of Withdrawal Bleeding, by Cycle | Cycle 13 (n=543,173) | 5.9 Percentage of participants |
| ENG-EE (NuvaRing) | Percentage of Participants With Absence of Withdrawal Bleeding, by Cycle | Cycle 1 (n=596,199) | 8.6 Percentage of participants |
| DRSP-EE | Percentage of Participants With Absence of Withdrawal Bleeding, by Cycle | Cycle 13 (n=543,173) | 10.4 Percentage of participants |
| DRSP-EE | Percentage of Participants With Absence of Withdrawal Bleeding, by Cycle | Cycle 1 (n=596,199) | 14.6 Percentage of participants |
| DRSP-EE | Percentage of Participants With Absence of Withdrawal Bleeding, by Cycle | Cycle 2 (n=602,195) | 9.7 Percentage of participants |
| DRSP-EE | Percentage of Participants With Absence of Withdrawal Bleeding, by Cycle | Cycle 3 (n=577,196) | 11.7 Percentage of participants |
| DRSP-EE | Percentage of Participants With Absence of Withdrawal Bleeding, by Cycle | Cycle 4 (n=586,194) | 7.7 Percentage of participants |
| DRSP-EE | Percentage of Participants With Absence of Withdrawal Bleeding, by Cycle | Cycle 5 (n=590,187) | 6.4 Percentage of participants |
| DRSP-EE | Percentage of Participants With Absence of Withdrawal Bleeding, by Cycle | Cycle 6 (n=588,185) | 9.7 Percentage of participants |
| DRSP-EE | Percentage of Participants With Absence of Withdrawal Bleeding, by Cycle | Cycle 7 (n=581,186) | 7.5 Percentage of participants |
| DRSP-EE | Percentage of Participants With Absence of Withdrawal Bleeding, by Cycle | Cycle 8 (n=583,188) | 6.9 Percentage of participants |
| DRSP-EE | Percentage of Participants With Absence of Withdrawal Bleeding, by Cycle | Cycle 9 (n=575,187) | 8.6 Percentage of participants |
| DRSP-EE | Percentage of Participants With Absence of Withdrawal Bleeding, by Cycle | Cycle 10 (n=571,183) | 6.6 Percentage of participants |
| DRSP-EE | Percentage of Participants With Absence of Withdrawal Bleeding, by Cycle | Cycle 11 (n=576,177) | 7.3 Percentage of participants |
| DRSP-EE | Percentage of Participants With Absence of Withdrawal Bleeding, by Cycle | Cycle 12 (n=568,176) | 10.2 Percentage of participants |
Comparison: For Cycle 1, a two-sided 95% CI for the difference in percentage between the treatment groups (ENG-EE vs. DRSP-EE) was calculated using the method of Miettinen and Nurminen.p-value: 0.01595% CI: [-12, -1.1]Miettinen and Nurminen method
Comparison: For Cycle 2, a two-sided 95% CI for the difference in percentage between the treatment groups (ENG-EE vs. DRSP-EE) was calculated using the method of Miettinen and Nurminen.p-value: 0.01295% CI: [-10.1, -1]Miettinen and Nurminen method
Comparison: For Cycle 3, a two-sided 95% CI for the difference in percentage between the treatment groups (ENG-EE vs. DRSP-EE) was calculated using the method of Miettinen and Nurminen.p-value: 0.00295% CI: [-12, -2.2]Miettinen and Nurminen method
Comparison: For Cycle 4, a two-sided 95% CI for the difference in percentage between the treatment groups (ENG-EE vs. DRSP-EE) was calculated using the method of Miettinen and Nurminen.p-value: 0.04495% CI: [-8.5, -0.1]Miettinen and Nurminen method
Comparison: For Cycle 5, a two-sided 95% CI for the difference in percentage between the treatment groups (ENG-EE vs. DRSP-EE) was calculated using the method of Miettinen and Nurminen.p-value: 0.60995% CI: [-5.7, 2.5]Miettinen and Nurminen method
Comparison: For Cycle 6, a two-sided 95% CI for the difference in percentage between the treatment groups (ENG-EE vs. DRSP-EE) was calculated using the method of Miettinen and Nurminen.p-value: 0.06295% CI: [-9.3, 0.2]Miettinen and Nurminen method
Comparison: For Cycle 7, a two-sided 95% CI for the difference in percentage between the treatment groups (ENG-EE vs. DRSP-EE) was calculated using the method of Miettinen and Nurminen.p-value: 0.01995% CI: [-9, -0.6]Miettinen and Nurminen method
Comparison: For Cycle 8, a two-sided 95% CI for the difference in percentage between the treatment groups (ENG-EE vs. DRSP-EE) was calculated using the method of Miettinen and Nurminen.p-value: 0.30895% CI: [-6.7, 1.6]Miettinen and Nurminen method
Comparison: For Cycle 9, a two-sided 95% CI for the difference in percentage between the treatment groups (ENG-EE vs. DRSP-EE) was calculated using the method of Miettinen and Nurminen.p-value: 0.02795% CI: [-9.3, -0.4]Miettinen and Nurminen method
Comparison: For Cycle 10, a two-sided 95% CI for the difference in percentage between the treatment groups (ENG-EE vs. DRSP-EE) was calculated using the method of Miettinen and Nurminen.p-value: 0.09895% CI: [-7.6, 0.5]Miettinen and Nurminen method
Comparison: For Cycle 11, a two-sided 95% CI for the difference in percentage between the treatment groups (ENG-EE vs. DRSP-EE) was calculated using the method of Miettinen and Nurminen.p-value: 0.00995% CI: [-9.4, -1]Miettinen and Nurminen method
Comparison: For Cycle 12, a two-sided 95% CI for the difference in percentage between the treatment groups (ENG-EE vs. DRSP-EE) was calculated using the method of Miettinen and Nurminen.p-value: 0.00295% CI: [-11.7, -2.1]Miettinen and Nurminen method
Comparison: For Cycle 13, a two-sided 95% CI for the difference in percentage between the treatment groups (ENG-EE vs. DRSP-EE) was calculated using the method of Miettinen and Nurminen.p-value: 0.04395% CI: [-10.2, -0.1]Miettinen and Nurminen method
Secondary
Percentage of Participants With Intermenstrual (Breakthrough) Bleeding/Spotting, by Cycle
Participants kept diaries to record vaginal bleeding events. They were asked to record, on a daily basis, whether they experienced vaginal bleeding, which included BLEEDING or SPOTTING, at any time during a cycle other than normal menstruation while in the study. (This is also known as breakthough bleeding.) Vaginal bleeding that required \>=2 pads/tampons per day was classified as BLEEDING. Vaginal bleeding that required \<=1 pad/tampon per day was classified as SPOTTING.
Time frame: Up to 1 year
Population: ITT Group, which consisted of all randomized participants who used at least one ring/pill.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ENG-EE (NuvaRing) | Percentage of Participants With Intermenstrual (Breakthrough) Bleeding/Spotting, by Cycle | Cycle 3 (n=578,196) | 8.5 Percentage of participants |
| ENG-EE (NuvaRing) | Percentage of Participants With Intermenstrual (Breakthrough) Bleeding/Spotting, by Cycle | Cycle 8 (n=585,188) | 6.3 Percentage of participants |
| ENG-EE (NuvaRing) | Percentage of Participants With Intermenstrual (Breakthrough) Bleeding/Spotting, by Cycle | Cycle 5 (n=592,187) | 6.8 Percentage of participants |
| ENG-EE (NuvaRing) | Percentage of Participants With Intermenstrual (Breakthrough) Bleeding/Spotting, by Cycle | Cycle 9 (n=576,187) | 6.9 Percentage of participants |
| ENG-EE (NuvaRing) | Percentage of Participants With Intermenstrual (Breakthrough) Bleeding/Spotting, by Cycle | Cycle 2 (n=604,195) | 12.3 Percentage of participants |
| ENG-EE (NuvaRing) | Percentage of Participants With Intermenstrual (Breakthrough) Bleeding/Spotting, by Cycle | Cycle 10 (n=572,183) | 5.9 Percentage of participants |
| ENG-EE (NuvaRing) | Percentage of Participants With Intermenstrual (Breakthrough) Bleeding/Spotting, by Cycle | Cycle 6 (n=590,185) | 6.9 Percentage of participants |
| ENG-EE (NuvaRing) | Percentage of Participants With Intermenstrual (Breakthrough) Bleeding/Spotting, by Cycle | Cycle 11 (n=578,177) | 4.2 Percentage of participants |
| ENG-EE (NuvaRing) | Percentage of Participants With Intermenstrual (Breakthrough) Bleeding/Spotting, by Cycle | Cycle 4 (n=587,194) | 7.5 Percentage of participants |
| ENG-EE (NuvaRing) | Percentage of Participants With Intermenstrual (Breakthrough) Bleeding/Spotting, by Cycle | Cycle 12 (n=569,176) | 5.3 Percentage of participants |
| ENG-EE (NuvaRing) | Percentage of Participants With Intermenstrual (Breakthrough) Bleeding/Spotting, by Cycle | Cycle 7 (n=583,186) | 7.5 Percentage of participants |
| ENG-EE (NuvaRing) | Percentage of Participants With Intermenstrual (Breakthrough) Bleeding/Spotting, by Cycle | Cycle 13 (n=544,173) | 6.4 Percentage of participants |
| ENG-EE (NuvaRing) | Percentage of Participants With Intermenstrual (Breakthrough) Bleeding/Spotting, by Cycle | Cycle 1 (n=598,199) | 18.6 Percentage of participants |
| DRSP-EE | Percentage of Participants With Intermenstrual (Breakthrough) Bleeding/Spotting, by Cycle | Cycle 13 (n=544,173) | 11.0 Percentage of participants |
| DRSP-EE | Percentage of Participants With Intermenstrual (Breakthrough) Bleeding/Spotting, by Cycle | Cycle 1 (n=598,199) | 21.6 Percentage of participants |
| DRSP-EE | Percentage of Participants With Intermenstrual (Breakthrough) Bleeding/Spotting, by Cycle | Cycle 2 (n=604,195) | 18.5 Percentage of participants |
| DRSP-EE | Percentage of Participants With Intermenstrual (Breakthrough) Bleeding/Spotting, by Cycle | Cycle 3 (n=578,196) | 14.3 Percentage of participants |
| DRSP-EE | Percentage of Participants With Intermenstrual (Breakthrough) Bleeding/Spotting, by Cycle | Cycle 4 (n=587,194) | 15.5 Percentage of participants |
| DRSP-EE | Percentage of Participants With Intermenstrual (Breakthrough) Bleeding/Spotting, by Cycle | Cycle 5 (n=592,187) | 8.0 Percentage of participants |
| DRSP-EE | Percentage of Participants With Intermenstrual (Breakthrough) Bleeding/Spotting, by Cycle | Cycle 6 (n=590,185) | 10.8 Percentage of participants |
| DRSP-EE | Percentage of Participants With Intermenstrual (Breakthrough) Bleeding/Spotting, by Cycle | Cycle 7 (n=583,186) | 11.3 Percentage of participants |
| DRSP-EE | Percentage of Participants With Intermenstrual (Breakthrough) Bleeding/Spotting, by Cycle | Cycle 8 (n=585,188) | 10.6 Percentage of participants |
| DRSP-EE | Percentage of Participants With Intermenstrual (Breakthrough) Bleeding/Spotting, by Cycle | Cycle 9 (n=576,187) | 8.0 Percentage of participants |
| DRSP-EE | Percentage of Participants With Intermenstrual (Breakthrough) Bleeding/Spotting, by Cycle | Cycle 10 (n=572,183) | 10.4 Percentage of participants |
| DRSP-EE | Percentage of Participants With Intermenstrual (Breakthrough) Bleeding/Spotting, by Cycle | Cycle 11 (n=578,177) | 7.9 Percentage of participants |
| DRSP-EE | Percentage of Participants With Intermenstrual (Breakthrough) Bleeding/Spotting, by Cycle | Cycle 12 (n=569,176) | 9.7 Percentage of participants |
Comparison: For Cycle 1, a two-sided 95% CI for the difference in percentage between the treatment groups (ENG-EE vs. DRSP-EE) was calculated using the method of Miettinen and Nurminen.p-value: 0.34695% CI: [-9.9, 3.1]Miettinen and Nurminen method
Comparison: For Cycle 2, a two-sided 95% CI for the difference in percentage between the treatment groups (ENG-EE vs. DRSP-EE) was calculated using the method of Miettinen and Nurminen.p-value: 0.02995% CI: [-12.7, -0.6]Miettinen and Nurminen method
Comparison: For Cycle 3, a two-sided 95% CI for the difference in percentage between the treatment groups (ENG-EE vs. DRSP-EE) was calculated using the method of Miettinen and Nurminen.p-value: 0.01995% CI: [-11.8, -0.9]Miettinen and Nurminen method
Comparison: For Cycle 4, a two-sided 95% CI for the difference in percentage between the treatment groups (ENG-EE vs. DRSP-EE) was calculated using the method of Miettinen and Nurminen.p-value: 0.00195% CI: [-14, -2.9]Miettinen and Nurminen method
Comparison: For Cycle 5, a two-sided 95% CI for the difference in percentage between the treatment groups (ENG-EE vs. DRSP-EE) was calculated using the method of Miettinen and Nurminen.p-value: 0.55695% CI: [-6.4, 2.6]Miettinen and Nurminen method
Comparison: For Cycle 6, a two-sided 95% CI for the difference in percentage between the treatment groups (ENG-EE vs. DRSP-EE) was calculated using the method of Miettinen and Nurminen.p-value: 0.08995% CI: [-9.5, 0.5]Miettinen and Nurminen method
Comparison: For Cycle 7, a two-sided 95% CI for the difference in percentage between the treatment groups (ENG-EE vs. DRSP-EE) was calculated using the method of Miettinen and Nurminen.p-value: 0.1195% CI: [-9.4, 0.8]Miettinen and Nurminen method
Comparison: For Cycle 8, a two-sided 95% CI for the difference in percentage between the treatment groups (ENG-EE vs. DRSP-EE) was calculated using the method of Miettinen and Nurminen.p-value: 0.04995% CI: [-9.8, 0]Miettinen and Nurminen method
Comparison: For Cycle 9, a two-sided 95% CI for the difference in percentage between the treatment groups (ENG-EE vs. DRSP-EE) was calculated using the method of Miettinen and Nurminen.p-value: 0.62195% CI: [-6.2, 2.9]Miettinen and Nurminen method
Comparison: For Cycle 10, a two-sided 95% CI for the difference in percentage between the treatment groups (ENG-EE vs. DRSP-EE) was calculated using the method of Miettinen and Nurminen.p-value: 0.04195% CI: [-10, -0.2]Miettinen and Nurminen method
Comparison: For Cycle 11, a two-sided 95% CI for the difference in percentage between the treatment groups (ENG-EE vs. DRSP-EE) was calculated using the method of Miettinen and Nurminen.p-value: 0.04695% CI: [-8.9, -0.1]Miettinen and Nurminen method
Comparison: For Cycle 12, a two-sided 95% CI for the difference in percentage between the treatment groups (ENG-EE vs. DRSP-EE) was calculated using the method of Miettinen and Nurminen.p-value: 0.03795% CI: [-9.9, -0.2]Miettinen and Nurminen method
Comparison: For Cycle 13, a two-sided 95% CI for the difference in percentage between the treatment groups (ENG-EE vs. DRSP-EE) was calculated using the method of Miettinen and Nurminen.p-value: 0.04895% CI: [-10.4, 0]Miettinen and Nurminen method