Acromegaly
Conditions
Brief summary
The purpose is to compare the efficacy and safety of lanreotide autogel® 60mg, 90mg or 120mg with lanreotide 40mg PR in subjects with active acromegaly.
Interventions
DRUGLanreotide Autogel®
Lanreotide Autogel 60mg, 90mg, and 120mg, pre-filled syringe, deep subcutaneous injection (provided as a supersaturated solution of lanreotide acetate).
Lanreotide PR 40mg white freeze-drying cake, 40mg/vial, deep subcutaneous injection (provided as a sterile injectable lyophilisate of lanreotide acetate).
Sponsors
Ipsen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Subject has active acromegaly defined as elevated GH and IGF-1 levels (measured at a central laboratory) as outlined below: * A serum level for IGF-1 ≥1.3 x upper limit of normal range (ULN) during the screening period (applicable to both treatment naïve subjects and subjects who have stopped treatment and undergone a washout period prior to Visit 1(Week -4). * Subjects must have mean serum GH concentration ≥2.5 μg/L in a GH cycle (5 samples taken at 0, 30, 60, 90 and 120 minutes) during the screening period. * The subject has undergone surgical removal of an adenoma for acromegaly at least 3 months prior to Screening, or is likely to require pituitary surgery in the future but not before completing at least 32 weeks of study treatment plus an additional follow up of 8 weeks for subjects taking part in the pharmacokinetics (PK) extension, or for whom pituitary surgery is not an option (due to contraindications, refusal etc.) and is therefore never likely to undergo pituitary surgery.
Exclusion criteria
* The subject has been treated with radiotherapy within 10 years prior to Screening. * The subject has been treated with lanreotide Autogel, lanreotide PR, pegvisomant, cabergoline or octreotide LAR within 3 months of Screening or octreotide immediate release (IR) or bromocriptin within 2 weeks of Screening. * The subject has a history of or currently presents with clinically significant ventricular or atrial dysrhythmias ≥Grade 2, using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0. * The subject has uncontrolled diabetes (glycosylated haemoglobin (HbA1c) \>8.5%).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Standardised Mean Change From Baseline in Age-adjusted IGF-1 Levels at the EOST/EW Visit | Baseline to EOST/EW Visit (up to Week 33 for the lanreotide Autogel group and up to Week 32 for the lanreotide PR group). | The standardised mean change from Baseline in age-adjusted log-transformed IGF-1 standard deviation score (SDS) at EOST/EW is presented for subjects treated with both lanreotide Autogel and lanreotide PR. Back-transformed results are presented in addition to the results without back-transformation. For each subject the IGF-1 SDS value was calculated based on the z-score derivation: IGF-1 SDS = (IGF-1 - mean)/ standard deviation (SD), with mean and SD derived from the upper limit of normal (ULN) and lower limit of normal (LLN) margins for each age category. ULN = Mean + 2 SD; LLN = Mean - 2 SD. The SDS indicates the number of standard deviations away from the mean. A SDS of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. A negative change in the SDS indicates a decrease in the mean age-adjusted IGF-1 values. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects With GH ≤2.5 Micrograms Per Litre (mcg/L) at the EOST/EW Visit | Baseline to EOST/EW Visit (up to Week 33 for the lanreotide Autogel group and up to Week 32 for the lanreotide PR group). | The percentage of subjects with GH ≤2.5 mcg/L at the EOST/EW Visit is presented for subjects treated with lanreotide Autogel and lanreotide PR. At baseline, all subjects had GH levels \>2.5 mcg/L as per protocol entry criteria. |
| The Percentage of Subjects With GH ≤1 mcg/L at the EOST/EW Visit | Baseline to EOST/EW Visit (up to Week 33 for the lanreotide Autogel group and up to Week 32 for the lanreotide PR group). | The percentage of subjects with GH ≤1 mcg/L at the EOST/EW Visit is presented for subjects treated with lanreotide Autogel and lanreotide PR. At baseline, all subjects had GH levels \>2.5 mcg/L as per protocol entry criteria. |
| Percentage of Subjects With Normal Age-adjusted IGF-1 Levels and Who Have GH Levels >1 mcg/L and ≤2.5 mcg/L at the EOST/EW Visit | Baseline to EOST/EW Visit (up to Week 33 for the lanreotide Autogel group and up to Week 32 for the lanreotide PR group). | The percentage of subjects with normal age-adjusted IGF-1 levels and who have GH levels \>1 mcg/L but ≤2.5 mcg/L at the EOST/EW Visit is presented for subjects treated with lanreotide Autogel and lanreotide PR. The calculation of percentages was based on the overall ITT population. At baseline, all subjects had abnormal IGF-1 levels and GH levels \>2.5 mcg/L as per protocol entry criteria. |
| Percentage of Subjects With Normal Age-adjusted IGF-1 Levels at the EOST/EW Visit | Baseline to EOST/EW Visit (up to Week 33 for the lanreotide Autogel group and up to Week 32 for the lanreotide PR group). | The percentage of subjects with normal age-adjusted IGF-1 levels at the EOST/EW Visit is presented for subjects treated with Lanreotide Autogel and Lanreotide PR. At baseline, all subjects had abnormal IGF-1 levels as per protocol entry criteria. |
| Percentage of Subjects With at Least 20% Reduction in Tumour Volume at EOST/EW Visit Compared to Baseline | Baseline to EOST/EW Visit (up to Week 33 for the lanreotide Autogel group and up to Week 32 for the lanreotide PR group). | The percentage of subjects with at least a 20% reduction in the solid component of the tumour volume at the EOST/EW Visit compared to baseline is presented for the subgroup of subjects who had solid tumours at baseline. The tumour volume was measured by Magnetic Resonance Imaging (MRI) at Screening and at the EOST/EW Visit, and then assessed by two independent blinded readers. |
| Median Percentage Change From Baseline in Tumour Volume at the EOST/EW Visit | Baseline to EOST/EW Visit (up to Week 33 for the lanreotide Autogel group and up to Week 32 for the lanreotide PR group). | The median percentage change in the solid component of the tumour volume from baseline to the EOST/EW Visit is presented. The tumour volume was measured by MRI at Screening and at the EOST/EW Visit, and then assessed by two independent blinded readers. |
| Percentage of Subjects With at Least One Symptom of Acromegaly at Week 13 and at the EOST/EW Visit Compared to Baseline | Baseline, Week 13 Visit and EOST/EW Visit (up to Week 33 for the lanreotide Autogel group and up to Week 32 for the lanreotide PR group). | The percentage of subjects with at least one symptom of acromegaly at Week 13 and at the EOST/EW Visit compared with baseline is presented for subjects treated with lanreotide Autogel and lanreotide PR. The symptoms of acromegaly monitored included: headache, excessive perspiration, fatigue, soft tissue swelling and arthralgia. |
| Mean Change From Baseline in GH Values at the EOST/EW Visit | Baseline to EOST/EW Visit (up to Week 33 for the lanreotide Autogel group and up to Week 32 for the lanreotide PR group). | The mean change from baseline in GH values at the EOST/EW Visit is presented for subjects treated with lanreotide Autogel and lanreotide PR. |
Countries
China
Participant flow
Recruitment details
Adult subjects with active acromegaly, defined as elevated Insulin-like Growth Factor 1 (IGF-1) and Growth Hormone (GH) levels, were recruited into 10 study sites in China.
Pre-assignment details
170 subjects were screened and 128 eligible subjects were stratified according to surgical history (previous pituitary surgery or no previous pituitary surgery) and randomised in a 1:1 ratio to receive lanreotide Autogel or lanreotide prolonged release (PR). All randomised subjects were treated.
Participants by arm
| Arm | Count |
|---|---|
| Lanreotide Autogel Subjects were randomised to receive lanreotide Autogel. Lanreotide Autogel was administered s.c. at a fixed dose of 90 mg every 4 weeks from Day 1, Week 1 to Week 17. At Week 17 the dose was continued at 90 mg or titrated to 60 mg or 120 mg every 4 weeks according to the individual subject's response as determined by the mean value of the GH cycles and IGF-1 measured at the previous Week 13 Visit. The last dose of lanreotide Autogel was given at Week 29, followed by EOST/EW Visit at Week 33. | 64 |
| Lanreotide PR Subjects were randomised to receive lanreotide PR. Lanreotide PR was administered i.m. every 10 days from Day 1, Week 1 up to Week 16. At Week 16 the injection interval was maintained at 10 days or was adjusted to 7 or 14 days according to the individual subject's response as determined by the mean value of GH cycle and IGF-1 measured at the previous visit at Week 13. The last dose of lanreotide PR was administered at Week 31. The EOST/EW Visit was at Week 32. | 64 |
| Total Title | 128 |
| Total | 256 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 |
| Overall Study | Missed study visit | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Lanreotide PR | Total Title | Lanreotide Autogel |
|---|---|---|---|
| Age, Continuous | 40.8 years STANDARD_DEVIATION 12.6 | 39.4 years STANDARD_DEVIATION 11.9 | 37.9 years STANDARD_DEVIATION 11.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 64 Participants | 128 Participants | 64 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 40 Participants | 78 Participants | 38 Participants |
| Sex: Female, Male Male | 24 Participants | 50 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 64 | 0 / 64 |
| other Total, other adverse events | 59 / 64 | 62 / 64 |
| serious Total, serious adverse events | 1 / 64 | 2 / 64 |
Outcome results
Primary
Standardised Mean Change From Baseline in Age-adjusted IGF-1 Levels at the EOST/EW Visit
The standardised mean change from Baseline in age-adjusted log-transformed IGF-1 standard deviation score (SDS) at EOST/EW is presented for subjects treated with both lanreotide Autogel and lanreotide PR. Back-transformed results are presented in addition to the results without back-transformation. For each subject the IGF-1 SDS value was calculated based on the z-score derivation: IGF-1 SDS = (IGF-1 - mean)/ standard deviation (SD), with mean and SD derived from the upper limit of normal (ULN) and lower limit of normal (LLN) margins for each age category. ULN = Mean + 2 SD; LLN = Mean - 2 SD. The SDS indicates the number of standard deviations away from the mean. A SDS of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. A negative change in the SDS indicates a decrease in the mean age-adjusted IGF-1 values.
Time frame: Baseline to EOST/EW Visit (up to Week 33 for the lanreotide Autogel group and up to Week 32 for the lanreotide PR group).
Population: The Per Protocol population consisted of all subjects who were randomised and treated with at least one baseline and at least one postbaseline assessment of the primary efficacy parameter and for whom no major protocol deviations occurred with impact on efficacy assessment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Lanreotide Autogel | Standardised Mean Change From Baseline in Age-adjusted IGF-1 Levels at the EOST/EW Visit | Without back-transformation | -0.84 SDS | Standard Error 0.15 |
| Lanreotide Autogel | Standardised Mean Change From Baseline in Age-adjusted IGF-1 Levels at the EOST/EW Visit | With back transformation | 0.43 SDS | Standard Error 1.16 |
| Lanreotide PR | Standardised Mean Change From Baseline in Age-adjusted IGF-1 Levels at the EOST/EW Visit | Without back-transformation | -0.52 SDS | Standard Error 0.17 |
| Lanreotide PR | Standardised Mean Change From Baseline in Age-adjusted IGF-1 Levels at the EOST/EW Visit | With back transformation | 0.59 SDS | Standard Error 1.19 |
Comparison: The Least Square (LS) Means and 95% Confidence Intervals (CIs) were based on the generalised linear model (GLM) with IGF-1 SDS change from baseline values as dependent variable, with treatment group and previous pituitary surgery as independent factors, and the baseline value of IGF-1 SDS as independent covariate. A log-transformation with base e was applied to the IGF-1 SDS data before analysing.~The treatment difference (lanreotide Autogel - lanreotide PR) is presented.95% CI: [-0.74, 0.11]
Comparison: The LS Means and 95% CIs were based on the GLM with IGF-1 SDS change from baseline values as dependent variable, with treatment group and previous pituitary surgery as independent factors, and the baseline value of IGF-1 SDS as independent covariate. A log-transformation with base e was applied to the IGF-1 SDS data before analysing.~The LS Mean ratio (lanreotide Autogel versus lanreotide PR) is presented.95% CI: [0.48, 1.11]
Secondary
Mean Change From Baseline in GH Values at the EOST/EW Visit
The mean change from baseline in GH values at the EOST/EW Visit is presented for subjects treated with lanreotide Autogel and lanreotide PR.
Time frame: Baseline to EOST/EW Visit (up to Week 33 for the lanreotide Autogel group and up to Week 32 for the lanreotide PR group).
Population: The ITT population consisted of all randomised and treated subjects who had at least one baseline and at least one postbaseline assessment of the primary efficacy parameter. The ITT population was analysed using subjects as randomised. Subjects with data available at time of analysis are presented.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lanreotide Autogel | Mean Change From Baseline in GH Values at the EOST/EW Visit | -9.548 mcg/L | Standard Deviation 22.852 |
| Lanreotide PR | Mean Change From Baseline in GH Values at the EOST/EW Visit | -13.182 mcg/L | Standard Deviation 20.224 |
Comparison: Treatment difference (lanreotide Autogel - lanreotide PR) is presented.95% CI: [-3.98, 11.25]
Secondary
Median Percentage Change From Baseline in Tumour Volume at the EOST/EW Visit
The median percentage change in the solid component of the tumour volume from baseline to the EOST/EW Visit is presented. The tumour volume was measured by MRI at Screening and at the EOST/EW Visit, and then assessed by two independent blinded readers.
Time frame: Baseline to EOST/EW Visit (up to Week 33 for the lanreotide Autogel group and up to Week 32 for the lanreotide PR group).
Population: The ITT population consisted of all randomised and treated subjects who had at least one baseline and at least one postbaseline assessment of the primary efficacy parameter. The ITT population was analysed using subjects as randomised. Data is presented for the subgroup of subjects in the ITT population who had solid tumours at baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lanreotide Autogel | Median Percentage Change From Baseline in Tumour Volume at the EOST/EW Visit | -17.870 Percentage change in tumour volume |
| Lanreotide PR | Median Percentage Change From Baseline in Tumour Volume at the EOST/EW Visit | -20.120 Percentage change in tumour volume |
Secondary
Percentage of Subjects With at Least 20% Reduction in Tumour Volume at EOST/EW Visit Compared to Baseline
The percentage of subjects with at least a 20% reduction in the solid component of the tumour volume at the EOST/EW Visit compared to baseline is presented for the subgroup of subjects who had solid tumours at baseline. The tumour volume was measured by Magnetic Resonance Imaging (MRI) at Screening and at the EOST/EW Visit, and then assessed by two independent blinded readers.
Time frame: Baseline to EOST/EW Visit (up to Week 33 for the lanreotide Autogel group and up to Week 32 for the lanreotide PR group).
Population: The ITT population consisted of all randomised and treated subjects who had at least one baseline and at least one postbaseline assessment of the primary efficacy parameter. The ITT population was analysed using subjects as randomised. Data is presented for the subgroup of subjects in the ITT population who had solid tumours at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lanreotide Autogel | Percentage of Subjects With at Least 20% Reduction in Tumour Volume at EOST/EW Visit Compared to Baseline | 45.5 Percentage of Subjects |
| Lanreotide PR | Percentage of Subjects With at Least 20% Reduction in Tumour Volume at EOST/EW Visit Compared to Baseline | 50.9 Percentage of Subjects |
Comparison: Risk difference (lanreotide Autogel - lanreotide PR) in the percentage of subjects with at least 20% reduction in the solid component of tumour volume compared to Baseline is presented.95% CI: [-24.3, 13.3]
Secondary
Percentage of Subjects With at Least One Symptom of Acromegaly at Week 13 and at the EOST/EW Visit Compared to Baseline
The percentage of subjects with at least one symptom of acromegaly at Week 13 and at the EOST/EW Visit compared with baseline is presented for subjects treated with lanreotide Autogel and lanreotide PR. The symptoms of acromegaly monitored included: headache, excessive perspiration, fatigue, soft tissue swelling and arthralgia.
Time frame: Baseline, Week 13 Visit and EOST/EW Visit (up to Week 33 for the lanreotide Autogel group and up to Week 32 for the lanreotide PR group).
Population: The ITT population consisted of all randomised and treated subjects who had at least one baseline and at least one postbaseline assessment of the primary efficacy parameter. The ITT population was analysed using subjects as randomised.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lanreotide Autogel | Percentage of Subjects With at Least One Symptom of Acromegaly at Week 13 and at the EOST/EW Visit Compared to Baseline | Week 13 Visit | 70.3 Percentage of Subjects |
| Lanreotide Autogel | Percentage of Subjects With at Least One Symptom of Acromegaly at Week 13 and at the EOST/EW Visit Compared to Baseline | EOST/EW Visit | 75.0 Percentage of Subjects |
| Lanreotide PR | Percentage of Subjects With at Least One Symptom of Acromegaly at Week 13 and at the EOST/EW Visit Compared to Baseline | Week 13 Visit | 59.4 Percentage of Subjects |
| Lanreotide PR | Percentage of Subjects With at Least One Symptom of Acromegaly at Week 13 and at the EOST/EW Visit Compared to Baseline | EOST/EW Visit | 59.4 Percentage of Subjects |
Secondary
Percentage of Subjects With GH ≤2.5 Micrograms Per Litre (mcg/L) at the EOST/EW Visit
The percentage of subjects with GH ≤2.5 mcg/L at the EOST/EW Visit is presented for subjects treated with lanreotide Autogel and lanreotide PR. At baseline, all subjects had GH levels \>2.5 mcg/L as per protocol entry criteria.
Time frame: Baseline to EOST/EW Visit (up to Week 33 for the lanreotide Autogel group and up to Week 32 for the lanreotide PR group).
Population: The ITT population consisted of all randomised and treated subjects who had at least one baseline and at least one postbaseline assessment of the primary efficacy parameter. The ITT population was analysed using subjects as randomised.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lanreotide Autogel | Percentage of Subjects With GH ≤2.5 Micrograms Per Litre (mcg/L) at the EOST/EW Visit | 29.7 Percentage of Subjects |
| Lanreotide PR | Percentage of Subjects With GH ≤2.5 Micrograms Per Litre (mcg/L) at the EOST/EW Visit | 31.3 Percentage of Subjects |
Comparison: The risk difference (lanreotide Autogel - lanreotide PR) in the percentage of GH levels ≤2.5 mcg/L at EOST/EW Visit is presented.95% CI: [-17.5, 14.4]
Secondary
Percentage of Subjects With Normal Age-adjusted IGF-1 Levels and Who Have GH Levels >1 mcg/L and ≤2.5 mcg/L at the EOST/EW Visit
The percentage of subjects with normal age-adjusted IGF-1 levels and who have GH levels \>1 mcg/L but ≤2.5 mcg/L at the EOST/EW Visit is presented for subjects treated with lanreotide Autogel and lanreotide PR. The calculation of percentages was based on the overall ITT population. At baseline, all subjects had abnormal IGF-1 levels and GH levels \>2.5 mcg/L as per protocol entry criteria.
Time frame: Baseline to EOST/EW Visit (up to Week 33 for the lanreotide Autogel group and up to Week 32 for the lanreotide PR group).
Population: The ITT population consisted of all randomised and treated subjects who had at least one baseline and at least one postbaseline assessment of the primary efficacy parameter. The ITT population was analysed using subjects as randomised.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lanreotide Autogel | Percentage of Subjects With Normal Age-adjusted IGF-1 Levels and Who Have GH Levels >1 mcg/L and ≤2.5 mcg/L at the EOST/EW Visit | 7.8 Percentage of Subjects |
| Lanreotide PR | Percentage of Subjects With Normal Age-adjusted IGF-1 Levels and Who Have GH Levels >1 mcg/L and ≤2.5 mcg/L at the EOST/EW Visit | 3.1 Percentage of Subjects |
Comparison: The risk difference (lanreotide Autogel - lanreotide PR) in the percentage subjects with normal IGF-1 levels and who have GH levels \>1 mcg/L and ≤2.5 mcg/L at EOST/EW Visit is presented.95% CI: [-3.1, 12.5]
Secondary
Percentage of Subjects With Normal Age-adjusted IGF-1 Levels at the EOST/EW Visit
The percentage of subjects with normal age-adjusted IGF-1 levels at the EOST/EW Visit is presented for subjects treated with Lanreotide Autogel and Lanreotide PR. At baseline, all subjects had abnormal IGF-1 levels as per protocol entry criteria.
Time frame: Baseline to EOST/EW Visit (up to Week 33 for the lanreotide Autogel group and up to Week 32 for the lanreotide PR group).
Population: The Intention-To-Treat (ITT) population consisted of all randomised and treated subjects who had at least one baseline and at least one postbaseline assessment of the primary efficacy parameter. The ITT population was analysed using subjects as randomised.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lanreotide Autogel | Percentage of Subjects With Normal Age-adjusted IGF-1 Levels at the EOST/EW Visit | 15.6 Percentage of Subjects |
| Lanreotide PR | Percentage of Subjects With Normal Age-adjusted IGF-1 Levels at the EOST/EW Visit | 9.4 Percentage of Subjects |
Comparison: The risk difference (lanreotide Autogel - lanreotide PR) in the percentage of normal IGF-1 SDS values at EOST/EW Visit is presented.95% CI: [-5.2, 17.7]
Secondary
The Percentage of Subjects With GH ≤1 mcg/L at the EOST/EW Visit
The percentage of subjects with GH ≤1 mcg/L at the EOST/EW Visit is presented for subjects treated with lanreotide Autogel and lanreotide PR. At baseline, all subjects had GH levels \>2.5 mcg/L as per protocol entry criteria.
Time frame: Baseline to EOST/EW Visit (up to Week 33 for the lanreotide Autogel group and up to Week 32 for the lanreotide PR group).
Population: The ITT population consisted of all randomised and treated subjects who had at least one baseline and at least one postbaseline assessment of the primary efficacy parameter. The ITT population was analysed using subjects as randomised.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lanreotide Autogel | The Percentage of Subjects With GH ≤1 mcg/L at the EOST/EW Visit | 10.9 Percentage of Subjects |
| Lanreotide PR | The Percentage of Subjects With GH ≤1 mcg/L at the EOST/EW Visit | 9.4 Percentage of Subjects |
Comparison: The risk difference (lanreotide Autogel - lanreotide PR) in the percentage of GH levels ≤1 mcg/L at EOST/EW Visit is presented.95% CI: [-8.9, 12]