Endometriosis
Conditions
Brief summary
To assess the efficacy of triptorelin pamoate prolonged release (PR) 3-month formulation in Chinese female subjects with endometriosis by demonstrating the non-inferiority of triptorelin pamoate PR 3-month formulation injected once as compared to triptorelin acetate PR 1-month formulation injected 3 times consecutively.
Interventions
DRUGTriptorelin Pamoate PR 3-month
15mg/injection, administered as an intramuscular injection once every 12 weeks (a total of 2 injections).
DRUGTriptorelin Acetate PR 1-month
3.75mg/injection, administered as an intramuscular injection once every 4 weeks (a total of 6 injections)
Sponsors
Ipsen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
* Female subjects aged from 18 to 45 years inclusive at the date of informed consent. * A history of active and regular menstrual cycles of 21 to 35 days (inclusive) in the 6 months prior to the screening visit. * A diagnosis of endometriosis, confirmed by laparoscopy or laparotomy within10 years prior to the screening visit. * Requires treatment with a Gonadotrophin releasing hormone (GnRH) agonist for a period of 6 months in the judgement of the investigator.
Exclusion criteria
* A current history of undiagnosed abnormal genital bleeding. * Received treatment with a GnRH agonist within 6 months prior to the screening visit. * Received any other hormonal treatment within 3 months prior to the screening visit (oestrogens, progestogens, danazol, gestrinone and cyproterone acetate etc). * Chronic pelvic pain that is not caused by endometriosis, that would interfere with the assessment of endometriosis-associated pelvic pain.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects Castrated (E2 ≤184 Pmol/L or 50 pg/mL) at Week 12 | Week 12 | Castration was defined as serum oestradiol (E2) ≤184 picomoles/litre (pmol/L) or 50 picograms/millilitre (pg/mL). The primary endpoint was evaluated based on centralised blinded bioanalysis of serum samples for E2. The percentage of subjects castrated and the 95% asymptotic confidence intervals (CIs), calculated from binomial distribution, are presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects Castrated (E2 ≤110 Pmol/L or 30 pg/mL) at Weeks 4, 8 and 12 | Weeks 4, 8 and 12 | The percentages of subjects who were castrated at Weeks 4, 8 and 12 where castration was defined as serum E2 ≤110 pmol/L or 30 pg/mL are presented. The 95% asymptotic CIs were calculated from the binomial distribution. |
| Change From Baseline in Endometriosis-associated Pelvic Pain at Weeks 4, 8 and 12 | Baseline (Day 1) and Weeks 4, 8 and 12 | Endometriosis-associated pelvic pain was assessed using a 100 millimetres (mm) visual analogue scale (VAS) where subjects indicated the subjective level of their most severe endometriosis pain over the last 4 weeks by making a single vertical mark on the line ranging from 'absence of pain' (0 mm) to 'unbearable pain' (100 mm). Lower scores indicated a better outcome. Baseline was defined as the last available assessment prior to the first dose of study medication. The least squares (LS) mean change from baseline at each timepoint as measured by the VAS is presented. |
| Mean E2 Concentration at Weeks Baseline and 4, 8 and 12 | Baseline (Day 1) and Weeks 4, 8 and 12 | The mean serum E2 concentrations at baseline and Weeks 4, 8 and 12 are presented. |
| Percentage of Subjects Castrated (E2 ≤184 Pmol/L or 50 pg/mL) at Weeks 4 and 8 | Weeks 4 and 8 | The percentages of subjects who were castrated at Weeks 4 and 8 where castration was defined as serum E2 ≤184 pmol/L or 50 pg/mL are presented. The 95% asymptotic CIs were calculated from the binomial distribution. |
| Mean Luteinising Hormone (LH) Concentration at Baseline and Weeks 4, 8 and 12 | Baseline and Weeks 4, 8 and 12 | The mean LH concentrations at baseline and Weeks 4, 8 and 12 are presented. |
| Median Time to Menses Recovery | Baseline (Day 1) up to Week 40 (end of study visit) | Time to menses recovery was defined as the time (in days) between the date of the last dose of study medication and the date of the first day the subject observed menstrual bleeding of the next menstrual period. Menses recovery status was assessed at all study visits from Day 1 to the end of study visit. The median time to menses recovery was analysed using the Kaplan-Meier method. |
| Mean Follicle Stimulating Hormone (FSH) Concentration at Baseline and Weeks 4, 8 and 12 | Baseline (Day 1) and Weeks 4, 8 and 12 | The mean FSH concentrations at baseline and Weeks 4, 8 and 12 are presented. |
Countries
China
Participant flow
Recruitment details
Female subjects aged from 18 to 45 years were recruited to this Phase 3 randomised, open-label study at 24 study centres in China between 28 July 2017 and 16 November 2019.
Pre-assignment details
Subjects who met the inclusion criteria and none of the exclusion criteria were randomised in a 1:1 ratio, stratified according to endometriotic surgical history and the severity of endometriosis-associated pelvic pain.
Participants by arm
| Arm | Count |
|---|---|
| Triptorelin Pamoate PR 3-month Subjects received 15 mg triptorelin pamoate per injection, administered as an IM injection once every 12 weeks (a total of 2 injections, at baseline and Week 12). | 150 |
| Triptorelin Acetate PR 1-month Subjects received 3.75 mg triptorelin acetate per injection, administered as an IM injection once every 4 weeks (a total of 6 injections, at baseline and Weeks 4, 8, 12, 16 and 20). | 150 |
| Total | 300 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Protocol Deviation | 1 | 1 |
| Overall Study | Withdrawal by Subject | 5 | 4 |
Baseline characteristics
| Characteristic | Triptorelin Pamoate PR 3-month | Triptorelin Acetate PR 1-month | Total |
|---|---|---|---|
| Age, Continuous | 32.4 years STANDARD_DEVIATION 6.1 | 32.6 years STANDARD_DEVIATION 6.2 | 32.5 years STANDARD_DEVIATION 6.1 |
| Race/Ethnicity, Customized Chinese | 150 Participants | 150 Participants | 300 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 150 Participants | 150 Participants | 300 Participants |
| Region of Enrollment China | 150 participants | 150 participants | 300 participants |
| Sex: Female, Male Female | 150 Participants | 150 Participants | 300 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 | 0 / 149 | 0 / 150 |
| other Total, other adverse events | 132 / 149 | 135 / 150 |
| serious Total, serious adverse events | 2 / 149 | 1 / 150 |
Outcome results
Primary
Percentage of Subjects Castrated (E2 ≤184 Pmol/L or 50 pg/mL) at Week 12
Castration was defined as serum oestradiol (E2) ≤184 picomoles/litre (pmol/L) or 50 picograms/millilitre (pg/mL). The primary endpoint was evaluated based on centralised blinded bioanalysis of serum samples for E2. The percentage of subjects castrated and the 95% asymptotic confidence intervals (CIs), calculated from binomial distribution, are presented.
Time frame: Week 12
Population: The per protocol set included all randomised subjects who received at least one dose of study medication with at least one baseline and at least one post-baseline assessment of the primary efficacy parameter, and without major protocol violations/deviations affecting the primary efficacy endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Triptorelin Pamoate PR 3-month | Percentage of Subjects Castrated (E2 ≤184 Pmol/L or 50 pg/mL) at Week 12 | 98.6 percentage of subjects |
| Triptorelin Acetate PR 1-month | Percentage of Subjects Castrated (E2 ≤184 Pmol/L or 50 pg/mL) at Week 12 | 99.3 percentage of subjects |
Comparison: The null hypothesis was that triptorelin pamoate PR 3-month was inferior to triptorelin acetate PR 1-month. The alternative hypothesis was that triptorelin pamoate PR 3-month was non-inferior to triptorelin acetate PR 1-month.95% CI: [-4.41, 2.58]
Secondary
Change From Baseline in Endometriosis-associated Pelvic Pain at Weeks 4, 8 and 12
Endometriosis-associated pelvic pain was assessed using a 100 millimetres (mm) visual analogue scale (VAS) where subjects indicated the subjective level of their most severe endometriosis pain over the last 4 weeks by making a single vertical mark on the line ranging from 'absence of pain' (0 mm) to 'unbearable pain' (100 mm). Lower scores indicated a better outcome. Baseline was defined as the last available assessment prior to the first dose of study medication. The least squares (LS) mean change from baseline at each timepoint as measured by the VAS is presented.
Time frame: Baseline (Day 1) and Weeks 4, 8 and 12
Population: The full analysis set included all randomised subjects who received at least one dose of study medication with at least one baseline and at least one post-baseline assessment of the primary efficacy parameter.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Triptorelin Pamoate PR 3-month | Change From Baseline in Endometriosis-associated Pelvic Pain at Weeks 4, 8 and 12 | Week 4 | -24.4 mm |
| Triptorelin Pamoate PR 3-month | Change From Baseline in Endometriosis-associated Pelvic Pain at Weeks 4, 8 and 12 | Week 8 | -28.5 mm |
| Triptorelin Pamoate PR 3-month | Change From Baseline in Endometriosis-associated Pelvic Pain at Weeks 4, 8 and 12 | Week 12 | -28.1 mm |
| Triptorelin Acetate PR 1-month | Change From Baseline in Endometriosis-associated Pelvic Pain at Weeks 4, 8 and 12 | Week 4 | -24.4 mm |
| Triptorelin Acetate PR 1-month | Change From Baseline in Endometriosis-associated Pelvic Pain at Weeks 4, 8 and 12 | Week 8 | -27.8 mm |
| Triptorelin Acetate PR 1-month | Change From Baseline in Endometriosis-associated Pelvic Pain at Weeks 4, 8 and 12 | Week 12 | -28.4 mm |
Secondary
Mean E2 Concentration at Weeks Baseline and 4, 8 and 12
The mean serum E2 concentrations at baseline and Weeks 4, 8 and 12 are presented.
Time frame: Baseline (Day 1) and Weeks 4, 8 and 12
Population: The full analysis set included all randomised subjects who received at least one dose of study medication with at least one baseline and at least one post-baseline assessment of the primary efficacy parameter.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Triptorelin Pamoate PR 3-month | Mean E2 Concentration at Weeks Baseline and 4, 8 and 12 | Baseline | 192.302 pmol/L | Standard Deviation 258.209 |
| Triptorelin Pamoate PR 3-month | Mean E2 Concentration at Weeks Baseline and 4, 8 and 12 | Week 4 | 25.347 pmol/L | Standard Deviation 46.253 |
| Triptorelin Pamoate PR 3-month | Mean E2 Concentration at Weeks Baseline and 4, 8 and 12 | Week 8 | 47.175 pmol/L | Standard Deviation 156.521 |
| Triptorelin Pamoate PR 3-month | Mean E2 Concentration at Weeks Baseline and 4, 8 and 12 | Week 12 | 36.600 pmol/L | Standard Deviation 76.882 |
| Triptorelin Acetate PR 1-month | Mean E2 Concentration at Weeks Baseline and 4, 8 and 12 | Week 12 | 26.695 pmol/L | Standard Deviation 31.174 |
| Triptorelin Acetate PR 1-month | Mean E2 Concentration at Weeks Baseline and 4, 8 and 12 | Baseline | 218.893 pmol/L | Standard Deviation 296.825 |
| Triptorelin Acetate PR 1-month | Mean E2 Concentration at Weeks Baseline and 4, 8 and 12 | Week 8 | 21.863 pmol/L | Standard Deviation 12.55 |
| Triptorelin Acetate PR 1-month | Mean E2 Concentration at Weeks Baseline and 4, 8 and 12 | Week 4 | 18.959 pmol/L | Standard Deviation 3.944 |
Secondary
Mean Follicle Stimulating Hormone (FSH) Concentration at Baseline and Weeks 4, 8 and 12
The mean FSH concentrations at baseline and Weeks 4, 8 and 12 are presented.
Time frame: Baseline (Day 1) and Weeks 4, 8 and 12
Population: The full analysis set included all randomised subjects who received at least one dose of study medication with at least one baseline and at least one post-baseline assessment of the primary efficacy parameter.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Triptorelin Pamoate PR 3-month | Mean Follicle Stimulating Hormone (FSH) Concentration at Baseline and Weeks 4, 8 and 12 | Baseline | 6.099 International Units/L (IU/L) | Standard Deviation 3.929 |
| Triptorelin Pamoate PR 3-month | Mean Follicle Stimulating Hormone (FSH) Concentration at Baseline and Weeks 4, 8 and 12 | Week 4 | 1.762 International Units/L (IU/L) | Standard Deviation 1.373 |
| Triptorelin Pamoate PR 3-month | Mean Follicle Stimulating Hormone (FSH) Concentration at Baseline and Weeks 4, 8 and 12 | Week 8 | 2.891 International Units/L (IU/L) | Standard Deviation 1.163 |
| Triptorelin Pamoate PR 3-month | Mean Follicle Stimulating Hormone (FSH) Concentration at Baseline and Weeks 4, 8 and 12 | Week 12 | 3.344 International Units/L (IU/L) | Standard Deviation 1.347 |
| Triptorelin Acetate PR 1-month | Mean Follicle Stimulating Hormone (FSH) Concentration at Baseline and Weeks 4, 8 and 12 | Week 12 | 3.325 International Units/L (IU/L) | Standard Deviation 1.414 |
| Triptorelin Acetate PR 1-month | Mean Follicle Stimulating Hormone (FSH) Concentration at Baseline and Weeks 4, 8 and 12 | Baseline | 6.258 International Units/L (IU/L) | Standard Deviation 4.52 |
| Triptorelin Acetate PR 1-month | Mean Follicle Stimulating Hormone (FSH) Concentration at Baseline and Weeks 4, 8 and 12 | Week 8 | 2.766 International Units/L (IU/L) | Standard Deviation 1.329 |
| Triptorelin Acetate PR 1-month | Mean Follicle Stimulating Hormone (FSH) Concentration at Baseline and Weeks 4, 8 and 12 | Week 4 | 1.699 International Units/L (IU/L) | Standard Deviation 1.049 |
Secondary
Mean Luteinising Hormone (LH) Concentration at Baseline and Weeks 4, 8 and 12
The mean LH concentrations at baseline and Weeks 4, 8 and 12 are presented.
Time frame: Baseline and Weeks 4, 8 and 12
Population: The full analysis set included all randomised subjects who received at least one dose of study medication with at least one baseline and at least one post-baseline assessment of the primary efficacy parameter.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Triptorelin Pamoate PR 3-month | Mean Luteinising Hormone (LH) Concentration at Baseline and Weeks 4, 8 and 12 | Baseline | 3.376 IU/L | Standard Deviation 1.902 |
| Triptorelin Pamoate PR 3-month | Mean Luteinising Hormone (LH) Concentration at Baseline and Weeks 4, 8 and 12 | Week 4 | 0.660 IU/L | Standard Deviation 1.771 |
| Triptorelin Pamoate PR 3-month | Mean Luteinising Hormone (LH) Concentration at Baseline and Weeks 4, 8 and 12 | Week 8 | 0.444 IU/L | Standard Deviation 1.928 |
| Triptorelin Pamoate PR 3-month | Mean Luteinising Hormone (LH) Concentration at Baseline and Weeks 4, 8 and 12 | Week 12 | 0.324 IU/L | Standard Deviation 0.555 |
| Triptorelin Acetate PR 1-month | Mean Luteinising Hormone (LH) Concentration at Baseline and Weeks 4, 8 and 12 | Week 12 | 0.251 IU/L | Standard Deviation 0.239 |
| Triptorelin Acetate PR 1-month | Mean Luteinising Hormone (LH) Concentration at Baseline and Weeks 4, 8 and 12 | Baseline | 3.487 IU/L | Standard Deviation 1.858 |
| Triptorelin Acetate PR 1-month | Mean Luteinising Hormone (LH) Concentration at Baseline and Weeks 4, 8 and 12 | Week 8 | 0.255 IU/L | Standard Deviation 0.122 |
| Triptorelin Acetate PR 1-month | Mean Luteinising Hormone (LH) Concentration at Baseline and Weeks 4, 8 and 12 | Week 4 | 0.500 IU/L | Standard Deviation 0.173 |
Secondary
Median Time to Menses Recovery
Time to menses recovery was defined as the time (in days) between the date of the last dose of study medication and the date of the first day the subject observed menstrual bleeding of the next menstrual period. Menses recovery status was assessed at all study visits from Day 1 to the end of study visit. The median time to menses recovery was analysed using the Kaplan-Meier method.
Time frame: Baseline (Day 1) up to Week 40 (end of study visit)
Population: The full analysis set included all randomised subjects who received at least one dose of study medication with at least one baseline and at least one post-baseline assessment of the primary efficacy parameter.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Triptorelin Pamoate PR 3-month | Median Time to Menses Recovery | 179.0 days |
| Triptorelin Acetate PR 1-month | Median Time to Menses Recovery | 85.0 days |
Secondary
Percentage of Subjects Castrated (E2 ≤110 Pmol/L or 30 pg/mL) at Weeks 4, 8 and 12
The percentages of subjects who were castrated at Weeks 4, 8 and 12 where castration was defined as serum E2 ≤110 pmol/L or 30 pg/mL are presented. The 95% asymptotic CIs were calculated from the binomial distribution.
Time frame: Weeks 4, 8 and 12
Population: The full analysis set included all randomised subjects who received at least one dose of study medication with at least one baseline and at least one post-baseline assessment of the primary efficacy parameter.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Triptorelin Pamoate PR 3-month | Percentage of Subjects Castrated (E2 ≤110 Pmol/L or 30 pg/mL) at Weeks 4, 8 and 12 | Week 4 | 98.0 percentage of subjects |
| Triptorelin Pamoate PR 3-month | Percentage of Subjects Castrated (E2 ≤110 Pmol/L or 30 pg/mL) at Weeks 4, 8 and 12 | Week 8 | 95.2 percentage of subjects |
| Triptorelin Pamoate PR 3-month | Percentage of Subjects Castrated (E2 ≤110 Pmol/L or 30 pg/mL) at Weeks 4, 8 and 12 | Week 12 | 95.9 percentage of subjects |
| Triptorelin Acetate PR 1-month | Percentage of Subjects Castrated (E2 ≤110 Pmol/L or 30 pg/mL) at Weeks 4, 8 and 12 | Week 4 | 99.3 percentage of subjects |
| Triptorelin Acetate PR 1-month | Percentage of Subjects Castrated (E2 ≤110 Pmol/L or 30 pg/mL) at Weeks 4, 8 and 12 | Week 8 | 99.3 percentage of subjects |
| Triptorelin Acetate PR 1-month | Percentage of Subjects Castrated (E2 ≤110 Pmol/L or 30 pg/mL) at Weeks 4, 8 and 12 | Week 12 | 98.7 percentage of subjects |
Comparison: Rate difference at Week 4. The null hypothesis was that triptorelin pamoate PR 3-month was inferior to triptorelin acetate PR 1-month. The alternative hypothesis was that triptorelin pamoate PR 3-month was non-inferior to triptorelin acetate PR 1-month.95% CI: [-5.26, 1.93]
Comparison: Rate difference at Week 8. The null hypothesis was that triptorelin pamoate PR 3-month was inferior to triptorelin acetate PR 1-month. The alternative hypothesis was that triptorelin pamoate PR 3-month was non-inferior to triptorelin acetate PR 1-month.95% CI: [-8.93, -0.52]
Comparison: Rate difference at Week 12. The null hypothesis was that triptorelin pamoate PR 3-month was inferior to triptorelin acetate PR 1-month. The alternative hypothesis was that triptorelin pamoate PR 3-month was non-inferior to triptorelin acetate PR 1-month.95% CI: [-7.44, 1.17]
Secondary
Percentage of Subjects Castrated (E2 ≤184 Pmol/L or 50 pg/mL) at Weeks 4 and 8
The percentages of subjects who were castrated at Weeks 4 and 8 where castration was defined as serum E2 ≤184 pmol/L or 50 pg/mL are presented. The 95% asymptotic CIs were calculated from the binomial distribution.
Time frame: Weeks 4 and 8
Population: The full analysis set included all randomised subjects who received at least one dose of study medication with at least one baseline and at least one post-baseline assessment of the primary efficacy parameter.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Triptorelin Pamoate PR 3-month | Percentage of Subjects Castrated (E2 ≤184 Pmol/L or 50 pg/mL) at Weeks 4 and 8 | Week 8 | 97.3 percentage of subjects |
| Triptorelin Pamoate PR 3-month | Percentage of Subjects Castrated (E2 ≤184 Pmol/L or 50 pg/mL) at Weeks 4 and 8 | Week 4 | 98.0 percentage of subjects |
| Triptorelin Acetate PR 1-month | Percentage of Subjects Castrated (E2 ≤184 Pmol/L or 50 pg/mL) at Weeks 4 and 8 | Week 4 | 99.3 percentage of subjects |
| Triptorelin Acetate PR 1-month | Percentage of Subjects Castrated (E2 ≤184 Pmol/L or 50 pg/mL) at Weeks 4 and 8 | Week 8 | 100.0 percentage of subjects |
Comparison: Rate difference at Week 4. The null hypothesis was that triptorelin pamoate PR 3-month was inferior to triptorelin acetate PR 1-month. The alternative hypothesis was that triptorelin pamoate PR 3-month was non-inferior to triptorelin acetate PR 1-month.95% CI: [-5.26, 1.93]
Comparison: Rate difference at Week 8. The null hypothesis was that triptorelin pamoate PR 3-month was inferior to triptorelin acetate PR 1-month. The alternative hypothesis was that triptorelin pamoate PR 3-month was non-inferior to triptorelin acetate PR 1-month.95% CI: [-6.8, -0.16]