Uterine Myomas
Conditions
Keywords
Uterine Myomas
Brief summary
This trial will assess the efficacy and safety of PGL4001 versus GnRH agonist, over a 3-month period for the pre-operative treatment of pre-menopausal women suffering from excessive uterine bleeding due to uterine myoma.
Interventions
DRUGPGL4001
tablets
DRUGleuprorelin
solution for injection
Sponsors
PregLem SA
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
* Be a pre-menopausal woman between 18 and 50 years inclusive. * Have excessive uterine bleeding due to myoma * Have a myomatous uterus with at least one myoma of ≥ 3 cm diameter in size * Be eligible for one surgical procedure: e.g. hysterectomy, myomectomy or others. * If of childbearing potential the subject must be practicing a non-hormonal method of contraception. * Have a Body Mass Index (BMI) ≥ 18 and ≤ 40.
Exclusion criteria
* Has a history of or current uterine, cervical, ovarian or breast cancer. * Has a history of or current endometrium atypical hyperplasia or adenocarcinoma. * Has a known severe coagulation disorder. * Has a history of or current treatment for myoma with a Selective Progesterone Receptor Modulator (SPRM) or a GnRH-agonist. * Has a history of or known current osteoporosis. * Has abnormal hepatic function at study entry. * Has a positive pregnancy test at baseline or is nursing or planning a pregnancy during the course of the study. * Has a current (within twelve months) problem with alcohol or drug abuse. * Is currently enrolled in an investigational drug or device study or has participated in such a study within the last 30 days.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects With Reduction of Uterine Bleeding at Week 13 Visit Defined as Pictorial Blood-loss Assessment Chart (PBAC) Score < 75 at End-of-treatment Visit (Week 13 Visit) | 3 months | Uterine bleeding was assessed with the use of the PBAC, a validated self-reporting method to estimate menstrual blood loss. Patients recorded daily the number of tampons and towels used and the degree to which individual items were soiled with blood (plus small or large clots). Monthly scores range from 0 (amenorrhea) to more than 500, with higher numbers indicating more bleeding. A slightly stained tampon/towel scores 1, a partially stained tampon/towel scores 5, a completely saturated tampon scores 10 and a completely saturated towel scores 20. Small clots/flooding (2cm) score 1. Large clots/flooding (3cm) score 5. Menorrhagia is defined as a PBAC \> 100 during one menstrual period which approximates to a blood loss of \> 80 mL. A PBAC of 400 corresponds to a blood loss of around 300 mL or approximately 80 tampons/towels used. The week 13 PBAC score was calculated using the last 28 days of treatment. |
| Co-primary Safety Endpoint: Serum Estradiol Levels at End of Treatment Visit (Week 13 Visit) for PGL4001 Compared With GnRHagonist | Week 13 visit | Measured by log 10 (log pg/ml) transformed values for estradiol (E2) in blood samples |
| Co-primary Safety Endpoint: % of Subjects Reporting Moderate or Severe Hot Flushes as Adverse Events Throughout the Treatment Period for PGL4001 Compared With GnRH-agonist | Up to week 17 | Difference in percentage of subjects reporting moderate or severe hot flushes: Frequency and severity of this adverse event(as spontaneously reported by patients or elicited by nonleading questions) were recorded on standard forms at every visit up to week 17. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Total Volume of the Three Largest Myomas From Baseline to Week 13 | 3 months | Assessment of PGL4001 capacity to decrease volume of the three largest myomas was performed at each center by means of ultrasonography at baseline and at week 13. The total volume of the three largest myomas assessed at screening and at end-of-treatment visit (Week 13) was analysed on a logarithm transformed scale (to base 10). |
Countries
Austria, Belgium, France, Germany, Israel, Italy, Netherlands, Poland, Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| A (PGL4001 5mg) Drug: PGL4001 5mg (oral tablets) and leuproreline matching placebo (intramuscular injection) | 97 |
| B (PGL4001 10mg) Drug: PGL4001 10 mg (oral tablets) and leuproreline matching placebo (intramuscular injection) | 103 |
| C (GnRH-agonist) PGL4001 matching placebo (oral tablets) and leuprorelin 3.75 mg (intramuscular injection) | 101 |
| Total | 301 |
Baseline characteristics
| Characteristic | A (PGL4001 5mg) | B (PGL4001 10mg) | C (GnRH-agonist) | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 97 Participants | 103 Participants | 101 Participants | 301 Participants |
| Age Continuous | 40.1 years STANDARD_DEVIATION 6.2 | 40.7 years STANDARD_DEVIATION 6.3 | 40.3 years STANDARD_DEVIATION 6.2 | 40.3 years STANDARD_DEVIATION 6.2 |
| Region of Enrollment Austria | 8 participants | 12 participants | 8 participants | 28 participants |
| Region of Enrollment Belgium | 12 participants | 16 participants | 13 participants | 41 participants |
| Region of Enrollment Germany | 4 participants | 0 participants | 3 participants | 7 participants |
| Region of Enrollment Israel | 4 participants | 6 participants | 2 participants | 12 participants |
| Region of Enrollment Italy | 6 participants | 7 participants | 7 participants | 20 participants |
| Region of Enrollment Poland | 42 participants | 34 participants | 50 participants | 126 participants |
| Region of Enrollment Spain | 21 participants | 28 participants | 18 participants | 67 participants |
| Sex: Female, Male Female | 97 Participants | 103 Participants | 101 Participants | 301 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 75 / 97 | 79 / 103 | 85 / 101 |
| serious Total, serious adverse events | 5 / 97 | 4 / 103 | 4 / 101 |
Outcome results
Primary
Co-primary Safety Endpoint: % of Subjects Reporting Moderate or Severe Hot Flushes as Adverse Events Throughout the Treatment Period for PGL4001 Compared With GnRH-agonist
Difference in percentage of subjects reporting moderate or severe hot flushes: Frequency and severity of this adverse event(as spontaneously reported by patients or elicited by nonleading questions) were recorded on standard forms at every visit up to week 17.
Time frame: Up to week 17
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A (PGL4001 5mg) | Co-primary Safety Endpoint: % of Subjects Reporting Moderate or Severe Hot Flushes as Adverse Events Throughout the Treatment Period for PGL4001 Compared With GnRH-agonist | 11.3 percentage of patients |
| B (PGL4001 10mg) | Co-primary Safety Endpoint: % of Subjects Reporting Moderate or Severe Hot Flushes as Adverse Events Throughout the Treatment Period for PGL4001 Compared With GnRH-agonist | 9.7 percentage of patients |
| C (GnRH-agonist) | Co-primary Safety Endpoint: % of Subjects Reporting Moderate or Severe Hot Flushes as Adverse Events Throughout the Treatment Period for PGL4001 Compared With GnRH-agonist | 39.6 percentage of patients |
p-value: <0.00195% CI: [-40.6, -14.6]Cochran-Mantel-Haenszel
p-value: <0.00195% CI: [-42, -16.6]Cochran-Mantel-Haenszel
Primary
Co-primary Safety Endpoint: Serum Estradiol Levels at End of Treatment Visit (Week 13 Visit) for PGL4001 Compared With GnRHagonist
Measured by log 10 (log pg/ml) transformed values for estradiol (E2) in blood samples
Time frame: Week 13 visit
Population: Safety population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| A (PGL4001 5mg) | Co-primary Safety Endpoint: Serum Estradiol Levels at End of Treatment Visit (Week 13 Visit) for PGL4001 Compared With GnRHagonist | 1.897 log 10 (log pg/ml) E2 | Standard Error 0.041 |
| B (PGL4001 10mg) | Co-primary Safety Endpoint: Serum Estradiol Levels at End of Treatment Visit (Week 13 Visit) for PGL4001 Compared With GnRHagonist | 1.843 log 10 (log pg/ml) E2 | Standard Error 0.041 |
| C (GnRH-agonist) | Co-primary Safety Endpoint: Serum Estradiol Levels at End of Treatment Visit (Week 13 Visit) for PGL4001 Compared With GnRHagonist | 1.381 log 10 (log pg/ml) E2 | Standard Error 0.041 |
p-value: <0.00195% CI: [-40.6, -14.6]Cochran-Mantel-Haenszel
p-value: <0.00195% CI: [-42, -16.6]Cochran-Mantel-Haenszel
Primary
Percentage of Subjects With Reduction of Uterine Bleeding at Week 13 Visit Defined as Pictorial Blood-loss Assessment Chart (PBAC) Score < 75 at End-of-treatment Visit (Week 13 Visit)
Uterine bleeding was assessed with the use of the PBAC, a validated self-reporting method to estimate menstrual blood loss. Patients recorded daily the number of tampons and towels used and the degree to which individual items were soiled with blood (plus small or large clots). Monthly scores range from 0 (amenorrhea) to more than 500, with higher numbers indicating more bleeding. A slightly stained tampon/towel scores 1, a partially stained tampon/towel scores 5, a completely saturated tampon scores 10 and a completely saturated towel scores 20. Small clots/flooding (2cm) score 1. Large clots/flooding (3cm) score 5. Menorrhagia is defined as a PBAC \> 100 during one menstrual period which approximates to a blood loss of \> 80 mL. A PBAC of 400 corresponds to a blood loss of around 300 mL or approximately 80 tampons/towels used. The week 13 PBAC score was calculated using the last 28 days of treatment.
Time frame: 3 months
Population: Per protocol
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A (PGL4001 5mg) | Percentage of Subjects With Reduction of Uterine Bleeding at Week 13 Visit Defined as Pictorial Blood-loss Assessment Chart (PBAC) Score < 75 at End-of-treatment Visit (Week 13 Visit) | 90.3 percentage of patients |
| B (PGL4001 10mg) | Percentage of Subjects With Reduction of Uterine Bleeding at Week 13 Visit Defined as Pictorial Blood-loss Assessment Chart (PBAC) Score < 75 at End-of-treatment Visit (Week 13 Visit) | 97.9 percentage of patients |
| C (GnRH-agonist) | Percentage of Subjects With Reduction of Uterine Bleeding at Week 13 Visit Defined as Pictorial Blood-loss Assessment Chart (PBAC) Score < 75 at End-of-treatment Visit (Week 13 Visit) | 89.1 percentage of patients |
Comparison: As comparison involved two doses of PGL4001 vs GnRH-agonist, Bonferroni correction used to adjust confidence intervals.
Comparison: As comparison involved two doses of PGL4001 vs GnRH-agonist, Bonferroni correction used to adjust confidence intervals.
Secondary
Change in the Total Volume of the Three Largest Myomas From Baseline to Week 13
Assessment of PGL4001 capacity to decrease volume of the three largest myomas was performed at each center by means of ultrasonography at baseline and at week 13. The total volume of the three largest myomas assessed at screening and at end-of-treatment visit (Week 13) was analysed on a logarithm transformed scale (to base 10).
Time frame: 3 months
Population: Per protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| A (PGL4001 5mg) | Change in the Total Volume of the Three Largest Myomas From Baseline to Week 13 | -0.179 Log 10 (Log cm3) Total volume | Standard Error 0.037 |
| B (PGL4001 10mg) | Change in the Total Volume of the Three Largest Myomas From Baseline to Week 13 | -0.220 Log 10 (Log cm3) Total volume | Standard Error 0.036 |
| C (GnRH-agonist) | Change in the Total Volume of the Three Largest Myomas From Baseline to Week 13 | -0.268 Log 10 (Log cm3) Total volume | Standard Error 0.037 |
95% CI: [-0.003, 0.181]ANCOVA
95% CI: [-0.043, 0.14]ANCOVA