E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Uterine myomas are benign, monoclonal, hormone-sensitive, smooth muscle tumours of the uterus. They are the most common tumour of the female reproductive tract in pre-menopausal women and mostly asymptomatic affecting approximately 40% of women between 35 and 55 years. When symptomatic, the main symptoms are heavy uterine bleeding, abdominal pressure, abdominal pain, increased urinary frequency and infertility. |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Body processes [G] - Reproductive physiologi cal processes [G08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10046801 |
E.1.2 | Term | Uterine myoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• To assess the sustained efficacy of three 3-month treatment cycles of ulipristal acetate on myoma symptoms, specifically uterine bleeding. |
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E.2.2 | Secondary objectives of the trial |
Efficacy:
• To assess the sustained efficacy of three 3-month treatment cycles of ulipristal acetate on myoma symptoms other than uterine bleeding (i.e. myoma size, pain, quality of life (QoL)).
Safety:
• To assess the overall safety of the on-off 3-month administration of PGL4001 for up to a total of four treatment cycles (including PGL09-026 PEARL III treatment cycle).
Exploratory:
• To assess, recruitment permitting, the long-term clinical efficacy and safety benefit of following each of the three 3-month treatment cycles with ulipristal acetate by a ten-day course of norethisterone acetate or placebo
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
To be eligible for inclusion into this study, the subjects must fulfil all of the following criteria:
1. Provision of written informed consent prior to any PGL09-027 study related procedures.
2. Subject completed visit 6 of PGL09-026 study, 10 to 18 days after menstruation following end of treatment with PGL4001, and did not take medications forbidden by the protocol.
3. Subject has no contraindication to enter the extension study, based on the responsible investigator’s judgment.
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E.4 | Principal exclusion criteria |
To be eligible for inclusion in this study the subjects must not meet any of the following criteria:
1. Subject has a large uterine polyp (> 2cm).
2. Subject has one or more ovarian cysts ≥ 4cm diagnosed by ultrasound at visit 6 of PGL09-026.
3. Subject is likely to require treatment during the study with drugs that are not permitted by the study protocol: progestins (systemic or progestin releasing intra-uterine system), hormonal contraceptives, systemic glucocorticoids (oral and injectable), acetylsalicylic acid, mefenamic acid, anticoagulants such as cumarins, antifibrynolytic drugs such as tranexamic acid, treatments containing PgP substrates (digoxin, fexofenadine), and/or treatments containing moderate or potent inhibitors or inducers of CYP3A4.
4. Subject has abnormal hepatic function at re-test (defined as aspartate transaminase [AST], alanine transaminase [ALT], gamma glutamyl transferase [GGT], hepatic alkaline phosphatase, or total bilirubin above twice the upper limit of normal). A re-test will be performed if hepatic function test values are above twice the upper limit of normal at visit 5 of PGL09-026 study. If the second test result is still above twice the upper limit of normal, the subject cannot be included. In case of isolated GGT, the subject may be enrolled if the re-test is within the allowed limits.
5. Subject has a lactose or galactose intolerance (i.e. lapp lactase deficiency or glucose-galactose malabsorption)
6. Subject has a positive pregnancy test or is planning a pregnancy during the course of the study.
7. Subject has a current problem with alcohol or drug abuse.
8. Subject has a mental condition rendering her unable to understand the nature, scope and possible consequences of the study, and/or evidence of an uncooperative attitude.
9. Subject has clinically significant abnormal findings at visit A or any other medical condition(s) or laboratory findings that, in the opinion of the investigator, might jeopardize the subject’s safety or interfere with study evaluations.
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary efficacy endpoint:
•Percentage of subjects in amenorrhea at the end of each course of PGL4001 treatment received. |
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E.5.2 | Secondary end point(s) |
Secondary endpoints:
Efficacy:
•Change from baseline (measured at baseline in PGL09-026 study) to approximately 14 days after start of menses following each of the three PGL4001 and norethisterone acetate or placebo treatment periods and at follow-up (respectively visit B, visit C, visit D and visit F), in myoma size, measured on the three largest myomas identified at visit 1 of PGL09-026, by transvaginal ultrasound.
•Change from baseline to visit B, visit C, visit D and to visit F in patient-reported pain using the short-form McGill Pain Questionnaire.
•Change from baseline to visit B, visit C, visit D and to visit F in quality of life measured using the specific UFS-QoL questionnaire.
•Change from baseline to visit B, visit C, visit D and to visit F in quality of life measured using the general EQ-5D questionnaire.
Safety:
•Changes from baseline observed during a physical examination
•Changes from baseline observed during a gynaecological and/or breast examination.
•Changes from baseline observed in vital sign measurements, ECG.
•Changes from baseline observed in endometrial thickness assessed by transvaginal ultrasound.
•Changes from baseline of the ovary observed by transvaginal ultrasound.
•Serum levels of estradiol (E2).
•Changes from baseline in serum Adrenocorticotropic hormone (ACTH), Thyroid Stimulating Hormone (TSH) and prolactin levels.
•Change from baseline in the following laboratory parameters: haematology, coagulation, biochemistry and lipids.
•Changes from baseline in endometrium biopsy (i.e. hyperplasia, adenocarcinoma).
•Number and proportion of subjects experiencing treatment-emergent adverse events including patient-reported adverse events and clinically significant changes in the parameters listed above.
Exploratory:
•Assessment of the strength of the first menstrual bleed after each PGL4001 treatment, using the Pictorial Bleeding Assessment Chart (PBAC).
•Time to return of menstruation following each PGL4001 treatment discontinuation.
•Frequency of Progesterone receptor modulator associated endometrial changes (PAEC) observed in the endometrial biopsy at visit E, approximately 14 days after last treatment cycle with PGL4001 followed by norethisterone acetate or placebo. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 22 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |