| 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 |
Efficacy:
•To investigate the efficacy of PGL4001 on uterine bleeding from baseline to end of PGL4001 treatment (visit 5) when given orally once a day at doses of 10 mg for 3 months.
•To investigate the efficacy of a 3 months course of the 10mg dose of PGL4001 on myoma size from baseline to end of PGL4001 treatment and to approximately 2 weeks after end of double-blind norethisterone acetate/placebo treatment (visit 6).
•To investigate the efficacy of the 10mg dose of PGL4001 on pain (from baseline to end of PGL4001 treatment).
•To investigate the efficacy of the 10mg dose of PGL4001 on quality of life (from baseline to end of PGL4001 treatment).
Safety:
•To assess the overall safety of PGL4001 administration
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| E.2.2 | Secondary objectives of the trial |
Exploratory:
•To assess uterine bleeding characteristics upon return of menses following treatment with PGL4001 followed by norethisterone acetate or placebo.
•To assess the histology of the endometrium, including PAEC, at visit 6 and approximately three months later during the follow-up visit (visit 7b). The latter does not apply to subjects who elect to have a hysterectomy or to take part in the extension of this study.
•To investigate time to return of menstruation after PGL4001 treatment discontinuation.
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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 study related procedures.
2.Subject is a pre-menopausal woman aged between 18 and 48 years inclusive.
3.Subject with a Body Mass Index ≥18 and ≤40.
4.Subject with hormonal levels FSH ≤ 20 mIU/mL at screening.
5.Subject with regular menstrual cycles ≥22 and ≤35 days.
6.Subject with myomatous uterus size < 16 weeks.
7.Subject must have at least one uterine myoma of at least 3 cm diameter in size and no myoma larger than 10 cm diameter diagnosed by ultrasound.
8.Subject complained of strong uterine bleeding (subjective assessment).
9.Subject is eligible for hysterectomy or myomectomy.
10.Subject has no significant findings at clinical breast examination at the screening visit.
11.Females of childbearing potential have to practice a non-hormonal method of contraception until completion of visit 7 among one of the following:
-Sexual abstinence
-Diaphragms
-Condom or partner with a vasectomy with confirmed azoospermia or performed at least 6 months prior to the study.
12.Females of non childbearing potential, defined as women with tubal ligation sterilisation at least two months before the screening visit (visit 1)
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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 history of uterus surgery that would interfere with the study, including endometrial ablation or uterine artery embolization.
2.Subject has a history of or current uterus, cervix, ovarian or breast cancer.
3.Subject has a significant finding on Papanikolaou test (PAP) smear within the past 12 months.
4.Subject has a history of endometrium hyperplasia or adenocarcinoma in a biopsy performed within the past 6 months or similar lesions in the screening biopsy.
5.Subject has a large uterine polyp (> 2cm).
6.Subject has calcified myomas and/or calcified uterus.
7.Subject has a known severe coagulation disorder.
8.Subject has one or more ovarian cysts ≥ 4cm diagnosed by ultrasound.
9.Subject has a history of treatment for myoma with a SPRM, including ulipristal acetate.
10.Subject has been taking:
-Treatments with progestins (systemic or progestin releasing intra-uterine system) or an oral contraceptive: within one month before the screening visit.
-Acetylsalicylic acid, mefenamic acid, anticoagulants such as cumarins and/or antifibrinolytic drugs such as tranexamic acid: within one week before the screening visit,
-Treatments with an PRM or progesterone antagonist within one month before the screening visit
-Systemic glucocorticoid treatments and/or systemic depot glucocorticoid treatments within one or three months before the screening visit, respectively.
-GnRH agonist within 3 months before the screening visit.
-Treatments which contain PgP substrate (digoxin, fexofenadine), two weeks prior to visit 2.
-Treatments which contain moderate or potent inhibitors or inducers of CYP3A4, two weeks prior to visit 2.
11.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), GnRH-Agonists, acetylsalicylic acid, mefenamic acid, anticoagulants such as cumarins and/or antifibrinolytic drugs such as tranexamic acid, treatments which contain PgP substrate (digoxin, fexofenadine), treatments which contain moderate or potent inhibitors or inducers of CYP3A4.
12.Subject has abnormal hepatic function at study entry (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). In case of an isolated increase of GGT, the subject may be enrolled if the re-test is within the allowed limits.
13.Subject has lactose or galactose intolerance (i.e. lapp lactase deficiency or glucose-galactose malabsorption).
14.Subject is at high risk of thromboembolic disease. This precaution is necessary because subjects may be randomised to norethisterone acetate.
15.Subject has a positive pregnancy test at baseline, is nursing or planning a pregnancy during the course of the study.
16.Subject has a current (within twelve months prior to screening visit) problem with alcohol or drug abuse.
17.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.
18.Subject has abnormal baseline findings, any other medical condition(s) or laboratory findings that, in the opinion of the investigator, might jeopardise the subject’s safety or interfere with study evaluations.
19.The subject has an allergy to SPRMs or progestins or any of the ingredients of the study drug tablet (see list of ingredients in the PGL4001 investigator’s brochure and Norethisterone acetate Patient Information Leaflet).
20.The subject is currently enrolled in an investigational drug or device study or participated in such a study within the previous 30 days and is still in exclusion period.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy
•Percentage of subjects in amenorrhea at end of PGL4001 treatment.
•Change from baseline to end of PGL4001 treatment and to visit 6 (approximately 2 weeks after menstruation following end of norethisterone acetate/placebo treatment) in myoma size, measured on the three largest myomas identified at visit 1, by transvaginal ultrasound.
•Change from baseline to end of PGL4001 treatment in patient-reported pain using the short-form McGill Pain Questionnaire.
•Change from baseline to end of PGL4001 treatment in QoL measured using the specific UFS-QoL questionnaire
•Change from baseline to end of PGL4001 treatment in QoL measured using the general EQ-5D questionnaire.
Safety
•Number and proportion of subjects experiencing treatment-emergent adverse events:
-Clinically significant changes observed during the physical examination
-Clinically significant changes observed during gynaecological and breast examination.
-Clinically significant changes in vital sign measurements, ECG.
-Changes from baseline to end of PGL4001 treatment, and to end of double-blind, progestin placebo-controlled treatment in endometrial thickness assessed by transvaginal ultrasound.
-Clinically significant changes observed on the transvaginal ultrasound of ovary from baseline to visit 6.
-Serum levels of E2.
-Change from baseline in serum ACTH, TSH and prolactin.
-Change from baseline in the following laboratory parameters: haematology, coagulation, biochemistry and lipids.
-Clinically significant changes in endometrium biopsy (i.e. hyperplasia, adenocarcinoma).
Exploratory
•Assessment of the strength of the first menstrual bleed after PGL4001 treatment, using the Pictorial Bleeding Assessment Chart (PBAC) (See protocol appendix C).
•Time to return of menstruation following PGL4001 treatment discontinuation.
•Frequency of PAEC observed in the endometrial biopsy after return of menstruation after treatment with PGL4001 followed by double-blind treatment with 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.8.2.4 | Number of treatment arms in the trial | 2 |
| 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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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| Final clinical database lock |
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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 | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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