Efficacy Objectives:- Primary objective of this study is to demonstrate non inferior efficacy of PGL4001 versus GnRH-agonist to reduce, prior to surgery, excessive uterine bleeding caused by uterine myomas.- Secondary objectives are to demonstrate…
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Brief title
Condition
- Reproductive neoplasms female benign
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary efficacy endpoint is:
- the percentage of subjects with reduction of uterine bleeding defined as a
PBAC score < 75 at end-of-treatment visit (Week 13 visit).
Exploratory endpoints are the:
- Change from baseline to Week 26 and Week 38 follow-up visit in bleeding
pattern recorded (PBAC), if no hysterectomy and no endometrial ablation was
performed during Week 13.
- Change from baseline to Week 17, Week 26 and Week 38 visits in Hemoglobin,
Hematocrit and Ferritine.
- Amenorrhea assessed at Week 26 and Week 38 follow-up visits, if no
hysterectomy and no endometrial ablation was performed during Week 13.
- Change from screening to Week 17, Week 26 and Week 38 visits in the total
volume of the three largest myomas assessed by ultrasound, if no hysterectomy
and no myomectomy were performed during Week 13.
- Change from screening to Week 17, Week 26 and Week 38 visits in uterine
volume assessed by ultrasound, if no hysterectomy was performed during Week 13.
- Change from baseline to Week 26 and Week 38 follow-up visits, in global pain
score (Short-form Mc Gill Pain questionnaire).
- Change from baseline to Week 26 and Week 38 follow-up visits, in UFS-QoL
score.
- Proportion of subjects for whom surgery is cancelled because of improvement
of symptoms.
- Proportion of subjects switched to less invasive surgery.
- Proportion of subjects undergoing blood transfusion.
- Number of transfusions per transfused subject.
- Volume transfused per subject.
Primary safety endpoint are the:
- Mean serum E2 levels at end of treatment visit (Week 13 visit) for PGL4001
compared with GnRH-agonist.
- Percentage of subjects reporting moderate or severe hot flushes as adverse
events throughout the treatment period for PGL4001 compared with GnRH-agonist.
Pharmacokinetic Endpoints are:
- Pre-dose plasma levels of PGL4001 and PGL4002 at baseline, Week 5, Week 9 and
Week 13 visits.
Secondary outcome
Secondary efficacy endpoints are the:
- Change from baseline to Week 5, Week 9, and Week 13 visits in bleeding
pattern recorded by subjects using the Pictorial Bleeding Assessment Chart
(PBAC).
- Change from baseline to Week 5, Week 9 and Week 13 visits in Hemoglobin,
Hematocrit and Ferritine.
- Percentage of subjects in amenorrhea at Week 5, Week 9, and Week 13 visits.
- Change from screening to Week 13 visit in the total volume of the three
largest myomas assessed by ultrasound.
- Change from screening to Week 13 visit in uterine volume assessed by
ultrasound.
- Change from baseline to Week 5, Week 9, and Week 13 visits in global pain
score (Short-form Mc Gill Pain questionnaire).
- Change from baseline to Week 13 visit in Uterine Fibroid Symptom and
health-related Quality of Life (UFS-QoL) score.
Secondary safety endpoint are:
- Adverse events frequency and severity including castration-related symptoms
such as vaginitis.
- Bone turnover assessed by blood and urinary dosage of biochemical markers of
bone-resorption and bone-formation at baseline, Week 9 and Week 13 visits.
- Endometrium thickness assessed by ultrasound at screening, Week 13 and Week
17 visits, and Weeks 26 and 38 follow-up visits if no hysterectomy and no
endometrial ablation were performed during Week 13.
- Serum P4 levels, Adrenocorticotropic hormone (ACTH), Thyroid-stimulating
hormone (TSH) and Prolactin assessments at baseline, Week 5, Week 9, Week 13,
Week 17 visits.
- Serum E2 levels at baseline, Week 5, Week 9 and Week 17 visits.
- Haematology, biochemistry, lipids, and glucose assessments at screening,
baseline, Week 5, Week 9, Week 13, Week 17 visits, and Weeks 26 and 38
follow-up visits.
- Ultrasound of ovary at Week 17 visit, and Week 26 and Week 38 follow-up
visits if abnormal ovaries were detected at ultrasound at Week 13 visit and no
ovariectomy was performed.
- Uterine cavity deformation assessed by ultrasound at screening, Week 13, Week
17 visits, and Week 26 and Week 38 follow-up visits (if no hysterectomy was
performed during Week 13).
- Endometrium biopsy at screening and Week 13 visit (prior to the surgery) and
Week 38 follow-up visit (if no hysterectomy and no endometrial ablation were
performed during Week 13).
Background summary
PGL4001 has the potential to provide therapeutic effect similar to GnRH
agonists without reducing circulating oestrogen levels to castration levels,
hence very significantly increasing safety and tolerance of the treatment.
PGL4001 immediately stops uterine bleeding while GnRH agonists initial flair
effect leads to an additional episode of bleeding which sometimes can be
heavy. PGL4001 also has the advantage of being an orally active compound while
GnRH agonists have to be injected intramuscularly or subcutaneously.
Given the promising pharmacological and pharmacodynamic profile of the PGL4001
and the treatment potential demonstrated in the Phase II studies, it was
decided to test the compound as a treatment for the management of symptoms
caused by uterine myoma prior to surgery.
Study objective
Efficacy Objectives:
- Primary objective of this study is to demonstrate non inferior efficacy of
PGL4001 versus GnRH-agonist to reduce, prior to surgery, excessive uterine
bleeding caused by uterine myomas.
- Secondary objectives are to demonstrate improvement over baseline in
myoma-related symptoms such as impaired Quality of Life (QoL) and pain, and to
assess PGL4001 capacity to decrease uterine volume as well as volume of the
three largest myomas.
Exploratory objectives are:
- (i) the proportion of subjects switched to less invasive surgery or for whom
surgery is cancelled due to improved condition at treatment completion.
- (ii) the proportion of subjects undergoing blood transfusion, the number of
transfusions and volume transfused per subject.
Safety Objectives:
- Primary safety objective is to demonstrate superior safety and tolerance of
PGL4001 versus Gonadotropin Releasing Hormone agonist (GnRH-agonist) regarding
castration-related symptoms and their consequences which principal parameters
are serum oestradiol levels and hot flushes.
- Secondary safety objective is to assess overall safety of PGL4001 in subjects
with uterine myomas.
Pharmacokinetic Objectives:
To establish the possible relationship between PGL4001 and its metabolite
(PGL4002) through plasma levels and the efficacy markers such as amenorrhea,
PBAC (Pictorial Bleeding Assessment Chart) score and uterine myoma volume.
Study design
This is a prospective, randomised, parallel group, double-blind, double-dummy,
active comparator-controlled Phase III study to assess the efficacy and safety
of PGL4001 for the pre-operative treatment of symptomatic uterine myomas.
Intervention
Subjects will be randomized to one of three treatment groups in a 1:1:1 ratio
to receive:
• either PGL4001 5mg + saline solution
• either PGL4001 10mg + saline solution
• either PGL4001 matching placebo + leuprorelin 3.75mg
Study burden and risks
Patients will return to the hospital for 14 times, 38 weeks in total.
During these visits a blood sample wille be taken, vital signs will be checked,
ECGs will be done, gynaecological exam will be performed, breast exams will be
done, PAP test will be done including an endometrium biopsy and a ultrasound
will be done from the lower abdomen.
The side-effects of PGL4001 were evaluated in healthy women and in patients
suffering from myomas of the womb.
The side-effects which some patients experienced in the preceding clinical
trials with PGL4001 were:
• Fatigue
• Headache
• Nausea
• Vertigo
• Pain in the womb
• Mild acne
In some patients it was reported that a cyst in the ovary disappeared
spontaneously.
The other treatment (leuprorelin) that is used to compare the effect of PGL4001
in this trial with is one of the medicines that is currently used for the
treatment of myomas in the womb.
It has been showed that leuprorelin can reduce bleeding related to myomas in
the womb, correct anaemia, reduce symptoms in the lower abdomen and reduce both
the size of the myomas and the womb. It also suppresses the production of
oestrogen which can lead to symptoms that are found at the menopause such as:
• hot flushes,
• depression,
• mood swings,
• loss of libido (less interest in sex),
• tension,
• vaginitis.
These side-effects disappear rapidly after stopping the treatment.
In addition leuprorelin can reduce the mass of the buttocks. The loss of
buttock mass kan mostly be reversed although it may take time.
12 chemin des Aulx
1228 Plan-Les-Quates, Geneva
CH
12 chemin des Aulx
1228 Plan-Les-Quates, Geneva
CH
Listed location countries
Age
Inclusion criteria
Written informed consent prior to any study related procedures.
Pre-menopausal woman between 18 and 50 years inclusive.
PBAC score >100 during day 1 to day 8 of menstruation preceding the baseline visit.
Myomatous uterus <= 16 weeks.
At least one uterine myoma of >= 3 cm diameter in size and no myoma larger than 10 cm diameter in size diagnosed by ultrasound.
Must be eligible for one of these surgical procedures: i.e. hysterectomy, myomectomy, uterine artery embolization or endometrial ablation within 13 weeks and up to 14 weeks from baseline study visit.
Clinical breast examination without significant findings at the screening visit.
No clinically significant findings at PAP smear, performed within the past 12 months or at the screening visit.
If of childbearing potential, the subject must be practicing a non-hormonal method of contraception
Non childbearing potential, tubal ligation sterilisation at least two months before study start.
BMI >= 18 and <= 40.
Exclusion criteria
Uterus surgery (except caesarean section or cervical conisation), endometrium ablation or uterine artery embolization.
History of or current uterine, cervical, ovarian or breast cancer.
Has a history of atypical hyperplasia or current endometrium hyperplasia (atypical or non-atypical) or adenocarcinoma or similar lesions in the screening biopsy or in a biopsy performed within the past 6 months.
Condition requiring immediate blood transfusion or a level of Hb <= 6 g/dL.
Known hemoglobinopathy (i.e. Sickel Cell anaemia and Thalassämia).
Known severe coagulation disorder.
Large uterine polyp (> 2cm).
One or more ovarian cysts >= 4cm in diameter diagnosed by US.
History of or current treatment for myoma with a SPRM or a GnRH-agonist.
Taking treatments with progestins (systemic or progestin releasing intra-uterine system) or an oral contraceptive: within the month before the screening visit. Or Acetylsalicylic acid and/or mefenamic acid, anticoagulants such as cumarins and /or antifibrinolytic drugs such as tranexamic: within one week before the screening visit, or Systemic glucocorticoid treatments and/or systemic depot glucocorticoid treatments within one week or two months before the screening visit, respectively.
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), oral contraceptives, systemic glucocorticoids (oral and injectable), acetylsalicylic acid, mefenamic acid, anticoagulants such as cumarins and/or antifibrynolytic drugs such as tranexamic acid
History of or known current osteoporosis.
Abnormal hepatic function at study entry (defined as AST, ALT, γGT, alkaline phosphatase or total bilirubin above 2 ULN).
Positive pregnancy test at baseline or is nursing or planning a pregnancy during the course of the study.
Current (within twelve months) problem with alcohol or drug abuse.
Mental condition rendering the subject unable to understand the nature, scope and possible consequences of the study, and/or evidence of an uncooperative attitude.
The subject has abnormal baseline findings, any other medical condition(s) or psychiatric condition(s) or laboratory findings that, in the opinion of the investigator, might jeopardise the subject*s safety or interfere with study evaluations. This does include the use of agents known to induce or inhibit the hepatic cytochrome CYP3A4.
Allergy to GnRH agonist, SPRMs or progestins or any of the ingredients of the study drug tablet (see list of ingredients in the investigator*s brochure),
Currently enrolled in an investigational drug or device study or has participated in such a study within the last 30 days.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
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Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2008-001805-40-NL |
| CCMO | NL24788.041.08 |