PEARLI: PGL4001 Versus Placebo in Uterine Myomas

• Sponsor: PregLem SA (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00755755
• Collaborator: (none)
• Enrollment: 241
• Locations: 38
• Arms: 3
• Duration (Months): 22
• Patients Per Site: 6.3
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This trial will assess the efficacy and safety of PGL4001 with concomitant iron administration versus placebo with concomitant iron administration, over a 3-month period for the pre-operative treatment of pre-menopausal women suffering from excessive uterine bleeding due to uterine myoma.

Condition or Disease	Intervention/Treatment	Phase
Uterine Myomas	Drug: PGL4001 (ulipristal) and iron; Drug: PGL4001 matching placebo and iron; Drug: PGL4001 (ulipristal) and iron	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 241 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase III, Randomized, Parallel Group, Double-Blind, Placebo-Controlled, Multi-Center Study to Assess the Efficacy and Safety of PGL4001 (Ulipristal) Versus Placebo for Pre-Operative Treatment of Symptomatic Uterine Myomas
• Study Start Date: Oct 1, 2008
• Actual Primary Completion Date: Mar 1, 2010
• Actual Study Completion Date: Aug 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: A (PGL4001 5mg) PGL4001 5 mg (oral tablets) with concomitant oral administration of 1 tablet containing 80 mg Fe2+	Drug: PGL4001 (ulipristal) and iron; tablets; Other Names: Ulipristal acetate
Experimental: B (PGL4001 10mg) PGL4001 10 mg (oral tablets) with concomitant oral administration of 1 tablet containing 80 mg Fe2+	Drug: PGL4001 (ulipristal) and iron; Tablets; Other Names: Ulipristal acetate
Placebo Comparator: C (placebo) PGL4001 matching placebo (oral tablets) with concomitant oral administration of 1 tablet containing 80 mg Fe2+	Drug: PGL4001 matching placebo and iron; tablets; Other Names: Placebo of ulipristal

Outcome Measures

Primary Outcome Measures

1. Co-primary Endpoint: Percentage of Subjects With Reduction in Uterine Bleeding Defined as a Pictorial Blood-loss Assessment Chart (PBAC) Score <75 at End-of-treatment Visit (Week 13) [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.

2. Co-primary Endpoint: Percent Change in Total Myoma Volume Assessed by Magnetic Resonance Imaging (MRI) From Screening to End of Treatment Visit (Week 13 Visit) [Week 13]

   Percent change in total fibroid volume from screening to end of treatment visit (Week 13 visit) assessed by MRI and read centrally by a radiologist who was unaware of the study-group assignments. The total fibroid volume was the sum of the individual fibroid volumes.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: Female
• Accepts 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 myoma-related anaemia.

• 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.

• 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 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Gynekologicko-porodnicka klinika FN Brno	Brno		Czech Republic	625 00
2	Mediva	Praha		Czech Republic	110 00
3	Gynekologicko-porodnicka klinika 1.LF UK a VFN	Praha		Czech Republic	128 00
4	Gynekologicko-porodnicka klinika UK 2.LF a FN	Praha		Czech Republic	150 06
5	Rethy-Pal Hospital-Clinic Bekescsaba, Department of Obstetrics and Gynecology	Bekescsaba		Hungary	5600
6	Saint Stephen Hospital of Budapest,Department of Obstetrics, Gynecology and Gynecological Oncology	Budapest		Hungary	1096
7	Fovarosi Bajcsy-Zsilinszky Hospital, Department of Obstetrics and Gynecology	Budapest		Hungary	1106
8	Saint George Hospital of Fejer County, Department of Obstetrics and Gynecology	Szekesfehervar		Hungary	8000
9	Dr. Bugyi Istvan Hospital, Department of Obstetrics and Gynecology	Szentes		Hungary	6600
10	Saint Borbala Hospital of Komarom-Esztergom County, Department of Obstetrics and Gynecology	Tatabanya		Hungary	2800
11	Dr. Jilla Hospital	Aurangabad		India	431001
12	M. S. Ramaiah Medical College and Memorial Hospital	Bangalore		India	560054
13	Divakars Speciality Hospital	Bangalore		India	560078
14	Sri Ramachandra Medical College and Research Institute	Chennai		India	600116
15	Om Women's Hospital	Nagpur		India	440010
16	Nagpur Test Tube Baby Centre	Nagpur		India	440022
17	Central Medical Sanador	Bucharest		Romania	011026
18	Departamentul de Obstretica Ginecologie si Nou Nascuti	Bucharest		Romania	020395
19	Sectia Obstretica-Ginecologie Spitalul Clinic Dr. Ioan Cantacuzino	Bucharest		Romania	70266
20	Centrul Medical Euromed, departementul de Obstetrica/Ginecologie	Bucuresti		Romania	020762
21	Spitalul Clinic de Obstetrica Ginecologie Oradea	Oradea		Romania	410053
22	Spitalul Clinic Judetean de urgenta, sectia de obstetrica Ginecologie I	Targu Mures		Romania	540136
23	Northern State Medical University	Arkhangelsk		Russian Federation	163001
24	Kursk State Medical University	Kursk		Russian Federation	305035
25	OAO "Medical company IDK"	Samara		Russian Federation	443067
26	American Medical Clinic	St. Petersburg		Russian Federation	190000
27	Saint-Petersburg City Alexandrovsky Hospital	St.Petersburg		Russian Federation	193312
28	Military Medical Academy n.a.S.M Kirov, chair of Obstetrics and Gynecology	St.Petersburg		Russian Federation	194044
29	Medical Research Institute (MRI)	St.Petersburg		Russian Federation	196084
30	Russian Scientific Research Center of Radiology and Surgical Technologies	St.Petersburg		Russian Federation	197758
31	Scientific Research Institute of Obstetrics and Gynecology n.a. D.O.Ott of RAMS	St.Petersburg		Russian Federation	199034
32	Donetsk National Medical University, Department of Obstetrics, Gynecology and Perinatology FPE	Donetsk		Ukraine
33	City Clinical Hospital N9	Kiev		Ukraine	04112
34	Institute of Pediatrics, Obstetrics and Gynecology, Department of Endocrine Gynecology	Kiev		Ukraine
35	Kiev Maternity Hospital No.2	Kiev		Ukraine
36	State Enterprise "Institute of Pediatrics, Obstetrics and Gynecology of AMS of Ukraine	Kyiv		Ukraine
37	Lviv National Medical University named after Danylo Halytskyy	Lviv		Ukraine	79032
38	Medical Sanitory Centre VAT "Motor Sich" Gynecology department	Zaporizhzhya		Ukraine

Sponsors and Collaborators

• PregLem SA

Investigators

• Study Director: Dr Elke Bestel, PregLem SA

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: PregLem SA
• ClinicalTrials.gov Identifier: NCT00755755
• Other Study ID Numbers: PGL07-021
• First Posted: Sep 19, 2008
• Last Update Posted: Dec 13, 2012
• Last Verified: Dec 1, 2012

• Additional relevant MeSH terms: Myoma; Leiomyoma; Myofibroma; Iron; Ulipristal acetate

Study Results

Participant Flow

Arm/Group Title	A (PGL4001 5mg)	B (PGL4001 10mg)	C (Placebo)
Arm/Group Description	PGL4001 5 mg (oral tablets) with concomitant oral administration of 1 tablet containing 80 mg Fe2+	PGL4001 10 mg (oral tablets) with concomitant oral administration of 1 tablet containing 80 mg Fe2+	PGL4001 matching placebo (oral tablets) with concomitant oral administration of 1 tablet containing 80 mg Fe2+
Period Title: Overall Study
STARTED	95	98	48
COMPLETED	89	90	45
NOT COMPLETED	6	8	3

Baseline Characteristics

Arm/Group Title	A (PGL4001 5mg)	B (PGL4001 10mg)	C (Placebo)	Total
Arm/Group Description	PGL4001 5 mg (oral tablets) with concomitant oral administration of 1 tablet containing 80 mg Fe2+	PGL4001 10 mg (oral tablets) with concomitant oral administration of 1 tablet containing 80 mg Fe2+	PGL4001 matching placebo (oral tablets) with concomitant oral administration of 1 tablet containing 80 mg Fe2+	Total of all reporting groups
Overall Participants	95	98	48	241
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	95 100%	98 100%	48 100%	241 100%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41.2 (5.9)	42.0 (5.5)	41.6 (5.6)	41.6 (5.7)
Sex: Female, Male (Count of Participants)
Female	95 100%	98 100%	48 100%	241 100%
Male	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Czech Republic	7 7.4%	6 6.1%	3 6.3%	16 6.6%
Hungary	7 7.4%	11 11.2%	9 18.8%	27 11.2%
India	10 10.5%	11 11.2%	7 14.6%	28 11.6%
Romania	17 17.9%	17 17.3%	8 16.7%	42 17.4%
Russian Federation	28 29.5%	19 19.4%	13 27.1%	60 24.9%
Ukraine	26 27.4%	34 34.7%	8 16.7%	68 28.2%

Outcome Measures

1. Primary Outcome

Title	Co-primary Endpoint: Percentage of Subjects With Reduction in Uterine Bleeding Defined as a Pictorial Blood-loss Assessment Chart (PBAC) Score <75 at End-of-treatment Visit (Week 13)
Description	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	Week 13 visit

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	A (PGL4001 5mg)	B (PGL4001 10mg)	C (Placebo)
Arm/Group Description	PGL4001 5 mg (oral tablets) with concomitant oral administration of 1 tablet containing 80 mg Fe2+	PGL4001 10 mg (oral tablets) with concomitant oral administration of 1 tablet containing 80 mg Fe2+	PGL4001 matching placebo (oral tablets) with concomitant oral administration of 1 tablet containing 80 mg Fe2+
Measure Participants	94	93	48
Number [percentage of patients]	91.5	92.5	18.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	A (PGL4001 5mg), C (Placebo)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	As comparison involved two doses of PGL4001 vs Placebo, Bonferroni correction used with p-values doubled (threshold was 0.05) and confidence intervals adjusted
	Method	Cochran-Mantel-Haenszel
	Comments	Adjustment for randomization strata
Method of Estimation	Estimation Parameter	Difference in proportions
	Estimated Value	72.7
	Confidence Interval	(2-Sided) 95%; 55.1 to 83.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Confidence intervals with the use of Newcombe-Wilson score method (uncorrected)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	B (PGL4001 10mg), C (Placebo)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	As comparison involved two doses of PGL4001 vs Placebo, Bonferroni correction used with p values doubled (threshold was 0.05) and confidence intervals adjusted
	Method	Cochran-Mantel-Haenszel
	Comments	Adjustment for randomization strata
Method of Estimation	Estimation Parameter	Difference in proportions
	Estimated Value	73.7
	Confidence Interval	(2-Sided) 95%; 56.2 to 84.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Confidence intervals with the use of Newcombe-Wilson score method (uncorrected)

2. Primary Outcome

Title	Co-primary Endpoint: Percent Change in Total Myoma Volume Assessed by Magnetic Resonance Imaging (MRI) From Screening to End of Treatment Visit (Week 13 Visit)
Description	Percent change in total fibroid volume from screening to end of treatment visit (Week 13 visit) assessed by MRI and read centrally by a radiologist who was unaware of the study-group assignments. The total fibroid volume was the sum of the individual fibroid volumes.
Time Frame	Week 13

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	A (PGL4001 5mg)	B (PGL4001 10mg)	C (Placebo)
Arm/Group Description	PGL4001 5 mg (oral tablets) with concomitant oral administration of 1 tablet containing 80 mg Fe2+	PGL4001 10 mg (oral tablets) with concomitant oral administration of 1 tablet containing 80 mg Fe2+	PGL4001 matching placebo (oral tablets) with concomitant oral administration of 1 tablet containing 80 mg Fe2+
Measure Participants	85	80	45
Median (Full Range) [percentage of change]	-21.2	-12.3	3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	A (PGL4001 5mg), C (Placebo)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	As comparison involved two doses of PGL4001 vs Placebo, Bonferroni correction used with p-values doubled (threshold was 0.05) and confidence intervals adjusted.
	Method	Wilcoxon (Mann-Whitney)
	Comments	Use of the Van Elteren extension to the Wilcoxon rank-sum test with adjustment for randomization strata
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-22.6
	Confidence Interval	(2-Sided) 95%; -36.1 to -8.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hodges-Lehmann point estimator with corresponding Moses confidence interval.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	B (PGL4001 10mg), C (Placebo)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments	As comparison involved two doses of PGL4001 vs Placebo, Bonferroni correction used with p values doubled (threshold was 0.05) and confidence intervals adjusted.
	Method	Wilcoxon (Mann-Whitney)
	Comments	Use of the Van Elteren extension to the Wilcoxon rank-sum test with adjustment for randomization strata
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-18.2
	Confidence Interval	(2-Sided) 95%; -33.0 to -5.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hodges-Lehmann point estimator with corresponding Moses confidence interval.

Adverse Events

Time Frame	3 years 2 months
Arm/Group Title	A (PGL4001 5mg)		B (PGL4001 10mg)		C (Placebo)
Arm/Group Description	PGL4001 5 mg (oral tablets) with concomitant oral administration of 1 tablet containing 80 mg Fe2+		PGL4001 10 mg (oral tablets) with concomitant oral administration of 1 tablet containing 80 mg Fe2+		PGL4001 matching placebo (oral tablets) with concomitant oral administration of 1 tablet containing 80 mg Fe2+
All Cause Mortality
	A (PGL4001 5mg)		B (PGL4001 10mg)		C (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	A (PGL4001 5mg)		B (PGL4001 10mg)		C (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/95 (2.1%)		1/98 (1%)		2/48 (4.2%)
Reproductive system and breast disorders
Ovarian hemorrhage	1/95 (1.1%)	1	0/98 (0%)	0	0/48 (0%)	0
Uterine hemorrhage	1/95 (1.1%)	1	1/98 (1%)	1	0/48 (0%)	0
New uterine leiomyoma	0/95 (0%)	0	0/98 (0%)	0	1/48 (2.1%)	1
breast cancer	0/95 (0%)	0	0/98 (0%)	0	1/48 (2.1%)	1
Other (Not Including Serious) Adverse Events
	A (PGL4001 5mg)		B (PGL4001 10mg)		C (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	47/95 (49.5%)		52/98 (53.1%)		22/48 (45.8%)
Endocrine disorders
Hypothyroidism	2/95 (2.1%)	2	4/98 (4.1%)	4	0/48 (0%)	0
Endocrine disorders	5/95 (5.3%)	8	8/98 (8.2%)	8	1/48 (2.1%)	2
Gastrointestinal disorders
Abdominal pain	2/95 (2.1%)	3	3/98 (3.1%)	5	2/48 (4.2%)	2
Constipation	4/95 (4.2%)	6	0/98 (0%)	0	1/48 (2.1%)	1
Gastrointestinal disorders	9/95 (9.5%)	16	10/98 (10.2%)	13	3/48 (6.3%)	7
General disorders
Pyrexia	3/95 (3.2%)	3	2/98 (2%)	2	2/48 (4.2%)	2
General disorders and administration site conditions	5/95 (5.3%)	5	4/98 (4.1%)	4	2/48 (4.2%)	3
Infections and infestations
Nasopharyngitis	3/95 (3.2%)	3	0/98 (0%)	0	0/48 (0%)	0
Infections and infestations	8/95 (8.4%)	8	12/98 (12.2%)	15	3/48 (6.3%)	4
Influenza	1/95 (1.1%)	1	3/98 (3.1%)	3	1/48 (2.1%)	1
Metabolism and nutrition disorders
Hypercholesterolemia	3/95 (3.2%)	4	2/98 (2%)	2	1/48 (2.1%)	1
Metabolism and nutrition disorders	7/95 (7.4%)	10	4/98 (4.1%)	4	2/48 (4.2%)	3
Nervous system disorders
Headache	4/95 (4.2%)	6	10/98 (10.2%)	19	2/48 (4.2%)	2
Nervous system disorders	4/95 (4.2%)	7	11/98 (11.2%)	22	3/48 (6.3%)	4
Diziness	1/95 (1.1%)	1	3/98 (3.1%)	3	0/48 (0%)	0
Reproductive system and breast disorders
Breat pain / tenderness / disconfort	2/95 (2.1%)	2	6/98 (6.1%)	6	0/48 (0%)	0
Dysmenorrhea	0/95 (0%)	0	0/98 (0%)	0	2/48 (4.2%)	3
Reproductive system and breast disorders	14/95 (14.7%)	18	14/98 (14.3%)	16	6/48 (12.5%)	10

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.