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Clinical Trial Results:
A Phase 3, multicentre, randomized, double-blind, placebo controlled study investigating the efficacy and safety of daily oral administration of OBE2109 alone and in combination with add-back therapy for the management of heavy menstrual bleeding associated with uterine fibroids in premenopausal women.

Summary
EudraCT number	2016-004059-53
Trial protocol	HU LV CZ BG PL LT
Global end of trial date	09 Nov 2020

Results information
Results version number	v1(current)
This version publication date	29 Mar 2022
First version publication date	29 Mar 2022
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

16-OBE2109-009

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

ObsEva SA

Sponsor organisation address

12, Chemin des Aulx, Geneva, Switzerland,

Public contact

Clinical Trial Information, ObsEva SA, +41 225523840, clinicaltrials@obseva.ch

Scientific contact

Clinical Trial Information, ObsEva SA, +41 225523840, clinicaltrials@obseva.ch

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

16 Mar 2021

Is this the analysis of the primary completion data?

Yes

Primary completion date

09 Nov 2020

Global end of trial reached?

Yes

Global end of trial date

09 Nov 2020

Was the trial ended prematurely?

Main objective of the trial

This was a prospective, randomized, parallel-group, double-blind, placebo-controlled phase 3 study investigating the efficacy and safety of linzagolix alone and in combination with add-back therapy for the management of heavy menstrual bleeding associated with uterine fibroids in premenopausal women. Note that add-back therapy (ABT) consists of estradiol 1 mg/norethisterone acetate 0.5 mg. The trial consists of 3 periods (24, 52 and 76 weeks) with 5 treatment groups per period. Efficacy objective: To demonstrate the superior efficacy versus placebo of linzagolix alone and in combination with add-back therapy for the reduction of heavy menstrual bleeding associated with uterine fibroids in premenopausal women. Safety objectives: - To assess the effect of linzagolix alone and in combination with add-back therapy versus placebo on bone mineral density. - To assess the overall safety of linzagolix alone and in combination with add-back therapy in subjects with uterine fibroids.

Protection of trial subjects

The study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki and with Good Clinical Practice (GCP) rules and in line with local regulatory requirements.

Background therapy

Evidence for comparator

Actual start date of recruitment

20 Jun 2017

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

6 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 156

Country: Number of subjects enrolled

Bulgaria: 17

Country: Number of subjects enrolled

Czechia: 23

Country: Number of subjects enrolled

Hungary: 17

Country: Number of subjects enrolled

Latvia: 17

Country: Number of subjects enrolled

Lithuania: 5

Country: Number of subjects enrolled

United States: 50

Country: Number of subjects enrolled

Romania: 37

Country: Number of subjects enrolled

Ukraine: 213

Worldwide total number of subjects

535

EEA total number of subjects

272

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

535

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study was conducted at 95 clinical sites throughout the world, including centers in Bulgaria, Czech Republic, Hungary, Latvia, Lithuania, Poland, Romania, Ukraine, and the United States of America.

Screening details

Number of subjects: - 1363 screened - 535 randomized; 21 discontinued between randomization and Day 1, main reason was subject’s request; a further 3 subjects discontinued the study after Day 1 without receiving any study drug - 501 included in Full Analysis Set (FAS) - 511 received at least one dose of study drug (Safety Analysis Set)

Period 1 title

Treatment period up to Week 24

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor

Blinding implementation details

Placebos were used for both the test drug (linzagolix) and the add-back therapy (ABT; E2/NETA). Commercially available E2/NETA tablets were overencapsulated to maintain study blinding. Placebo was also used to maintain the blind for linzagolix dose levels. Packaging and labeling did not identify whether a package contained active medication or placebo. The randomization list was secured in a computer file with access restricted to designated personnel only.

Are arms mutually exclusive

Yes

Placebo

Arm description

placebo linzagolix + placebo ABT (up to 24 weeks)

Arm type

Placebo

Investigational medicinal product name

placebo linzagolix

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

The subject was to take 2 tablets of linzagolix/placebo and 1 capsule of ABT/placebo orally, ideally in the morning of each day.

Investigational medicinal product name

placebo ABT

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

The subject was to take 2 tablets of linzagolix/placebo and 1 capsule of ABT/placebo orally, ideally in the morning of each day.

Linzagolix 100 mg

Arm description

linzagolix 100 mg + placebo ABT (up to 24 weeks)

Arm type

Experimental

Investigational medicinal product name

linzagolix

Investigational medicinal product code

OBE2109

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

The subject was to take 2 tablets of linzagolix/placebo and 1 capsule of ABT/placebo orally, ideally in the morning of each day.

Investigational medicinal product name

placebo ABT

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

The subject was to take 2 tablets of linzagolix/placebo and 1 capsule of ABT/placebo orally, ideally in the morning of each day.

Investigational medicinal product name

placebo linzagolix

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

The subject was to take 2 tablets of linzagolix/placebo and 1 capsule of ABT/placebo orally, ideally in the morning of each day.

Linzagolix 100 mg + ABT

Arm description

linzagolix 100 mg + E2/NETA (up to 24 weeks)

Arm type

Experimental

Investigational medicinal product name

linzagolix

Investigational medicinal product code

OBE2109

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

The subject was to take 2 tablets of linzagolix/placebo and 1 capsule of ABT/placebo orally, ideally in the morning of each day.

Investigational medicinal product name

E2/NETA

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

The subject was to take 2 tablets of linzagolix/placebo and 1 capsule of ABT/placebo orally, ideally in the morning of each day.

Investigational medicinal product name

placebo linzagolix

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

The subject was to take 2 tablets of linzagolix/placebo and 1 capsule of ABT/placebo orally, ideally in the morning of each day.

Linzagolix 200 mg

Arm description

linzagolix 200 mg + placebo ABT (up to 24 weeks)

Arm type

Experimental

Investigational medicinal product name

linzagolix

Investigational medicinal product code

OBE2109

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

The subject was to take 2 tablets of linzagolix/placebo and 1 capsule of ABT/placebo orally, ideally in the morning of each day.

Investigational medicinal product name

placebo ABT

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

The subject was to take 2 tablets of linzagolix/placebo and 1 capsule of ABT/placebo orally, ideally in the morning of each day.

Linzagolix 200 mg + ABT

Arm description

linzagolix 200 mg + E2/NETA (up to 24 weeks)

Arm type

Experimental

Investigational medicinal product name

linzagolix

Investigational medicinal product code

OBE2109

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

The subject was to take 2 tablets of linzagolix/placebo and 1 capsule of ABT/placebo orally, ideally in the morning of each day.

Investigational medicinal product name

E2/NETA

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

The subject was to take 2 tablets of linzagolix/placebo and 1 capsule of ABT/placebo orally, ideally in the morning of each day.

Number of subjects in period 1 ^[1]	Placebo	Linzagolix 100 mg	Linzagolix 100 mg + ABT	Linzagolix 200 mg	Linzagolix 200 mg + ABT
Started	102	97	101	103	98
Completed	90	80	81	88	85
Not completed	12	17	20	15	13
Adverse event, non-fatal	3	6	4	8	2
Other	-	2	3	1	1
Lost to follow-up	1	1	-	-	2
Subject's request	5	7	9	6	7
Lack of efficacy	3	1	3	-	1
Protocol deviation	-	-	1	-	-

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: The number of subjects reported to be in the baseline period are as per the Full Analysis Set (FAS). A total of 535 subjects were randomized, 501 subjects were included in the FAS. 34 randomized subjects were excluded: 21 subjects discontinued the study between randomization and Day 1 (i.e., before receiving study drug); the main reason was subject's request; 3 subjects discontinued the study after Day 1 without receiving any study drug; 10 subjects met exclusion criteria.

Period 2 title

Treatment period up to Week 52

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor

Blinding implementation details

Are arms mutually exclusive

Yes

Placebo / linzagolix 200 mg + ABT

Arm description

linzagolix 200 mg + E2/NETA (from 24 weeks up to 52 weeks)

Arm type

Experimental

Investigational medicinal product name

linzagolix

Investigational medicinal product code

OBE2109

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

The subject was to take 2 tablets of linzagolix/placebo and 1 capsule of ABT/placebo orally, ideally in the morning of each day.

Investigational medicinal product name

E2/NETA

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

The subject was to take 2 tablets of linzagolix/placebo and 1 capsule of ABT/placebo orally, ideally in the morning of each day.

Linzagolix 100 mg

Arm description

linzagolix 100 mg + placebo ABT (from 24 weeks up to 52 weeks)

Arm type

Experimental

Investigational medicinal product name

linzagolix

Investigational medicinal product code

OBE2109

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

The subject was to take 2 tablets of linzagolix/placebo and 1 capsule of ABT/placebo orally, ideally in the morning of each day.

Investigational medicinal product name

placebo linzagolix

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

The subject was to take 2 tablets of linzagolix/placebo and 1 capsule of ABT/placebo orally, ideally in the morning of each day.

Investigational medicinal product name

placebo ABT

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

The subject was to take 2 tablets of linzagolix/placebo and 1 capsule of ABT/placebo orally, ideally in the morning of each day.

Linzagolix 100 mg + ABT

Arm description

linzagolix 100 mg + E2/NETA (from 24 weeks up to 52 weeks)

Arm type

Experimental

Investigational medicinal product name

linzagolix

Investigational medicinal product code

OBE2109

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

The subject was to take 2 tablets of linzagolix/placebo and 1 capsule of ABT/placebo orally, ideally in the morning of each day.

Investigational medicinal product name

placebo linzagolix

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

The subject was to take 2 tablets of linzagolix/placebo and 1 capsule of ABT/placebo orally, ideally in the morning of each day.

Investigational medicinal product name

E2/NETA

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

The subject was to take 2 tablets of linzagolix/placebo and 1 capsule of ABT/placebo orally, ideally in the morning of each day.

Linzagolix 200 mg / linzagolix 200 mg + ABT

Arm description

linzagolix 200 mg + E2/NETA (from 24 weeks up to 52 weeks)

Arm type

Experimental

Investigational medicinal product name

linzagolix

Investigational medicinal product code

OBE2109

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

The subject was to take 2 tablets of linzagolix/placebo and 1 capsule of ABT/placebo orally, ideally in the morning of each day.

Investigational medicinal product name

E2/NETA

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

The subject was to take 2 tablets of linzagolix/placebo and 1 capsule of ABT/placebo orally, ideally in the morning of each day.

Linzagolix 200 mg + ABT

Arm description

linzagolix 200 mg + E2/NETA (from 24 weeks up to 52 weeks)

Arm type

Experimental

Investigational medicinal product name

linzagolix

Investigational medicinal product code

OBE2109

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

The subject was to take 2 tablets of linzagolix/placebo and 1 capsule of ABT/placebo orally, ideally in the morning of each day.

Investigational medicinal product name

E2/NETA

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

The subject was to take 2 tablets of linzagolix/placebo and 1 capsule of ABT/placebo orally, ideally in the morning of each day.

Number of subjects in period 2 ^[2]	Placebo / linzagolix 200 mg + ABT	Linzagolix 100 mg	Linzagolix 100 mg + ABT	Linzagolix 200 mg / linzagolix 200 mg + ABT	Linzagolix 200 mg + ABT
Started	89	79	80	88	83
Completed	75	60	68	62	72
Not completed	14	19	12	26	11
No Week 52 visit	-	-	-	1	-
Adverse event, non-fatal	4	3	-	4	-
Other	1	6	3	11	6
Pregnancy	-	1	-	-	-
Lost to follow-up	-	-	1	1	-
Subject's request	8	6	5	8	5
Missing	-	1	-	-	-
Lack of efficacy	1	2	3	-	-
Protocol deviation	-	-	-	1	-

Notes
[2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Overall 424 subjects completed the study up to Week 24 (Period 1). A total of 421 subjects received study drug after Week 24 and were included in the Week 52 Safety Analysis Set. Two of these subjects were excluded from the Week 52 FAS due to exclusion criteria 19 or 20 (these subjects entered the study before discontinuation was mandatory in such cases); thus, the Week 52 FAS included 419 subjects.

Period 3 title

Follow-up period

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor

Blinding implementation details

Treatment allocation, individual P4 and E2 levels, AH results (as of Study Day 1) and the Week 24 and Week 52 study results remained blinded up to the final Week 76 database lock for the Investigator and the subject.

Are arms mutually exclusive

Yes

Placebo / linzagolix 200 mg + ABT

Arm description

Subjects who completed 52 weeks of treatment were to be followed for 24 weeks after the end of treatment (up to week 76).

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Linzagolix 100 mg

Arm description

Subjects who completed 52 weeks of treatment were to be followed for 24 weeks after the end of treatment (up to week 76).

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Linzagolix 100 mg + ABT

Arm description

Subjects who completed 52 weeks of treatment were to be followed for 24 weeks after the end of treatment (up to week 76).

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Linzagolix 200 mg / linzagolix 200 mg + ABT

Arm description

Subjects who completed 52 weeks of treatment were to be followed for 24 weeks after the end of treatment (up to week 76).

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Linzagolix 200 mg + ABT

Arm description

Subjects who completed 52 weeks of treatment were to be followed for 24 weeks after the end of treatment (up to week 76).

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 3	Placebo / linzagolix 200 mg + ABT	Linzagolix 100 mg	Linzagolix 100 mg + ABT	Linzagolix 200 mg / linzagolix 200 mg + ABT	Linzagolix 200 mg + ABT
Started	75	60	67	63	72
Completed	68	52	57	59	66
Not completed	7	8	10	4	6
Adverse event, non-fatal	1	-	-	1	1
Other	1	-	3	-	-
Lost to follow-up	3	-	3	-	2
Subject's request	2	8	4	3	2
Lack of efficacy	-	-	-	-	1

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

placebo linzagolix + placebo ABT (up to 24 weeks)

Reporting group title

Linzagolix 100 mg

Reporting group description

linzagolix 100 mg + placebo ABT (up to 24 weeks)

Reporting group title

Linzagolix 100 mg + ABT

Reporting group description

linzagolix 100 mg + E2/NETA (up to 24 weeks)

Reporting group title

Linzagolix 200 mg

Reporting group description

linzagolix 200 mg + placebo ABT (up to 24 weeks)

Reporting group title

Linzagolix 200 mg + ABT

Reporting group description

linzagolix 200 mg + E2/NETA (up to 24 weeks)

Reporting group values	Placebo	Linzagolix 100 mg	Linzagolix 100 mg + ABT	Linzagolix 200 mg	Linzagolix 200 mg + ABT	Total
Number of subjects	102	97	101	103	98	501
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0
Adults (18-64 years)	102	97	101	103	98	501
From 65-84 years	0	0	0	0	0	0
85 years and over	0	0	0	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	42.9 ± 5.3	43.4 ± 5.4	42.5 ± 5.1	42.7 ± 5.8	43.1 ± 4.8	-
Gender categorical
Units: Subjects
Female	102	97	101	103	98	501
Male	0	0	0	0	0	0
Body Mass Index (BMI)
Units: kg/m2
arithmetic mean (standard deviation)	26.83 ± 5.42	27.44 ± 5.67	27.22 ± 5.82	26.82 ± 5.55	26.80 ± 5.47	-
Baseline menstrual blood loss (MBL)
Units: mL
arithmetic mean (standard deviation)	216.83 ± 129.14	244.52 ± 162.82	192.82 ± 92.79	216.81 ± 136.97	212.67 ± 142.76	-

End points

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Reporting group title

Placebo

Reporting group description

placebo linzagolix + placebo ABT (up to 24 weeks)

Reporting group title

Linzagolix 100 mg

Reporting group description

linzagolix 100 mg + placebo ABT (up to 24 weeks)

Reporting group title

Linzagolix 100 mg + ABT

Reporting group description

linzagolix 100 mg + E2/NETA (up to 24 weeks)

Reporting group title

Linzagolix 200 mg

Reporting group description

linzagolix 200 mg + placebo ABT (up to 24 weeks)

Reporting group title

Linzagolix 200 mg + ABT

Reporting group description

linzagolix 200 mg + E2/NETA (up to 24 weeks)

Reporting group title

Placebo / linzagolix 200 mg + ABT

Reporting group description

linzagolix 200 mg + E2/NETA (from 24 weeks up to 52 weeks)

Reporting group title

Linzagolix 100 mg

Reporting group description

linzagolix 100 mg + placebo ABT (from 24 weeks up to 52 weeks)

Reporting group title

Linzagolix 100 mg + ABT

Reporting group description

linzagolix 100 mg + E2/NETA (from 24 weeks up to 52 weeks)

Reporting group title

Linzagolix 200 mg / linzagolix 200 mg + ABT

Reporting group description

linzagolix 200 mg + E2/NETA (from 24 weeks up to 52 weeks)

Reporting group title

Linzagolix 200 mg + ABT

Reporting group description

linzagolix 200 mg + E2/NETA (from 24 weeks up to 52 weeks)

Reporting group title

Placebo / linzagolix 200 mg + ABT

Reporting group description

Subjects who completed 52 weeks of treatment were to be followed for 24 weeks after the end of treatment (up to week 76).

Reporting group title

Linzagolix 100 mg

Reporting group description

Subjects who completed 52 weeks of treatment were to be followed for 24 weeks after the end of treatment (up to week 76).

Reporting group title

Linzagolix 100 mg + ABT

Reporting group description

Subjects who completed 52 weeks of treatment were to be followed for 24 weeks after the end of treatment (up to week 76).

Reporting group title

Linzagolix 200 mg / linzagolix 200 mg + ABT

Reporting group description

Subjects who completed 52 weeks of treatment were to be followed for 24 weeks after the end of treatment (up to week 76).

Reporting group title

Linzagolix 200 mg + ABT

Reporting group description

Subjects who completed 52 weeks of treatment were to be followed for 24 weeks after the end of treatment (up to week 76).

Primary: Reduced menstrual blood loss at Week 24

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End point title

Reduced menstrual blood loss at Week 24

End point description

Reduced menstrual blood loss (MBL) is defined as MBL ≤ 80 mL and ≥ 50% reduction from baseline.

End point type

Primary

End point timeframe

Week 24

End point values	Placebo	Linzagolix 100 mg	Linzagolix 100 mg + ABT	Linzagolix 200 mg	Linzagolix 200 mg + ABT
Number of subjects analysed	102	97	101	103	98
Units: Proportion
number (confidence interval 95%)	29.4 (20.8 to 39.3)	56.7 (46.3 to 66.7)	77.2 (67.8 to 85.0)	77.7 (68.4 to 85.3)	93.9 (87.1 to 97.7)

Number of responders at Week 24

Statistical analysis description

Cochran-Mantel-Haenszel test with race as stratification factor.

Comparison groups

Placebo v Linzagolix 100 mg

Number of subjects included in analysis

199

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[1]

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

3.14

Confidence interval

level

95%

sides

2-sided

lower limit

1.74

upper limit

5.64

Notes
[1] - Each active treatment group is compared versus placebo at the 0.0125 level of significance.

Number of responders at Week 24

Statistical analysis description

Cochran-Mantel-Haenszel test with race as stratification factor.

Comparison groups

Placebo v Linzagolix 100 mg + ABT

Number of subjects included in analysis

203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[2]

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

9.72

Confidence interval

level

95%

sides

2-sided

lower limit

4.97

upper limit

18.99

Notes
[2] - Each active treatment group is compared versus placebo at the 0.0125 level of significance.

Number of responders at Week 24

Statistical analysis description

Cochran-Mantel-Haenszel test with race as stratification factor.

Comparison groups

Placebo v Linzagolix 200 mg

Number of subjects included in analysis

205

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[3]

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

7.95

Confidence interval

level

95%

sides

2-sided

lower limit

4.29

upper limit

14.75

Notes
[3] - Each active treatment group is compared versus placebo at the 0.0125 level of significance.

Number of responders at Week 24

Statistical analysis description

Cochran-Mantel-Haenszel test with race as stratification factor.

Comparison groups

Placebo v Linzagolix 200 mg + ABT

Number of subjects included in analysis

200

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[4]

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

35.11

Confidence interval

level

95%

sides

2-sided

lower limit

14.06

upper limit

87.68

Notes
[4] - Each active treatment group is compared versus placebo at the 0.0125 level of significance.

Secondary: Time to reduced menstrual blood loss up to Week 24

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End point title

Time to reduced menstrual blood loss up to Week 24

End point description

End point type

Secondary

End point timeframe

From Baseline up to Week 24

End point values	Placebo	Linzagolix 100 mg	Linzagolix 100 mg + ABT	Linzagolix 200 mg	Linzagolix 200 mg + ABT
Number of subjects analysed	30 ^[5]	97	101	103	98
Units: days
median (confidence interval 95%)	0 (0 to 0)	138.0 (112.0 to 148.0)	3.0 (2.0 to 14.0)	3.0 (1.0 to 7.0)	1.0 (1.0 to 3.0)

Notes
[5] - not estimable

Time to reduced MBL up to Week 24

Comparison groups

Linzagolix 100 mg v Placebo

Number of subjects included in analysis

127

Analysis specification

Pre-specified

Analysis type

superiority ^[6]

P-value

< 0.001 ^[7]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

2.42

Confidence interval

level

95%

sides

2-sided

lower limit

1.55

upper limit

3.77

Notes
[6] - Kaplan-Meier analysis: Estimated hazard ratios and 95% CIs obtained from stratified Cox model with treatment group as main effect and race as stratification factor.
[7] - P-value obtained from a 2-sided stratified log-rank test for each linzagolix group versus placebo comparison using race as stratification factor. Each active treatment group is compared versus placebo at the 0.0125 level of significance.

Time to reduced MBL up to Week 24

Comparison groups

Placebo v Linzagolix 100 mg + ABT

Number of subjects included in analysis

131

Analysis specification

Pre-specified

Analysis type

superiority ^[8]

P-value

< 0.001 ^[9]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

5.64

Confidence interval

level

95%

sides

2-sided

lower limit

3.68

upper limit

8.66

Notes
[8] - Kaplan-Meier analysis: Estimated hazard ratios and 95% CIs obtained from stratified Cox model with treatment group as main effect and race as stratification factor.
[9] - P-value obtained from a 2-sided stratified log-rank test for each linzagolix group versus placebo comparison using race as stratification factor. Each active treatment group is compared versus placebo at the 0.0125 level of significance.

Time to reduced MBL up to Week 24

Comparison groups

Placebo v Linzagolix 200 mg

Number of subjects included in analysis

133

Analysis specification

Pre-specified

Analysis type

superiority ^[10]

P-value

< 0.001 ^[11]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

5.47

Confidence interval

level

95%

sides

2-sided

lower limit

3.58

upper limit

8.37

Notes
[10] - Kaplan-Meier analysis: Estimated hazard ratios and 95% CIs obtained from stratified Cox model with treatment group as main effect and race as stratification factor.
[11] - P-value obtained from a 2-sided stratified log-rank test for each linzagolix group versus placebo comparison using race as stratification factor. Each active treatment group is compared versus placebo at the 0.0125 level of significance.

Time to reduced MBL up to Week 24

Comparison groups

Placebo v Linzagolix 200 mg + ABT

Number of subjects included in analysis

128

Analysis specification

Pre-specified

Analysis type

superiority ^[12]

P-value

< 0.001 ^[13]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

8.65

Confidence interval

level

95%

sides

2-sided

lower limit

5.65

upper limit

13.25

Notes
[12] - Kaplan-Meier analysis: Estimated hazard ratios and 95% CIs obtained from stratified Cox model with treatment group as main effect and race as stratification factor.
[13] - P-value obtained from a 2-sided stratified log-rank test for each linzagolix group versus placebo comparison using race as stratification factor. Each active treatment group is compared versus placebo at the 0.0125 level of significance.

Secondary: Amenorrhea at Week 24

Top of page

End point title

Amenorrhea at Week 24

End point description

Amenorrhea is defined as having no data from the alkaline hematin method from the central laboratory or volume below the lower limit of quantification over at least a 35-day interval and without showing bleeding after this interval.

End point type

Secondary

End point timeframe

Week 24

End point values	Placebo	Linzagolix 100 mg	Linzagolix 100 mg + ABT	Linzagolix 200 mg	Linzagolix 200 mg + ABT
Number of subjects analysed	102	97	101	103	98
Units: proportion
number (confidence interval 95%)	11.8 (6.2 to 19.6)	34.0 (24.7 to 44.3)	63.4 (53.2 to 72.7)	70.9 (61.1 to 79.4)	80.6 (71.4 to 87.9)

Amenorrhea at Week 24

Statistical analysis description

Cochran-Mantel-Haenszel test with race as stratification factor.

Comparison groups

Placebo v Linzagolix 100 mg

Number of subjects included in analysis

199

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[14]

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

3.83

Confidence interval

level

95%

sides

2-sided

lower limit

1.84

upper limit

7.94

Notes
[14] - Each active treatment group is compared versus placebo at the 0.0125 level of significance.

Amenorrhea at Week 24

Statistical analysis description

Cochran-Mantel-Haenszel test with race as stratification factor.

Comparison groups

Placebo v Linzagolix 100 mg + ABT

Number of subjects included in analysis

203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[15]

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

14.17

Confidence interval

level

95%

sides

2-sided

lower limit

6.76

upper limit

29.71

Notes
[15] - Each active treatment group is compared versus placebo at the 0.0125 level of significance.

Amenorrhea at Week 24

Statistical analysis description

Cochran-Mantel-Haenszel test with race as stratification factor.

Comparison groups

Placebo v Linzagolix 200 mg

Number of subjects included in analysis

205

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[16]

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

17.29

Confidence interval

level

95%

sides

2-sided

lower limit

8.38

upper limit

35.66

Notes
[16] - Each active treatment group is compared versus placebo at the 0.0125 level of significance.

Amenorrhea at Week 24

Statistical analysis description

Cochran-Mantel-Haenszel test with race as stratification factor.

Comparison groups

Placebo v Linzagolix 200 mg + ABT

Number of subjects included in analysis

200

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[17]

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

31.38

Confidence interval

level

95%

sides

2-sided

lower limit

14.27

upper limit

69.02

Notes
[17] - Each active treatment group is compared versus placebo at the 0.0125 level of significance.

Secondary: Time to amenorrhea up to Week 24

Top of page

End point title

Time to amenorrhea up to Week 24

End point description

Kaplan-Meier estimates of the first quartile (95% CI) for time to amenorrhea are shown.

End point type

Secondary

End point timeframe

From Baseline up to Week 24

End point values	Placebo	Linzagolix 100 mg	Linzagolix 100 mg + ABT	Linzagolix 200 mg	Linzagolix 200 mg + ABT
Number of subjects analysed	102 ^[18]	97	101	103	98
Units: days
number (confidence interval 95%)	0 (0 to 0)	104.0 (55.0 to 128.0)	6.0 (4.0 to 17.0)	3.0 (1.0 to 5.0)	2.0 (1.0 to 4.0)

Notes
[18] - Not estimable

Time to amenorrhea up to Week 24

Statistical analysis description

Estimated hazard ratios and 95% CIs obtained from stratified Cox model with treatment group as main effect and race as stratification factor.

Comparison groups

Placebo v Linzagolix 100 mg

Number of subjects included in analysis

199

Analysis specification

Pre-specified

Analysis type

superiority ^[19]

P-value

< 0.001 ^[20]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

3.47

Confidence interval

level

95%

sides

2-sided

lower limit

1.79

upper limit

6.73

Notes
[19] - p-value obtained from a 2-sided stratified log-rank test for each treatment group versus placebo comparison using race as stratification factor.
[20] - Each active treatment group is compared versus placebo at the 0.0125 level of significance.

Time to amenorrhea up to Week 24

Statistical analysis description

Estimated hazard ratios and 95% CIs obtained from stratified Cox model with treatment group as main effect and race as stratification factor.

Comparison groups

Placebo v Linzagolix 100 mg + ABT

Number of subjects included in analysis

203

Analysis specification

Pre-specified

Analysis type

superiority ^[21]

P-value

< 0.001 ^[22]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

8.9

Confidence interval

level

95%

sides

2-sided

lower limit

4.8

upper limit

16.53

Notes
[21] - p-value obtained from a 2-sided stratified log-rank test for each treatment group versus placebo comparison using race as stratification factor.
[22] - Each active treatment group is compared versus placebo at the 0.0125 level of significance.

Time to amenorrhea up to Week 24

Statistical analysis description

Estimated hazard ratios and 95% CIs obtained from stratified Cox model with treatment group as main effect and race as stratification factor.

Comparison groups

Placebo v Linzagolix 200 mg

Number of subjects included in analysis

205

Analysis specification

Pre-specified

Analysis type

superiority ^[23]

P-value

< 0.001 ^[24]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

11.89

Confidence interval

level

95%

sides

2-sided

lower limit

6.44

upper limit

21.96

Notes
[23] - p-value obtained from a 2-sided stratified log-rank test for each treatment group versus placebo comparison using race as stratification factor.
[24] - Each active treatment group is compared versus placebo at the 0.0125 level of significance.

Time to amenorrhea up to Week 24

Statistical analysis description

Estimated hazard ratios and 95% CIs obtained from stratified Cox model with treatment group as main effect and race as stratification factor.

Comparison groups

Linzagolix 200 mg + ABT v Placebo

Number of subjects included in analysis

200

Analysis specification

Pre-specified

Analysis type

superiority ^[25]

P-value

< 0.001 ^[26]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

14.29

Confidence interval

level

95%

sides

2-sided

lower limit

7.76

upper limit

26.32

Notes
[25] - p-value obtained from a 2-sided stratified log-rank test for each treatment group versus placebo comparison using race as stratification factor.
[26] - Each active treatment group is compared versus placebo at the 0.0125 level of significance.

Secondary: Number of days of uterine bleeding up to Week 24

Top of page

End point title

Number of days of uterine bleeding up to Week 24

End point description

Number of days of uterine bleeding for the last 28-day interval prior to Week 24 - Zero-inflated negative binomial model.

End point type

Secondary

End point timeframe

Number of days of uterine bleeding for each 28-day interval up to week 24.

End point values	Placebo	Linzagolix 100 mg	Linzagolix 100 mg + ABT	Linzagolix 200 mg	Linzagolix 200 mg + ABT
Number of subjects analysed	100	94	97	98	96
Units: percentage
number (not applicable)
0 days	18.0	52.1	76.3	79.6	85.4
1-5 days	54.0	36.2	9.3	9.2	8.3
>5 days	28.0	11.7	14.4	11.2	6.3

Number of days of uterine bleeding

Statistical analysis description

Zero-inflated negative binomial model: The zero-inflation probability model includes treatment group as main effect. The regression model for the mean includes treatment group as main effect and baseline value and race as covariates. LSMeans are computed for the regression model only and not for the zero-inflation probability model. The overall mean is calculated as (1 – Probability) * LSMean.

Comparison groups

Placebo v Linzagolix 100 mg

Number of subjects included in analysis

194

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[27]

Method

Regression, Logistic

Confidence interval

Notes
[27] - Testing joint null hypothesis of no treatment effect in zero-inflation probability model and the regression model for the mean. Each active treatment group is compared versus placebo at the 0.0125 level of significance.

Number of days of uterine bleeding

Statistical analysis description

Comparison groups

Placebo v Linzagolix 100 mg + ABT

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[28]

Method

Regression, Logistic

Confidence interval

Notes
[28] - Testing joint null hypothesis of no treatment effect in zero-inflation probability model and the regression model for the mean. Each active treatment group is compared versus placebo at the 0.0125 level of significance.

Number of days of uterine bleeding

Statistical analysis description

Comparison groups

Placebo v Linzagolix 200 mg

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[29]

Method

Regression, Logistic

Confidence interval

Notes
[29] - Testing joint null hypothesis of no treatment effect in zero-inflation probability model and the regression model for the mean. Each active treatment group is compared versus placebo at the 0.0125 level of significance.

Number of days of uterine bleeding

Statistical analysis description

Comparison groups

Placebo v Linzagolix 200 mg + ABT

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[30]

Method

Regression, Logistic

Confidence interval

Notes
[30] - Testing joint null hypothesis of no treatment effect in zero-inflation probability model and the regression model for the mean. Each active treatment group is compared versus placebo at the 0.0125 level of significance.

Secondary: Hemoglobin levels at Week 24 in anemic subjects

Top of page

End point title

Hemoglobin levels at Week 24 in anemic subjects

End point description

End point type

Secondary

End point timeframe

Week 24

End point values	Placebo	Linzagolix 100 mg	Linzagolix 100 mg + ABT	Linzagolix 200 mg	Linzagolix 200 mg + ABT
Number of subjects analysed	51	61	59	57	56
Units: g/dL
least squares mean (confidence interval 95%)	10.56 (10.05 to 11.07)	11.49 (10.99 to 11.99)	12.16 (11.65 to 12.68)	12.28 (11.79 to 12.77)	12.44 (11.95 to 12.93)

Hemoglobin level at Week 24 in anemic subjects

Statistical analysis description

Analysis using mixed model repeated measures with actual value as response variable, baseline hemoglobin value, treatment, visit and race as covariates and including treatment, baseline value and race by visit interactions.

Comparison groups

Placebo v Linzagolix 100 mg

Number of subjects included in analysis

112

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[31]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

0.94

Confidence interval

level

95%

sides

2-sided

lower limit

0.43

upper limit

1.45

Notes
[31] - Each active treatment group is compared versus placebo at the 0.0125 level of significance.

Hemoglobin level at Week 24 in anemi...

Statistical analysis description

Comparison groups

Placebo v Linzagolix 100 mg + ABT

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[32]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

1.61

Confidence interval

level

95%

sides

2-sided

lower limit

1.09

upper limit

2.13

Notes
[32] - Each active treatment group is compared versus placebo at the 0.0125 level of significance.

Hemoglobin level at Week 24 in anemi...

Statistical analysis description

Comparison groups

Placebo v Linzagolix 200 mg

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[33]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

1.72

Confidence interval

level

95%

sides

2-sided

lower limit

1.21

upper limit

2.24

Notes
[33] - Each active treatment group is compared versus placebo at the 0.0125 level of significance.

Hemoglobin level at Week 24 in anemi...

Statistical analysis description

Comparison groups

Placebo v Linzagolix 200 mg + ABT

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[34]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

1.88

Confidence interval

level

95%

sides

2-sided

lower limit

1.36

upper limit

2.39

Notes
[34] - Each active treatment group is compared versus placebo at the 0.0125 level of significance.

Other pre-specified: Change from Baseline in bone mineral density at the lumbar spine at Week 24

Top of page

End point title

Change from Baseline in bone mineral density at the lumbar spine at Week 24

End point description

End point type

Other pre-specified

End point timeframe

Week 24

End point values	Placebo	Linzagolix 100 mg	Linzagolix 100 mg + ABT	Linzagolix 200 mg	Linzagolix 200 mg + ABT
Number of subjects analysed	78	71	72	75	72
Units: %CfB
geometric mean (confidence interval 95%)	0.538 (-0.001 to 1.076)	-2.068 (-2.630 to -1.506)	-0.998 (-1.570 to -0.425)	-4.032 (-4.680 to -3.385)	-1.350 (-1.956 to -0.745)

No statistical analyses for this end point

Other pre-specified: Change from Baseline in bone mineral density at the lumbar spine at Week 52

Top of page

End point title

Change from Baseline in bone mineral density at the lumbar spine at Week 52

End point description

End point type

Other pre-specified

End point timeframe

Week 52

End point values	Placebo / linzagolix 200 mg + ABT	Linzagolix 100 mg	Linzagolix 100 mg + ABT	Linzagolix 200 mg / linzagolix 200 mg + ABT	Linzagolix 200 mg + ABT
Number of subjects analysed	66	55	54	53	60
Units: %CfB
geometric mean (confidence interval 95%)	-0.536 (-1.251 to 0.179)	-2.401 (-3.142 to -1.660)	-1.479 (-2.016 to -0.942)	-3.062 (-3.823 to -2.300)	-2.026 (-2.808 to -1.244)

No statistical analyses for this end point

Other pre-specified: Change from Baseline in bone mineral density at the lumbar spine at Week 76

Top of page

End point title

Change from Baseline in bone mineral density at the lumbar spine at Week 76

End point description

End point type

Other pre-specified

End point timeframe

Week 76

End point values	Placebo / linzagolix 200 mg + ABT	Linzagolix 100 mg	Linzagolix 100 mg + ABT	Linzagolix 200 mg / linzagolix 200 mg + ABT	Linzagolix 200 mg + ABT
Number of subjects analysed	50	40	41	47	47
Units: %CfB
geometric mean (confidence interval 95%)	0.297 (-0.494 to 1.088)	-2.282 (-3.076 to -1.489)	-0.664 (-1.436 to 0.109)	-1.508 (-2.454 to -0.563)	-1.133 (-2.033 to -0.234)

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

From Screening up to Week 76.

Adverse event reporting additional description

Data on adverse events were to be obtained at scheduled or unscheduled study visits, based on information spontaneously provided by the subject and/or through questioning of the subject. Only treatment-emergent adverse events are reported here.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.0

Reporting group title

Placebo 24w

Reporting group description

Reporting group title

Linzagolix 100 mg 24w

Reporting group description

Reporting group title

Linzagolix 100 mg + ABT 24w

Reporting group description

Reporting group title

Linzagolix 200 mg 24w

Reporting group description

Reporting group title

Linzagolix 200 mg + ABT 24w

Reporting group description

Reporting group title

Placebo / linzagolix 200 mg + ABT 52w

Reporting group description

Reporting group title

Linzagolix 100 mg 52w

Reporting group description

Reporting group title

Linzagolix 100 mg + ABT 52w

Reporting group description

Reporting group title

Linzagolix 200 mg / linzagolix 200 mg + ABT 52w

Reporting group description

Reporting group title

Linzagolix 200 mg + ABT 52w

Reporting group description

Reporting group title

Placebo / linzagolix 200 mg + ABT 76w

Reporting group description

Reporting group title

Linzagolix 100 mg 76w

Reporting group description

Reporting group title

Linzagolix 100 mg + ABT 76w

Reporting group description

Reporting group title

Linzagolix 200 mg / linzagolix 200 mg + ABT 76w

Reporting group description

Reporting group title

Linzagolix 200 mg + ABT 76w

Reporting group description

Placebo 24w

Linzagolix 100 mg 24w

Linzagolix 100 mg + ABT 24w

Linzagolix 200 mg 24w

Linzagolix 200 mg + ABT 24w

Placebo / linzagolix 200 mg + ABT 52w

Linzagolix 100 mg 52w

Linzagolix 100 mg + ABT 52w

Linzagolix 200 mg / linzagolix 200 mg + ABT 52w

Linzagolix 200 mg + ABT 52w

Placebo / linzagolix 200 mg + ABT 76w

Linzagolix 100 mg 76w

Linzagolix 100 mg + ABT 76w

Linzagolix 200 mg / linzagolix 200 mg + ABT 76w

Linzagolix 200 mg + ABT 76w

Total subjects affected by serious adverse events

subjects affected / exposed

2 / 105 (1.90%)

1 / 99 (1.01%)

5 / 102 (4.90%)

1 / 104 (0.96%)

1 / 101 (0.99%)

3 / 89 (3.37%)

1 / 79 (1.27%)

2 / 81 (2.47%)

2 / 87 (2.30%)

1 / 84 (1.19%)

2 / 75 (2.67%)

1 / 60 (1.67%)

0 / 68 (0.00%)

2 / 63 (3.17%)

2 / 73 (2.74%)

number of deaths (all causes)

number of deaths resulting from adverse events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Breast cancer

subjects affected / exposed

0 / 105 (0.00%)

0 / 99 (0.00%)

0 / 102 (0.00%)

1 / 104 (0.96%)

0 / 101 (0.00%)

1 / 89 (1.12%)

0 / 79 (0.00%)

0 / 81 (0.00%)

0 / 87 (0.00%)

0 / 84 (0.00%)

0 / 75 (0.00%)

0 / 60 (0.00%)

0 / 68 (0.00%)

0 / 63 (0.00%)

0 / 73 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Uterine leiomyoma

subjects affected / exposed

0 / 105 (0.00%)

0 / 99 (0.00%)

1 / 102 (0.98%)

0 / 104 (0.00%)

0 / 101 (0.00%)

0 / 89 (0.00%)

0 / 79 (0.00%)

0 / 81 (0.00%)

0 / 87 (0.00%)

0 / 84 (0.00%)

0 / 75 (0.00%)

0 / 60 (0.00%)

0 / 68 (0.00%)

0 / 63 (0.00%)

0 / 73 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cholesteatoma

alternative assessment type: Non-systematic

subjects affected / exposed

0 / 105 (0.00%)

0 / 99 (0.00%)

0 / 102 (0.00%)

0 / 104 (0.00%)

0 / 101 (0.00%)

0 / 89 (0.00%)

0 / 79 (0.00%)

1 / 81 (1.23%)

0 / 87 (0.00%)

0 / 84 (0.00%)

0 / 75 (0.00%)

0 / 60 (0.00%)

0 / 68 (0.00%)

0 / 63 (0.00%)

0 / 73 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Endometrial adenocarcinoma

subjects affected / exposed

0 / 105 (0.00%)

0 / 99 (0.00%)

0 / 102 (0.00%)

0 / 104 (0.00%)

0 / 101 (0.00%)

0 / 89 (0.00%)

0 / 79 (0.00%)

1 / 81 (1.23%)

0 / 87 (0.00%)

0 / 84 (0.00%)

0 / 75 (0.00%)

0 / 60 (0.00%)

0 / 68 (0.00%)

0 / 63 (0.00%)

0 / 73 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Colorectal adenocarcinoma

subjects affected / exposed

0 / 105 (0.00%)

0 / 99 (0.00%)

0 / 102 (0.00%)

0 / 104 (0.00%)

0 / 101 (0.00%)

0 / 89 (0.00%)

0 / 79 (0.00%)

0 / 81 (0.00%)

0 / 87 (0.00%)

0 / 84 (0.00%)

0 / 75 (0.00%)

0 / 60 (0.00%)

0 / 68 (0.00%)

1 / 63 (1.59%)

0 / 73 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Ovarian epithelial cancer

subjects affected / exposed

0 / 105 (0.00%)

0 / 99 (0.00%)

0 / 102 (0.00%)

0 / 104 (0.00%)

0 / 101 (0.00%)

0 / 89 (0.00%)

0 / 79 (0.00%)

0 / 81 (0.00%)

0 / 87 (0.00%)

0 / 84 (0.00%)

0 / 75 (0.00%)

0 / 60 (0.00%)

0 / 68 (0.00%)

0 / 63 (0.00%)

1 / 73 (1.37%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Injury, poisoning and procedural complications

Intervertebral disc injury

alternative assessment type: Non-systematic

subjects affected / exposed

1 / 105 (0.95%)

0 / 99 (0.00%)

0 / 102 (0.00%)

0 / 104 (0.00%)

0 / 101 (0.00%)

0 / 89 (0.00%)

0 / 79 (0.00%)

0 / 81 (0.00%)

0 / 87 (0.00%)

0 / 84 (0.00%)

0 / 75 (0.00%)

0 / 60 (0.00%)

0 / 68 (0.00%)

0 / 63 (0.00%)

0 / 73 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Vascular disorders

Hypertension

subjects affected / exposed

0 / 105 (0.00%)

1 / 99 (1.01%)

0 / 102 (0.00%)

0 / 104 (0.00%)

0 / 101 (0.00%)

0 / 89 (0.00%)

0 / 79 (0.00%)

0 / 81 (0.00%)

0 / 87 (0.00%)

0 / 84 (0.00%)

0 / 75 (0.00%)

0 / 60 (0.00%)

0 / 68 (0.00%)

0 / 63 (0.00%)

0 / 73 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Deep vein thrombosis

subjects affected / exposed

0 / 105 (0.00%)

0 / 99 (0.00%)

0 / 102 (0.00%)

0 / 104 (0.00%)

0 / 101 (0.00%)

1 / 89 (1.12%)

0 / 79 (0.00%)

0 / 81 (0.00%)

0 / 87 (0.00%)

0 / 84 (0.00%)

0 / 75 (0.00%)

0 / 60 (0.00%)

0 / 68 (0.00%)

0 / 63 (0.00%)

0 / 73 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Blood and lymphatic system disorders

Anaemia

subjects affected / exposed

0 / 105 (0.00%)

0 / 99 (0.00%)

2 / 102 (1.96%)

0 / 104 (0.00%)

0 / 101 (0.00%)

0 / 89 (0.00%)

0 / 79 (0.00%)

0 / 81 (0.00%)

0 / 87 (0.00%)

0 / 84 (0.00%)

0 / 75 (0.00%)

0 / 60 (0.00%)

0 / 68 (0.00%)

0 / 63 (0.00%)

0 / 73 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Reproductive system and breast disorders

Uterine haemorrhage

subjects affected / exposed

0 / 105 (0.00%)

0 / 99 (0.00%)

2 / 102 (1.96%)

0 / 104 (0.00%)

0 / 101 (0.00%)

0 / 89 (0.00%)

0 / 79 (0.00%)

0 / 81 (0.00%)

0 / 87 (0.00%)

0 / 84 (0.00%)

1 / 75 (1.33%)

1 / 60 (1.67%)

0 / 68 (0.00%)

1 / 63 (1.59%)

0 / 73 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Menorrhagia

subjects affected / exposed

0 / 105 (0.00%)

0 / 99 (0.00%)

0 / 102 (0.00%)

0 / 104 (0.00%)

0 / 101 (0.00%)

1 / 89 (1.12%)

0 / 79 (0.00%)

0 / 81 (0.00%)

0 / 87 (0.00%)

0 / 84 (0.00%)

1 / 75 (1.33%)

0 / 60 (0.00%)

0 / 68 (0.00%)

0 / 63 (0.00%)

0 / 73 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Vaginal haemorrhage

subjects affected / exposed

0 / 105 (0.00%)

0 / 99 (0.00%)

0 / 102 (0.00%)

0 / 104 (0.00%)

0 / 101 (0.00%)

0 / 89 (0.00%)

0 / 79 (0.00%)

0 / 81 (0.00%)

1 / 87 (1.15%)

0 / 84 (0.00%)

0 / 75 (0.00%)

0 / 60 (0.00%)

0 / 68 (0.00%)

0 / 63 (0.00%)

0 / 73 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Menometrorrhagia

subjects affected / exposed

0 / 105 (0.00%)

0 / 99 (0.00%)

0 / 102 (0.00%)

0 / 104 (0.00%)

0 / 101 (0.00%)

0 / 89 (0.00%)

0 / 79 (0.00%)

0 / 81 (0.00%)

0 / 87 (0.00%)

0 / 84 (0.00%)

0 / 75 (0.00%)

0 / 60 (0.00%)

0 / 68 (0.00%)

0 / 63 (0.00%)

1 / 73 (1.37%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Hepatobiliary disorders

Cholelithiasis

subjects affected / exposed

0 / 105 (0.00%)

0 / 99 (0.00%)

0 / 102 (0.00%)

0 / 104 (0.00%)

0 / 101 (0.00%)

0 / 89 (0.00%)

0 / 79 (0.00%)

0 / 81 (0.00%)

1 / 87 (1.15%)

0 / 84 (0.00%)

0 / 75 (0.00%)

0 / 60 (0.00%)

0 / 68 (0.00%)

0 / 63 (0.00%)

0 / 73 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory, thoracic and mediastinal disorders

Emphysema

subjects affected / exposed

0 / 105 (0.00%)

0 / 99 (0.00%)

0 / 102 (0.00%)

0 / 104 (0.00%)

0 / 101 (0.00%)

0 / 89 (0.00%)

0 / 79 (0.00%)

0 / 81 (0.00%)

0 / 87 (0.00%)

1 / 84 (1.19%)

0 / 75 (0.00%)

0 / 60 (0.00%)

0 / 68 (0.00%)

0 / 63 (0.00%)

0 / 73 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Skin and subcutaneous tissue disorders

Dermatitis

subjects affected / exposed

0 / 105 (0.00%)

0 / 99 (0.00%)

0 / 102 (0.00%)

0 / 104 (0.00%)

0 / 101 (0.00%)

0 / 89 (0.00%)

1 / 79 (1.27%)

0 / 81 (0.00%)

0 / 87 (0.00%)

0 / 84 (0.00%)

0 / 75 (0.00%)

0 / 60 (0.00%)

0 / 68 (0.00%)

0 / 63 (0.00%)

0 / 73 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Renal and urinary disorders

Urinary incontinence

subjects affected / exposed

0 / 105 (0.00%)

0 / 99 (0.00%)

0 / 102 (0.00%)

0 / 104 (0.00%)

1 / 101 (0.99%)

0 / 89 (0.00%)

0 / 79 (0.00%)

0 / 81 (0.00%)

0 / 87 (0.00%)

0 / 84 (0.00%)

0 / 75 (0.00%)

0 / 60 (0.00%)

0 / 68 (0.00%)

0 / 63 (0.00%)

0 / 73 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Musculoskeletal and connective tissue disorders

Intervertebral disc disorder

alternative assessment type: Non-systematic

subjects affected / exposed

1 / 105 (0.95%)

0 / 99 (0.00%)

0 / 102 (0.00%)

0 / 104 (0.00%)

0 / 101 (0.00%)

0 / 89 (0.00%)

0 / 79 (0.00%)

0 / 81 (0.00%)

0 / 87 (0.00%)

0 / 84 (0.00%)

0 / 75 (0.00%)

0 / 60 (0.00%)

0 / 68 (0.00%)

0 / 63 (0.00%)

0 / 73 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Placebo 24w

Linzagolix 100 mg 24w

Linzagolix 100 mg + ABT 24w

Linzagolix 200 mg 24w

Linzagolix 200 mg + ABT 24w

Placebo / linzagolix 200 mg + ABT 52w

Linzagolix 100 mg 52w

Linzagolix 100 mg + ABT 52w

Linzagolix 200 mg / linzagolix 200 mg + ABT 52w

Linzagolix 200 mg + ABT 52w

Placebo / linzagolix 200 mg + ABT 76w

Linzagolix 100 mg 76w

Linzagolix 100 mg + ABT 76w

Linzagolix 200 mg / linzagolix 200 mg + ABT 76w

Linzagolix 200 mg + ABT 76w

Total subjects affected by non serious adverse events

subjects affected / exposed

22 / 105 (20.95%)

39 / 99 (39.39%)

23 / 102 (22.55%)

58 / 104 (55.77%)

29 / 101 (28.71%)

11 / 89 (12.36%)

5 / 79 (6.33%)

5 / 81 (6.17%)

3 / 87 (3.45%)

5 / 84 (5.95%)

2 / 75 (2.67%)

4 / 60 (6.67%)

4 / 68 (5.88%)

0 / 63 (0.00%)

3 / 73 (4.11%)

Vascular disorders

Hot flush

subjects affected / exposed

4 / 105 (3.81%)

14 / 99 (14.14%)

8 / 102 (7.84%)

33 / 104 (31.73%)

13 / 101 (12.87%)

3 / 89 (3.37%)

2 / 79 (2.53%)

1 / 81 (1.23%)

1 / 87 (1.15%)

3 / 84 (3.57%)

0 / 75 (0.00%)

0 / 60 (0.00%)

0 / 68 (0.00%)

0 / 63 (0.00%)

0 / 73 (0.00%)

occurrences all number

Nervous system disorders

Headache

subjects affected / exposed

6 / 105 (5.71%)

4 / 99 (4.04%)

5 / 102 (4.90%)

14 / 104 (13.46%)

7 / 101 (6.93%)

0 / 89 (0.00%)

1 / 79 (1.27%)

2 / 81 (2.47%)

1 / 87 (1.15%)

1 / 84 (1.19%)

0 / 75 (0.00%)

0 / 60 (0.00%)

0 / 68 (0.00%)

0 / 63 (0.00%)

0 / 73 (0.00%)

occurrences all number

Blood and lymphatic system disorders

Anaemia

subjects affected / exposed

11 / 105 (10.48%)

19 / 99 (19.19%)

10 / 102 (9.80%)

4 / 104 (3.85%)

9 / 101 (8.91%)

6 / 89 (6.74%)

2 / 79 (2.53%)

2 / 81 (2.47%)

1 / 87 (1.15%)

1 / 84 (1.19%)

2 / 75 (2.67%)

4 / 60 (6.67%)

4 / 68 (5.88%)

0 / 63 (0.00%)

3 / 73 (4.11%)

occurrences all number

Skin and subcutaneous tissue disorders

Hyperhidrosis

subjects affected / exposed

1 / 105 (0.95%)

2 / 99 (2.02%)

0 / 102 (0.00%)

7 / 104 (6.73%)

0 / 101 (0.00%)

2 / 89 (2.25%)

0 / 79 (0.00%)

0 / 81 (0.00%)

0 / 87 (0.00%)

0 / 84 (0.00%)

0 / 75 (0.00%)

0 / 60 (0.00%)

0 / 68 (0.00%)

0 / 63 (0.00%)

0 / 73 (0.00%)

occurrences all number

More information

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Were there any global substantial amendments to the protocol? Yes

22 Jun 2017

• Changes and clarifications to screening and in- and exclusion criteria • PK - related: new data; OATP1B1/1B3 inhibitors were prohibited during the treatment period • Modification of the ABT dose for the linzagolix 100 mg group • Modification of the subject withdrawal section with respect to BMD measurements (DXA scan) at the time of withdrawal

18 Dec 2017

• Change in treatment discontinuation criteria related to BMD result and hepatic parameters measured at Day 1 and during treatment. • Clarification and addition of secondary efficacy objectives (incidence and time to amenorrhea, impact of submucosal fibroids on the primary endpoint). • Removal of the substrates of CYP2C8 and of OAT3 as prohibited medicines. • Addition of temperature storage requirements for the IMP. • Modification of statistical sections for consistency with the Statistical Analysis Plan. • Addition of a section presenting the definition and reporting procedures for protocol deviations.

28 May 2018

• Modification of myoma size inclusion criterion. • Addition of ECG monitoring. • Clarification: inclusion criterion on the menstrual cycle duration. • Addition of an ultrasound prior to washout for patients with an IUD (confirmation of fibroid size criterion). • Addition of the instruction that subjects who did not bleed for 50 days during screening were to be considered screen failures. • Removal of OATP1B1/1B3 inhibitors from the list of prohibited medicines.

04 Oct 2019

• Modification of the wording, ordering and ranking of secondary endpoints. • Clarification of the rules for discontinuation of study treatment in relation to elevated liver function tests, BMD decrease and endometrial biopsies and safety follow-up. • Specification of criteria for referring subjects to a with respect to QTc prolongation.

27 Nov 2019

• Clarification of the definition of baseline. • Clarification of the timing of the Week 52 visit.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Reduced menstrual blood loss at Week 24

Primary: Reduced menstrual blood loss at Week 24

Secondary: Time to reduced menstrual blood loss up to Week 24

Secondary: Time to reduced menstrual blood loss up to Week 24

Secondary: Amenorrhea at Week 24

Secondary: Amenorrhea at Week 24

Secondary: Time to amenorrhea up to Week 24

Secondary: Time to amenorrhea up to Week 24

Secondary: Number of days of uterine bleeding up to Week 24

Secondary: Number of days of uterine bleeding up to Week 24

Secondary: Hemoglobin levels at Week 24 in anemic subjects

Secondary: Hemoglobin levels at Week 24 in anemic subjects

Other pre-specified: Change from Baseline in bone mineral density at the lumbar spine at Week 24

Other pre-specified: Change from Baseline in bone mineral density at the lumbar spine at Week 24

Other pre-specified: Change from Baseline in bone mineral density at the lumbar spine at Week 52

Other pre-specified: Change from Baseline in bone mineral density at the lumbar spine at Week 52

Other pre-specified: Change from Baseline in bone mineral density at the lumbar spine at Week 76

Other pre-specified: Change from Baseline in bone mineral density at the lumbar spine at Week 76

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
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Outside EU/EEA