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Clinical Trial Results:
A randomized, double-blind, placebo-controlled, phase 2b dose-ranging study to assess the efficacy and safety of OBE2109 in subjects with endometriosis associated pain.

Summary
EudraCT number	2016-001736-35
Trial protocol	PL
Global end of trial date	04 Sep 2019

Results information
Results version number	v1(current)
This version publication date	20 May 2021
First version publication date	20 May 2021
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

15-OBE2109-001

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

ObsEva SA

Sponsor organisation address

12, Chemin des Aulx, Plan-les-Ouates, Geneva, Switzerland, 1228

Public contact

Clinical Trials Information, ObsEva SA, clinicaltrials@obseva.ch

Scientific contact

Clinical Trials Information, ObsEva SA, 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

04 Nov 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

04 Sep 2019

Was the trial ended prematurely?

Main objective of the trial

To assess the efficacy of a range of oral doses of linzagolix versus placebo, in reducing pelvic pain in subjects with moderate to severe endometriosis pain. To assess the safety and tolerability of linzagolix in subjects with endometriosis.

Protection of trial subjects

This study was performed in accordance with the protocol, the Declaration of Helsinki, the ICH Harmonised Tripartite Guideline for GCP, and all applicable local regulatory requirements. Subjects read and understood the Informed Consent Form (ICF) and voluntarily agreed to participation in this study.

Background therapy

Evidence for comparator

Actual start date of recruitment

26 Jul 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 67

Country: Number of subjects enrolled

Ukraine: 73

Country: Number of subjects enrolled

Russian Federation: 11

Country: Number of subjects enrolled

United States: 177

Worldwide total number of subjects

328

EEA total number of subjects

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)

328

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

A total of 328 females were randomized at 62 sites in 4 countries: 48 sites in USA (177 subjects), 5 sites in Poland (67 subjects), 5 sites in Ukraine (73 subjects) and 4 sites in Russia (11 subjects).

Screening details

716 subjects were screened and 328 were randomized; 327 were included in the safety set (1 not included as didn't receive study treatment). 323 subjects were included in the FAS, 5 randomized subjects were excluded: 1 as per the safety set and 4 were prematurely discontinued at one US site due to the site’s serious non-compliance to the protocol.

Period 1 title

Treatment period (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor

Are arms mutually exclusive

Yes

Linzagolix 50 mg

Arm description

50 mg linzagolix, once daily for 12 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

Study drug was taken at approximately the same time every morning (1 tablet of 50 mg). To maintain the blind, placebo tablet was also administered.

Linzagolix 75 mg

Arm description

75 mg linzagolix, once daily for 12 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

Study drug was taken at approximately the same time every morning (1 tablet of 75 mg). To maintain the blind, placebo tablet was also administered.

Linzagolix 100 mg

Arm description

100 mg linzagolix, once daily for 12 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

Study drug was taken at approximately the same time every morning (1 tablet of 100 mg). To maintain the blind, placebo tablet was also administered.

Linzagolix 200 mg

Arm description

200 mg linzagolix, once daily for 12 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

Two tablets of 100 mg linzagolix. Study drug was taken at approximately the same time every morning.

Placebo

Arm description

Placebo, once daily for 12 weeks.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Placebo

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Two placebo tablets were taken at approximately the same time every morning.

Number of subjects in period 1 ^[1]	Linzagolix 50 mg	Linzagolix 75 mg	Linzagolix 100 mg	Linzagolix 200 mg	Placebo
Started	49	114	51	56	53
Completed	45	104	45	49	45
Not completed	4	10	6	7	8
Consent withdrawn by subject	2	4	1	3	5
Adverse event, non-fatal	2	5	3	3	1
Dosing compliance issue	-	1	-	-	-
Sponsor request	-	-	1	-	-
Lost to follow-up	-	-	-	1	2
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 FAS. 328 subjects were randomized, 323 subjects were included in the FAS; 5 randomized subjects were excluded: 1 didn't receive study treatment and 4 subjects were prematurely discontinued at one US site due to the site’s serious non-compliance to the protocol.

Baseline characteristics

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Reporting group title

Linzagolix 50 mg

Reporting group description

50 mg linzagolix, once daily for 12 weeks.

Reporting group title

Linzagolix 75 mg

Reporting group description

75 mg linzagolix, once daily for 12 weeks.

Reporting group title

Linzagolix 100 mg

Reporting group description

100 mg linzagolix, once daily for 12 weeks.

Reporting group title

Linzagolix 200 mg

Reporting group description

200 mg linzagolix, once daily for 12 weeks.

Reporting group title

Placebo

Reporting group description

Placebo, once daily for 12 weeks.

Reporting group values	Linzagolix 50 mg	Linzagolix 75 mg	Linzagolix 100 mg	Linzagolix 200 mg	Placebo	Total
Number of subjects	49	114	51	56	53	323
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)	49	114	51	56	53	323
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)	30.9 ± 5.98	31.8 ± 6.17	33.0 ± 5.78	30.9 ± 6.03	32.4 ± 5.78	-
Gender categorical
Units: Subjects
Female	49	114	51	56	53	323
Male	0	0	0	0	0	0

End points

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Reporting group title

Linzagolix 50 mg

Reporting group description

50 mg linzagolix, once daily for 12 weeks.

Reporting group title

Linzagolix 75 mg

Reporting group description

75 mg linzagolix, once daily for 12 weeks.

Reporting group title

Linzagolix 100 mg

Reporting group description

100 mg linzagolix, once daily for 12 weeks.

Reporting group title

Linzagolix 200 mg

Reporting group description

200 mg linzagolix, once daily for 12 weeks.

Reporting group title

Placebo

Reporting group description

Placebo, once daily for 12 weeks.

Primary: 30% or Greater Reduction from Baseline to Week 12 in Mean Overall Pelvic Pain Score (0-3 VRS)

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End point title

30% or Greater Reduction from Baseline to Week 12 in Mean Overall Pelvic Pain Score (0-3 VRS)

End point description

The primary efficacy endpoint of the study was a response at Week 12, with response defined as a reduction of 30% or greater from baseline in mean overall pelvic pain, recorded daily and assessed via electronic diary during the preceding 28 days (4-week period) on a VRS of 0 (no pain) to 3 (severe pain).

End point type

Primary

End point timeframe

Week 12 of the treatment period

End point values	Linzagolix 50 mg	Linzagolix 75 mg	Linzagolix 100 mg	Linzagolix 200 mg	Placebo
Number of subjects analysed	48	114	51	55	52
Units: responder rate
number (not applicable)	49.4	61.5	56.4	56.3	34.5

Statistical Analysis 50 mg

Statistical analysis description

Analysis of the primary endpoint was conducted via a generalized linear model for binary data with repeated (correlated) measures, using generalized estimating equations (marginal model), with the model including terms for the treatment group, 4-week period, baseline, and the interactions: treatment group x 4-week period, and baseline x 4-week period.

Comparison groups

Linzagolix 50 mg v Placebo

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.155

Method

generalized linear model

Parameter type

Odds ratio (OR)

Point estimate

1.85

Confidence interval

level

95%

sides

2-sided

lower limit

0.791

upper limit

4.317

Statistical Analysis 75 mg

Statistical analysis description

Comparison groups

Linzagolix 75 mg v Placebo

Number of subjects included in analysis

166

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.003

Method

generalized linear model

Parameter type

Odds ratio (OR)

Point estimate

3.03

Confidence interval

level

95%

sides

2-sided

lower limit

1.469

upper limit

6.239

Statistical Analysis 100 mg

Statistical analysis description

Comparison groups

Linzagolix 100 mg v Placebo

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.039

Method

generalized linear model

Parameter type

Odds ratio (OR)

Point estimate

2.45

Confidence interval

level

95%

sides

2-sided

lower limit

1.049

upper limit

5.741

Statistical Analysis 200 mg

Statistical analysis description

Comparison groups

Linzagolix 200 mg v Placebo

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.034

Method

generalized linear model

Parameter type

Odds ratio (OR)

Point estimate

2.45

Confidence interval

level

95%

sides

2-sided

lower limit

1.069

upper limit

5.593

Adverse events

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Timeframe for reporting adverse events

From screening to Week 12

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

Linzagolix 50 mg

Reporting group description

50 mg linzagolix, once daily for 12 weeks.

Reporting group title

Linzagolix 75 mg

Reporting group description

75 mg linzagolix, once daily for 12 weeks.

Reporting group title

Linzagolix 100 mg

Reporting group description

100 mg linzagolix, once daily for 12 weeks.

Reporting group title

Linzagolix 200 mg

Reporting group description

200 mg linzagolix, once daily for 12 weeks.

Reporting group title

Placebo

Reporting group description

Placebo, once daily for 12 weeks.

Serious adverse events	Linzagolix 50 mg	Linzagolix 75 mg	Linzagolix 100 mg	Linzagolix 200 mg	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 49 (2.04%)	0 / 114 (0.00%)	1 / 52 (1.92%)	1 / 57 (1.75%)	1 / 55 (1.82%)
number of deaths (all causes)	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0
Injury, poisoning and procedural complications
Stab wound
subjects affected / exposed	0 / 49 (0.00%)	0 / 114 (0.00%)	0 / 52 (0.00%)	0 / 57 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Enterocolitis
subjects affected / exposed	0 / 49 (0.00%)	0 / 114 (0.00%)	1 / 52 (1.92%)	0 / 57 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism
subjects affected / exposed	0 / 49 (0.00%)	0 / 114 (0.00%)	0 / 52 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Pyelonephritis acute
subjects affected / exposed	1 / 49 (2.04%)	0 / 114 (0.00%)	0 / 52 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Linzagolix 50 mg	Linzagolix 75 mg	Linzagolix 100 mg	Linzagolix 200 mg	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	28 / 49 (57.14%)	70 / 114 (61.40%)	34 / 52 (65.38%)	41 / 57 (71.93%)	30 / 55 (54.55%)
Investigations
Blood creatine phosphokinase increased
subjects affected / exposed	1 / 49 (2.04%)	4 / 114 (3.51%)	0 / 52 (0.00%)	3 / 57 (5.26%)	1 / 55 (1.82%)
occurrences all number	1	4	0	3	1
Vascular disorders
Hot flush
subjects affected / exposed	7 / 49 (14.29%)	22 / 114 (19.30%)	14 / 52 (26.92%)	24 / 57 (42.11%)	6 / 55 (10.91%)
occurrences all number	7	22	15	28	6
Nervous system disorders
Headache
subjects affected / exposed	10 / 49 (20.41%)	23 / 114 (20.18%)	12 / 52 (23.08%)	17 / 57 (29.82%)	14 / 55 (25.45%)
occurrences all number	29	37	16	27	27
General disorders and administration site conditions
Fatigue
subjects affected / exposed	1 / 49 (2.04%)	0 / 114 (0.00%)	3 / 52 (5.77%)	2 / 57 (3.51%)	0 / 55 (0.00%)
occurrences all number	1	0	3	2	0
Gastrointestinal disorders
Nausea
subjects affected / exposed	3 / 49 (6.12%)	3 / 114 (2.63%)	3 / 52 (5.77%)	7 / 57 (12.28%)	1 / 55 (1.82%)
occurrences all number	3	6	3	7	1
Toothache
subjects affected / exposed	0 / 49 (0.00%)	1 / 114 (0.88%)	0 / 52 (0.00%)	1 / 57 (1.75%)	3 / 55 (5.45%)
occurrences all number	0	1	0	2	3
Reproductive system and breast disorders
Vulvovaginal dryness
subjects affected / exposed	0 / 49 (0.00%)	1 / 114 (0.88%)	2 / 52 (3.85%)	3 / 57 (5.26%)	0 / 55 (0.00%)
occurrences all number	0	1	2	3	0
Psychiatric disorders
Mood swings
subjects affected / exposed	2 / 49 (4.08%)	2 / 114 (1.75%)	2 / 52 (3.85%)	2 / 57 (3.51%)	5 / 55 (9.09%)
occurrences all number	2	2	2	2	6
Infections and infestations
Nasopharyngitis
subjects affected / exposed	4 / 49 (8.16%)	8 / 114 (7.02%)	1 / 52 (1.92%)	1 / 57 (1.75%)	3 / 55 (5.45%)
occurrences all number	5	8	1	1	4
Urinary tract infection
subjects affected / exposed	0 / 49 (0.00%)	5 / 114 (4.39%)	1 / 52 (1.92%)	4 / 57 (7.02%)	0 / 55 (0.00%)
occurrences all number	0	5	1	5	0
Bronchitis
subjects affected / exposed	0 / 49 (0.00%)	1 / 114 (0.88%)	1 / 52 (1.92%)	3 / 57 (5.26%)	0 / 55 (0.00%)
occurrences all number	0	1	1	3	0

More information

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Were there any global substantial amendments to the protocol? Yes

25 Nov 2016

• Addition of an optional treatment extension phase. • Change in inclusion criterion: most recent surgical diagnosis was increased from 7 to 10 years. • Change in inclusion criterion: e-Diary completion compliance limit was reduced from 80% to 75% during the screening period.

21 Apr 2017

• OATP1B1/1B3 inhibitors were prohibited during the treatment period. • The potential induction of CYP3A4 by linzagolix previously reported in Section 6.6.1 was removed. • Additional guidance was provided in the case of withdrawal from study during the first 4 weeks of treatment: Subjects should undergo the procedures required at Week 24 visit except the DXA. • Change in inclusion criterion: the lower limit of BMI ≥18 kg/m2 was included, upper limit was removed.

03 Aug 2017

• Clarification on sexual abstinence, as a birth control method (inclusion criteria for the main study and extension phase). • The washout period for the depot contraceptive, medroxyprogesterone acetate, was extended from 6 to 10 months. • Change in exclusion criterion for the extension phase: Subjects found to have had a BMD loss of >7% at any anatomic site or a Z-score ≤ -2.5 are to be excluded from the extension study. • Change in discontinuation criteria related to BMD loss: Subjects found to have a BMD loss of more than 7% at any anatomic site or a Z-score ≤ -2.5 should be discontinued from the study.

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

Clinical Trial Results:
A randomized, double-blind, placebo-controlled, phase 2b dose-ranging study to assess the efficacy and safety of OBE2109 in subjects with endometriosis associated pain.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: 30% or Greater Reduction from Baseline to Week 12 in Mean Overall Pelvic Pain Score (0-3 VRS)

Primary: 30% or Greater Reduction from Baseline to Week 12 in Mean Overall Pelvic Pain Score (0-3 VRS)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: A randomized, double-blind, placebo-controlled, phase 2b dose-ranging study to assess the efficacy and safety of OBE2109 in subjects with endometriosis associated pain.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: 30% or Greater Reduction from Baseline to Week 12 in Mean Overall Pelvic Pain Score (0-3 VRS)

Primary: 30% or Greater Reduction from Baseline to Week 12 in Mean Overall Pelvic Pain Score (0-3 VRS)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A randomized, double-blind, placebo-controlled, phase 2b dose-ranging study to assess the efficacy and safety of OBE2109 in subjects with endometriosis associated pain.