SPIRIT 2: Efficacy and Safety Study of Relugolix in Women With Endometriosis-Associated Pain

• Sponsor: Myovant Sciences GmbH (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03204331
• Collaborator: (none)
• Enrollment: 623
• Locations: 91
• Arms: 3
• Actual Duration (Months): 42.9
• Patients Per Site: 6.8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the benefit and safety of relugolix 40 milligrams (mg) once daily, co-administered with low-dose estradiol (E2) and norethindrone acetate (NETA) compared with placebo for 24 weeks, on dysmenorrhea and on nonmenstrual pelvic pain.

Condition or Disease	Intervention/Treatment	Phase
Endometriosis Related Pain	Drug: Relugolix; Drug: Estradiol/norethindrone acetate; Drug: Estradiol/norethindrone acetate placebo; Drug: Relugolix placebo	Phase 3

Detailed Description

This study is an international phase 3 randomized, double-blind, placebo-controlled efficacy and safety study to evaluate 24 weeks of oral, once-daily relugolix (40 mg) co-administered with either 12 or 24 weeks of low-dose E2 (1.0 mg) and NETA (0.5 mg), compared with placebo.

Approximately 600 women with endometriosis-associated pain were enrolled and randomized 1:1:1 to Group A - relugolix plus low-dose hormonal add-back therapy, Group B - relugolix monotherapy for 12 weeks followed by co-administration with low-dose hormonal add-back therapy, or Group C - placebo (N = 200 per group).

Eligible participants were randomized on Baseline Day 1 to Treatment Group A, B, or C, in the double-blind period.

Eligible participants, including those randomized to placebo, were offered the opportunity to enroll in an 80-week open label extension study where participants received relugolix co-administered with low-dose E2 and NETA. Participants who did not enroll into the extension study had a Follow-Up visit approximately 30 days after the participant's last dose of study drug.

Study Design

• Study Type: Interventional
• Actual Enrollment: 623 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: SPIRIT 2: An International Phase 3 Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study to Evaluate Relugolix Administered With and Without Low-Dose Estradiol and Norethindrone Acetate in Women With Endometriosis-Associated Pain
• Actual Study Start Date: Nov 1, 2017
• Actual Primary Completion Date: Apr 1, 2020
• Actual Study Completion Date: May 31, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Relugolix plus E2/NETA (Group A) Relugolix co-administered with E2/NETA for 24 weeks.	Drug: Relugolix; Relugolix 40-mg tablet administered orally once daily.; Other Names: TAK-385 MVT-601 ; Drug: Estradiol/norethindrone acetate; Capsule containing co-formulated tablet of E2 (1.0 mg)/NETA (0.5 mg) administered orally once daily.; Other Names: E2/NETA
Experimental: Relugolix plus Delayed E2/NETA (Group B) Relugolix co-administered with E2/NETA placebo for 12 weeks, followed by relugolix co-administered with E2/NETA for 12 weeks.	Drug: Relugolix; Relugolix 40-mg tablet administered orally once daily.; Other Names: TAK-385 MVT-601 ; Drug: Estradiol/norethindrone acetate; Capsule containing co-formulated tablet of E2 (1.0 mg)/NETA (0.5 mg) administered orally once daily.; Other Names: E2/NETA ; Drug: Estradiol/norethindrone acetate placebo; E2 (0 mg)/NETA (0 mg) placebo capsule administered orally once daily and designed to match the E2/NETA capsule in size, shape, color, and odor.
Placebo Comparator: Placebo (Group C) Relugolix placebo co-administered with E2/NETA placebo for 24 weeks.	Drug: Estradiol/norethindrone acetate placebo; E2 (0 mg)/NETA (0 mg) placebo capsule administered orally once daily and designed to match the E2/NETA capsule in size, shape, color, and odor.; Drug: Relugolix placebo; Relugolix (0 mg) placebo tablet administered orally once daily and manufactured to match the relugolix tablet in size, shape, color, and odor.

Outcome Measures

Primary Outcome Measures

1. Percentage Of Participants Who Meet The Dysmenorrhea Responder Criteria At Week 24 Or End Of Treatment (EOT) [Week 24 or EOT]

   Assessed using a Numerical Rating Scale (NRS) score (11-point scale) for pain recorded daily in an electronic diary (e-Diary). The criteria for a responder was based on a pre-defined threshold and accounted for analgesic use.

2. Percentage Of Participants Who Meet The Non-Menstrual Pelvic Pain (NMPP) Responder Criteria At Week 24 Or EOT [Week 24 or EOT]

   Assessed using an NRS score (11-point scale) for pain recorded daily in an e-Diary. The criteria for a responder was based on a pre-defined threshold and accounted for analgesic use.

Secondary Outcome Measures

1. Change From Baseline In The Endometriosis Health Profile (EHP)-30 Pain Score At Week 24 [Baseline, Week 24]

   Assessed using the Pain Domain of the EHP-30 questionnaire.

2. Change From Baseline In Dysmenorrhea NRS Score At Week 24 Or EOT [Baseline, Week 24 or EOT]

   Assessed using an NRS score (11-point scale) for pain recorded daily in an e-Diary.

3. Change From Baseline In NMPP NRS Score At Week 24 Or EOT [Baseline, Week 24 or EOT]

   Assessed using an NRS score (11-point scale) for pain recorded daily in an e-Diary.

4. Change From Baseline In Overall Pelvic Pain NRS Score At Week 24 Or EOT [Baseline, Week 24 or EOT]

   Assessed using an NRS score (11-point scale) for pain recorded daily in an e-Diary.

5. Change From Baseline In Dyspareunia NRS Scores At Week 24 Or EOT [Baseline, Week 24 or EOT]

   Assessed using an NRS score (11-point scale) for dyspareunia recorded daily in an e-Diary.

6. Percentage Of Participants Who Are Not Using Opioids For Endometriosis-associated Pain At Week 24 Or EOT [Week 24 or EOT]

   Assessed based on usage of protocol-specified opioids for endometriosis-associated pain recorded daily in an e-Diary.

7. Change From Baseline In Analgesic Use For Endometriosis-associated Pain Based On Mean Pill Count At Week 24 Or EOT [Baseline, Week 24 or EOT]

   Assessed based on usage of protocol-specified analgesic for endometriosis-associated pain recorded daily in an e-Diary.

8. Percentage Of Participants Who Have A Reduction Of At Least 20 Points In The EHP-30 Pain Domain From Baseline To Week 24 [Baseline to Week 24]

   Assessed using the pain domain of the EHP-30 questionnaire.

9. Dysmenorrhea Responder Rate By Month [Baseline to Week 24]

   The criteria for a responder was based on a pre-defined threshold and accounted for analgesic use.

10. NMPP Responder Rate By Month [Baseline to Week 24]

    The criteria for a responder was based on a pre-defined threshold and accounted for analgesic use.

11. Change In Dysmenorrhea NRS Score By Month [Baseline to Week 24]

    Assessed using an NRS score (11-point scale) for pain recorded daily in an e-Diary.

12. Change In NMPP NRS Score By Month [Baseline to Week 24]

    Assessed using an NRS score (11-point scale) for pain recorded daily in an e-Diary.

13. Change In Overall Pelvic Pain NRS Score By Month [Baseline to Week 24]

    Assessed using an NRS score (11-point scale) for pain recorded daily in an e-Diary.

14. Change In Dyspareunia NRS Score By Month [Baseline to Week 24]

    Assessed using an NRS score (11-point scale) for pain recorded daily in an e-Diary.

15. Change From Baseline In Ibuprofen Use At Week 24 Or EOT [Baseline, Week 24]

    Assessed using ibuprofen pill counts for endometriosis-associated pain recorded daily in an e-Diary.

16. Change From Baseline In Opioid Use At Week 24 Or EOT [Baseline, Week 24]

    Assessed using opioid pill counts for endometriosis-associated pain recorded daily in an e-Diary.

17. Change From Baseline In The Mean Dysmenorrhea Functional Impairment At Week 24 Or EOT [Baseline, Week 24 or EOT]

    Assessed using the subject modified Biberoglu and Behrman 5-point scale for dysmenorrhea recorded daily in an e-Diary.

18. Change From Baseline In The Mean NMPP Functional Impairment At Week 24 Or EOT [Baseline, Week 24 or EOT]

    Assessed using the subject modified Biberoglu and Behrman 4-point scale for pelvic pain recorded daily in an e-Diary.

19. Change From Baseline In The Mean Dyspareunia Functional Impairment At Week 24 Or EOT [Baseline, Week 24 or EOT]

    Assessed using the subject modified Biberoglu and Behrman 5-point scale for dyspareunia recorded daily in an e-Diary.

20. Change From Baseline In Patient Global Assessment (PGA) For Dysmenorrhea Symptom Severity At Week 24 [Baseline, Week 24]

    The PGA for dysmenorrhea is a 1-item questionnaire designed to assess participants' impression of the severity of pain during their menstrual cycle.

21. Percentage Of Participants With Improvement, No Change, Or Worsening From Baseline In PGA For Dysmenorrhea At Week 24 [Week 24]

    The PGA for dysmenorrhea is a 1-item questionnaire designed to assess participants' impression of the severity of pain during their menstrual cycle.

22. Change From Baseline In PGA For NMPP Symptom Severity At Week 24 [Baseline, Week 24]

    The PGA for NMPP is a 1-item questionnaire designed to assess participants' impression of the severity of pain when they are not menstruating.

23. Percentage Of Participants With Improvement, No Change, Or Worsening From Baseline In PGA For NMPP At Week 24 [Week 24]

    The PGA for NMPP is a 1-item questionnaire designed to assess participants' impression of the severity of pain when they are not menstruating.

24. Change From Baseline In PGA For Pain Severity At Week 24 [Baseline, Week 24]

    The PGA for pain severity is a 1-item questionnaire designed to assess participants' impression of how their pain affected their usual activities.

25. Percentage Of Participants With Improvement, No Change, Or Worsening From Baseline In PGA For Pain Severity At Week 24 [Week 24]

    The PGA for pain severity is a 1-item questionnaire designed to assess participants' impression of how their pain affected their usual activities.

26. Change From Baseline In PGA For Function At Week 24 [Baseline, Week 24]

    The PGA for function is a 1-item questionnaire designed to assess participants' impression of how their pain affected their usual activities.

27. Percentage Of Participants With Improvement, No Change, Or Worsening From Baseline In PGA For Function At Week 24 [Week 24]

    The PGA for function is a 1-item questionnaire designed to assess participants' impression of how their pain affected their usual activities.

28. Percentage Of Participants Who Are "Better" Or "Much Better" On The Patient Global Impression Of Change (PGIC) For Dysmenorrhea At Week 24 [Week 24]

    The PGIC for dysmenorrhea is a 1-item questionnaire designed to assess participants' impression of change in the severity of pain during their menstrual cycle.

29. Percentage Of Participants Who Are "Better" Or "Much Better" On The PGIC For NMPP At Week 24 [Week 24]

    The PGIC for NMPP is a 1-item questionnaire designed to assess participants' impression of change in the severity of pain during their menstrual cycle.

30. Percentage Of Participants Who Are "Better" Or "Much Better" On The PGIC For Dyspareunia At Week 24 [Week 24]

    The PGIC for dyspareunia is a 1-item questionnaire designed to assess participants' impression of change in the severity of pain during sexual intercourse.

31. Change From Baseline In The Non-Pain Of The EHP-30 Domains At Week 24 [Baseline, Week 24]

    Assessed using the non-pain domains (Control and Powerlessness, Social Support, Emotional Well-Being, and Self-Image) of the EHP-30 questionnaire.

32. Change From Baseline In The EHP-30 Scale Total Score At Week 24 [Baseline, Week 24]

    Assessed using the total score of the EHP-30 questionnaire.

33. Change From Baseline In The EHP Work Domain Score At Week 24 [Baseline, Week 24]

    The EHP Work domain is a 5-item questionnaire that assesses impact of pain on ability to work.

34. Categorical Change From Baseline In Quality Of Life Assessed By European Quality Of Life Five Dimension Five Level (EQ-5D-5L) Questionnaire At Week 24 [Baseline, Week 24]

    The EQ-5D-5L is a 5-item questionnaire designed to assess quality of life.

35. Change From Baseline To Week 24 In EQ-5D-5L Visual Analogue Scale Score At Week 24 [Baseline, Week 24]

    The EQ-5D-5L is a 5-item questionnaire designed to assess quality of life.

36. Percentage Of Participants Who Meet The Dysmenorrhea Responder Criteria At Week 24 Or EOT For Relugolix Plus Delayed E2/NETA [Week 24 or EOT]

    Assessed using an NRS score (11-point scale) for pain recorded daily in an e-Diary. The criteria for a responder was based on a pre-defined threshold and accounted for analgesic use.

37. Percentage Of Participants Who Meet The NMPP Responder Criteria At Week 24 Or EOT For Relugolix Plus Delayed E2/NETA [Week 24 or EOT]

    Assessed using an NRS score (11-point scale) for pain recorded daily in an e-Diary. The criteria for a responder was based on a pre-defined threshold and accounted for analgesic use.

38. Change From Baseline In The EHP-30 Pain Score At Week 24 For Relugolix Plus Delayed E2/NETA [Baseline, Week 24]

    Assessed using the Pain Domain of the EHP-30 questionnaire.

39. Percentage Of Participants Who Have A Reduction Of At Least 20 Points In The EHP-30 Pain Domain From Baseline To Week 24 For Relugolix Plus Delayed E2/NETA [Baseline to Week 24]

    Assessed using the pain domain of the EHP-30 questionnaire.

40. Percentage Change From Baseline In Bone Mineral Density At The Lumbar Spine (L1-L4) At Week 12 [Baseline, Week 12]

    Assessed by dual-energy X-ray absorptiometry (DXA) scan.

41. Percentage Change From Baseline In Bone Mineral Density At Lumbar Spine (L1-L4), Femoral Neck, And Total Hip At Week 24 [Baseline, Week 24]

    Assessed by DXA scan.

42. Percentage Of Participants Experiencing Vasomotor Symptoms At Week 12 Between Group A And B [Week 12]

43. Change From Baseline In Serum Concentrations Of Luteinizing Hormone, Follicle Stimulating Hormone, Estradiol, And Progesterone [Baseline, Week 24]

    Blood samples will be collected from participants for hormonal measurements.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

1. Is a premenopausal female aged 18 to 50 years old (inclusive) on the day of signing of the informed consent form.

2. Has agreed to use only study-specified analgesic medications during the study and is not known to be intolerant to these.

3. Has a diagnosis of endometriosis and has had, within 10 years prior to signing the informed consent form, surgical or direct visualization and/or histopathologic confirmation of endometriosis, for example, during a laparoscopy or laparotomy.

4. During the Run-In Period (35 to 70 days prior to treatment period) has a dysmenorrhea NRS score ≥ 4.0 on at least 2 days and

5. Mean NMPP NRS score ≥ 2.5, or

6. Mean NMPP NRS score ≥ 1.25 and NMPP NRS score ≥ 5.0 on ≥ 4 days.

Key Exclusion Criteria:

1. Has a history of chronic pelvic pain that is not caused by endometriosis.

2. Has any chronic pain or frequently recurring pain condition, other than endometriosis that is treated with opioids or requires analgesics for ≥ 7 days per month.

3. Has had surgical procedures for treatment of endometriosis within the 3 months prior to the Screening visit.

4. Has a history of or currently has osteoporosis or other metabolic bone disease.

5. Has a clinically significant gynecologic condition, other than endometriosis, identified during Screening or Run-In period transvaginal ultrasound or endometrial biopsy.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Andalusia	Andalusia	Alabama	United States	36420
2	Washington DC	Washington	District of Columbia	United States	20036
3	Aventura	Aventura	Florida	United States	33180
4	Deland	DeLand	Florida	United States	32720
5	Hialeah	Hialeah	Florida	United States	33012
6	Hialeah	Hialeah	Florida	United States	33016
7	Margate	Margate	Florida	United States	33063
8	Miami	Miami	Florida	United States	33176
9	Port St. Lucie	Port Saint Lucie	Florida	United States	34952
10	Tampa	Tampa	Florida	United States	33606
11	Atlanta	Atlanta	Georgia	United States	30312
12	Idaho Falls	Idaho Falls	Idaho	United States	83404
13	Park Ridge	Park Ridge	Illinois	United States	60068
14	Lafayette	Lafayette	Indiana	United States	47905
15	Covington	Covington	Louisiana	United States	70433
16	Marrero	Marrero	Louisiana	United States	70072
17	Towson	Towson	Maryland	United States	21204
18	Saginaw	Saginaw	Michigan	United States	48602
19	St. Louis	Saint Louis	Missouri	United States	63141
20	Omaha	Omaha	Nebraska	United States	68124
21	Albuquerque	Albuquerque	New Mexico	United States	87102
22	New York	New York	New York	United States	10038
23	New Bern	New Bern	North Carolina	United States	28562
24	Akron	Akron	Ohio	United States	44313
25	Columbus	Columbus	Ohio	United States	43231
26	Columbus	Columbus	Ohio	United States	43235
27	Franklin	Franklin	Ohio	United States	45005
28	Columbia	Columbia	South Carolina	United States	29201
29	Spartanburg	Spartanburg	South Carolina	United States	29301
30	Chattanooga	Chattanooga	Tennessee	United States	37404
31	Beaumont	Beaumont	Texas	United States	77702
32	Corpus Christi	Corpus Christi	Texas	United States	78412
33	Dallas	Dallas	Texas	United States	75231
34	Fort Worth	Fort Worth	Texas	United States	76104
35	Houston	Houston	Texas	United States	77054
36	Irving	Irving	Texas	United States	75062
37	San Antonio	San Antonio	Texas	United States	78258
38	Sugar Land	Sugar Land	Texas	United States	77479
39	Pleasant Grove	Pleasant Grove	Utah	United States	84062
40	Salt Lake City	Salt Lake City	Utah	United States	84102
41	Virginia Beach	Virginia Beach	Virginia	United States	23502
42	Sydney	Sydney	New South Wales	Australia	2000
43	Wollongong	Wollongong	New South Wales	Australia	2522
44	Sherwood	Sherwood	Queensland	Australia	4075
45	Adelaide	Adelaide	South Australia	Australia	5000
46	Nedlands	Nedlands	Western Australia	Australia	6009
47	Passo Fundo	Passo Fundo	RIO Grande DO SUL	Brazil	99010-080
48	Porto Alegre	Porto Alegre	Rio Grande Do Sul	Brazil	90430-001
49	Porto Alegre	Porto Alegre	RIO Grande DO SUL	Brazil	90510-040
50	Porto Alegre	Porto Alegre	RIO Grande DO SUL	Brazil	90610-000
51	Porto Alegre	Porto Alegre	SAO Paulo	Brazil	90035-903
52	São Bernardo do Campo	São Bernardo do Campo	SAO Paulo	Brazil	09715-090
53	São Paulo	São Paulo	SAO Paulo	Brazil	01317-000
54	São Paulo	São Paulo	SAO Paulo	Brazil	01323-900
55	São Paulo	São Paulo	SAO Paulo	Brazil	04023-062
56	São Paulo	São Paulo	SAO Paulo	Brazil	04266-010
57	São Paulo	São Paulo	SAO Paulo	Brazil	04708-001
58	Santiago	Santiago		Chile	7510186
59	Santiago	Santiago		Chile	8320165
60	Santiago	Santiago		Chile	8360160
61	Santiago	Santiago		Chile	8880465
62	Písek	Písek	Jihocesky KRAJ	Czechia	39701
63	Tábor	Tábor	Jihormoravsky KRAJ	Czechia	390 03
64	Praha 2	Praha 2	Praha	Czechia	128 08
65	Ceské Budejovice	České Budějovice		Czechia	370 01
66	Tbilisi	Tbilisi	Borjomi	Georgia	0159
67	Monserrato	Monserrato	Cagliari	Italy	09042
68	Catanzaro	Catanzaro		Italy	88100
69	Napoli	Napoli		Italy	80131
70	Pavia	Pavia		Italy	27100
71	Roma	Roma		Italy	00168
72	Birkenhead	Birkenhead	Auckland	New Zealand	0626
73	Remuera	Remuera	Auckland	New Zealand	1050
74	Tauranga	Tauranga	Bay Of Plenty	New Zealand	3112
75	Palmerston North	Palmerston North	Manawatu-wanganui	New Zealand	4442
76	Christchurch	Christchurch		New Zealand	8013
77	Lodz	Łódź	Lodzkie	Poland	90-602
78	Lublin	Lublin	Lubelskie	Poland	20-064
79	Lublin	Lublin	Lubelskie	Poland	20-093
80	Warszawa	Warszawa	Mazowieckie	Poland	02-066
81	Warszawa	Warszawa	Mazowieckie	Poland	02-201
82	Warszawa	Warszawa	Mazowieckie	Poland	02-929
83	Bialystok	Bialystok	Podlaskie	Poland	15-224
84	Białystok	Białystok	Podlaskie	Poland	15-464
85	Katowice	Katowice	Slaskie	Poland	40-301
86	Poznan	Poznan	Wielkopolskie	Poland	60-185
87	București	București	Bucuresti	Romania	20475
88	Brasov	Brasov		Romania	500091
89	Bucuresti	Bucuresti		Romania	012071
90	Bucuresti	Bucuresti		Romania	022441
91	Malmö	Malmö	Skane	Sweden	20502

Sponsors and Collaborators

• Myovant Sciences GmbH

Investigators

• Study Director: Myovant Medical Monitor, Myovant Sciences

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Myovant Sciences GmbH
• ClinicalTrials.gov Identifier: NCT03204331
• Other Study ID Numbers: MVT-601-3102; 2017-001632-19
• First Posted: Jul 2, 2017
• Last Update Posted: Jun 28, 2021
• Last Verified: Jun 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Myovant Sciences GmbH: Endometriosis; Pain; Dysmenorrhea
• Additional relevant MeSH terms: Endometriosis; Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Norethindrone; Norethindrone Acetate; Estradiol; Polyestradiol phosphate; Relugolix

Study Results

No Results Posted as of Jun 28, 2021