Trial Outcomes & Findings for Phase 3 Study of MAP0004 in Adult Migraineurs (NCT NCT00623636)

Last Updated: 2014-01-09

Results Overview

Pain relief at 2 hours was defined as change in rating from severe or moderate (score 3 or 2) to a rating of none or mild (score 0 or 1) at the 2-hour time point and no usage of rescue medications from the time of first dose to 2 hours. The 4-point scale from the International Headache Society was used: 0 = none; 1 = mild symptom, not interfering with normal daily activities; 2 = moderate symptom, causing some restriction to normal activities; 3 = severe, leading to inability to perform daily activities

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

902 participants

Primary outcome timeframe

2 hours from time of first dose

Results posted on

2014-01-09

Participant Flow

This study included a Double-blind period for 8 weeks followed by an open-label period that lasted an additional 52 weeks. All patients participating in the open-label period received MAP0004.

Participant milestones

Participant milestones
Measure	Placebo Placebo 1.0mg inhaled to treat a qualifying migraine up to 8 weeks followed by MAP0004 1.0mg inhaled to treat a qualifying migraine for up to an additional 52 weeks.	MAP0004 MAP0004 1.0mg inhaled to treat a qualifying migraine up to 8 weeks followed by MAP0004 1.0mg inhaled to treat qualifying migraines for up to an additional 52 weeks.
Double Blind STARTED	452	450
Double Blind COMPLETED	419	422
Double Blind NOT COMPLETED	33	28
Open Label STARTED	0	675
Open Label COMPLETED	0	263
Open Label NOT COMPLETED	0	412

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Phase 3 Study of MAP0004 in Adult Migraineurs

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=397 Participants Placebo 1.0mg inhaled to treat a qualifying migraine up to 8 weeks followed by MAP0004 1.0mg inhaled to treat a qualifying migraine for up to an additional 52 weeks.	MAP0004 n=397 Participants MAP0004 1.0mg inhaled to treat a qualifying migraine up to 8 weeks followed by MAP0004 1.0mg inhaled to treat qualifying migraines for up to an additional 52 weeks.	Total n=794 Participants Total of all reporting groups
Age, Continuous	39.6 years STANDARD_DEVIATION 11.67 • n=5 Participants	40.5 years STANDARD_DEVIATION 11.30 • n=7 Participants	40.1 years STANDARD_DEVIATION 11.49 • n=5 Participants
Sex: Female, Male Female	362 Participants n=5 Participants	365 Participants n=7 Participants	727 Participants n=5 Participants
Sex: Female, Male Male	35 Participants n=5 Participants	32 Participants n=7 Participants	67 Participants n=5 Participants

PRIMARY outcome

Timeframe: 2 hours from time of first dose

Population: mITT population was defined as all randomized subjects who reported a qualifying migraine and received at least one dose of study treatment, and had at least one post-treatment efficacy evaluation.

Outcome measures

Outcome measures
Measure	Placebo n=397 Participants Placebo 1.0mg inhaled to treat a qualifying migraine up to 8 weeks followed by MAP0004 1.0mg inhaled to treat a qualifying migraine for up to an additional 52 weeks.	MAP0004 n=397 Participants MAP0004 1.0mg inhaled to treat a qualifying migraine up to 8 weeks followed by MAP0004 1.0mg inhaled to treat qualifying migraines for up to an additional 52 weeks.
Number of Subjects With Pain Relief at 2 Hours From Time of First Dose	136 participants	231 participants

PRIMARY outcome

Timeframe: 2 hours from time of first dose

Photophobia free at 2 hours was defined as a rating of none (score 0) at the 2-hour time point and no usage of rescue medications from the time of first dose to 2 hours. The 4-point scale from the International Headache Society was used: 0 = none; 1 = mild symptom, not interfering with normal daily activities; 2 = moderate symptom, causing some restriction to normal activities; 3 = severe, leading to inability to perform daily activities

Outcome measures

Outcome measures
Measure	Placebo n=397 Participants Placebo 1.0mg inhaled to treat a qualifying migraine up to 8 weeks followed by MAP0004 1.0mg inhaled to treat a qualifying migraine for up to an additional 52 weeks.	MAP0004 n=397 Participants MAP0004 1.0mg inhaled to treat a qualifying migraine up to 8 weeks followed by MAP0004 1.0mg inhaled to treat qualifying migraines for up to an additional 52 weeks.
Number of Subjects Photophobia Free at 2 Hours From Time of First Dose	107 participants	182 participants

PRIMARY outcome

Timeframe: 2 hours from time of first dose

Phonophobia free at 2 hours was defined as a rating of none (score 0) at the 2-hour time point and no usage of rescue medications from the time of first dose to 2 hours. The 4-point scale from the International Headache Society was used: 0 = none; 1 = mild symptom, not interfering with normal daily activities; 2 = moderate symptom, causing some restriction to normal activities; 3 = severe, leading to inability to perform daily activities

Outcome measures

Outcome measures
Measure	Placebo n=397 Participants Placebo 1.0mg inhaled to treat a qualifying migraine up to 8 weeks followed by MAP0004 1.0mg inhaled to treat a qualifying migraine for up to an additional 52 weeks.	MAP0004 n=397 Participants MAP0004 1.0mg inhaled to treat a qualifying migraine up to 8 weeks followed by MAP0004 1.0mg inhaled to treat qualifying migraines for up to an additional 52 weeks.
Number of Subjects Phonophobia Free at 2 Hours From Time of First Dose	133 participants	208 participants

PRIMARY outcome

Timeframe: 2 hours from time of first dose

Nausea free was defined as a rating of none (score 0) at the 2-hour time point and no usage of rescue medications from the time of first dose to 2 hours post-dose. The 4-point scale from the International Headache Society was used: 0 = none; 1 = mild symptom, not interfering with normal daily activities; 2 = moderate symptom, causing some restriction to normal activities; 3 = severe, leading to inability to perform daily activities

Outcome measures

Outcome measures
Measure	Placebo n=397 Participants Placebo 1.0mg inhaled to treat a qualifying migraine up to 8 weeks followed by MAP0004 1.0mg inhaled to treat a qualifying migraine for up to an additional 52 weeks.	MAP0004 n=397 Participants MAP0004 1.0mg inhaled to treat a qualifying migraine up to 8 weeks followed by MAP0004 1.0mg inhaled to treat qualifying migraines for up to an additional 52 weeks.
Number of Subjects Nausea Free at 2 Hours From Time of First Dose	234 participants	266 participants

SECONDARY outcome

Timeframe: From 2 to 24 hours from time of first dose

Sustained Pain Relief was defined as a rating of none or mild (score 0 or 1) at the 2-hour time point that was maintained during the 2-24 hour post-dose period and no use of rescue medication from the time of first dose to 24 hours. The 4-point scale from the International Headache Society was used: 0 = none; 1 = mild symptom, not interfering with normal daily activities; 2 = moderate symptom, causing some restriction to normal activities; 3 = severe, leading to inability to perform daily activities

Outcome measures

Outcome measures
Measure	Placebo n=397 Participants Placebo 1.0mg inhaled to treat a qualifying migraine up to 8 weeks followed by MAP0004 1.0mg inhaled to treat a qualifying migraine for up to an additional 52 weeks.	MAP0004 n=397 Participants MAP0004 1.0mg inhaled to treat a qualifying migraine up to 8 weeks followed by MAP0004 1.0mg inhaled to treat qualifying migraines for up to an additional 52 weeks.
Number of Subjects With Sustained Pain Relief From 2 to 24 Hours	76 participants	166 participants

SECONDARY outcome

Timeframe: 2 hours from the first dose

The number of subjects who reported pain relief (score of 0 or 1) at any time within the 2 hours following the time of first dose and who did not use rescue medication on or prior to this point. Subjects who did not reach pain relief by the end of the time period were not included. The 4-point scale from the International Headache Society was used: 0 = none; 1 = mild symptom, not interfering with normal daily activities; 2 = moderate symptom, causing some restriction to normal activities; 3 = severe, leading to inability to perform daily activities

Outcome measures

Outcome measures
Measure	Placebo n=397 Participants Placebo 1.0mg inhaled to treat a qualifying migraine up to 8 weeks followed by MAP0004 1.0mg inhaled to treat a qualifying migraine for up to an additional 52 weeks.	MAP0004 n=397 Participants MAP0004 1.0mg inhaled to treat a qualifying migraine up to 8 weeks followed by MAP0004 1.0mg inhaled to treat qualifying migraines for up to an additional 52 weeks.
Number of Subjects Whose Time to Pain Relief Occurred Within 2 Hours	156 participants	244 participants

SECONDARY outcome

Timeframe: 4 hours from time of first dose

Pain Relief at 4 hours was defined as a change in rating from severe or moderate (score 3 or 2) to none or mild (score 0 or 1) at the 4-hour time point and no use of rescue medication from the time of first dose to 4 hours. The 4-point scale from the International Headache Society was used: 0 = none; 1 = mild symptom, not interfering with normal daily activities; 2 = moderate symptom, causing some restriction to normal activities; 3 = severe, leading to inability to perform daily activities

Outcome measures

Outcome measures
Measure	Placebo n=397 Participants Placebo 1.0mg inhaled to treat a qualifying migraine up to 8 weeks followed by MAP0004 1.0mg inhaled to treat a qualifying migraine for up to an additional 52 weeks.	MAP0004 n=397 Participants MAP0004 1.0mg inhaled to treat a qualifying migraine up to 8 weeks followed by MAP0004 1.0mg inhaled to treat qualifying migraines for up to an additional 52 weeks.
Number of Subjects With Pain Relief at 4 Hours	145 participants	254 participants

SECONDARY outcome

Timeframe: 2 hours from time of first dose

Pain Relief at 10 minutes was defined as a change in rating from severe or moderate (score 3 or 2) to none or mild (score 0 or 1) at the 10 minute time point and no use of rescue medication from the time of first dose to 2 hours. The 4-point scale from the International Headache Society was used: 0 = none; 1 = mild symptom, not interfering with normal daily activities; 2 = moderate symptom, causing some restriction to normal activities; 3 = severe, leading to inability to perform daily activities

Outcome measures

Outcome measures
Measure	Placebo n=397 Participants Placebo 1.0mg inhaled to treat a qualifying migraine up to 8 weeks followed by MAP0004 1.0mg inhaled to treat a qualifying migraine for up to an additional 52 weeks.	MAP0004 n=397 Participants MAP0004 1.0mg inhaled to treat a qualifying migraine up to 8 weeks followed by MAP0004 1.0mg inhaled to treat qualifying migraines for up to an additional 52 weeks.
Number of Subjects With Pain Relief at 10 Minutes	30 participants	37 participants

Adverse Events

Double-blind Placebo

Serious events: 0 serious events

Other events: 60 other events

Deaths: 0 deaths

Double-blind MAP0004

Serious events: 0 serious events

Other events: 86 other events

Deaths: 0 deaths

Open-label MAP0004

Serious events: 14 serious events

Other events: 454 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Double-blind Placebo n=404 participants at risk Placebo 1.0mg inhaled to treat a qualifying migraine up to 8 weeks followed by MAP0004 1.0mg inhaled to treat a qualifying migraine for up to an additional 52 weeks.	Double-blind MAP0004 n=410 participants at risk MAP0004 1.0mg inhaled to treat a qualifying migraine up to 8 weeks followed by MAP0004 1.0mg inhaled to treat qualifying migraines for up to an additional 52 weeks.	Open-label MAP0004 n=638 participants at risk MAP0004 1.0mg inhaled to treat a qualifying migraine for up to an additional 52 weeks.
Social circumstances Pharmaceutical Product Compaint	2.7% 11/404 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	6.1% 25/410 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	8.0% 51/638 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.
Gastrointestinal disorders Nausea	1.7% 7/404 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	4.4% 18/410 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	12.2% 78/638 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.
Gastrointestinal disorders Vomiting	0.74% 3/404 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	2.0% 8/410 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	5.2% 33/638 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.
Infections and infestations Upper Respiratory Tract Infection	3.0% 12/404 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	2.7% 11/410 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	14.6% 93/638 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.
Infections and infestations Sinusitis	1.2% 5/404 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.73% 3/410 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	10.2% 65/638 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.
Infections and infestations Nasopharyngitis	3.7% 15/404 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	2.0% 8/410 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	10.5% 67/638 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.
Infections and infestations Influenza	0.00% 0/404 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.73% 3/410 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	5.5% 35/638 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.
Respiratory, thoracic and mediastinal disorders Cough	1.7% 7/404 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	2.4% 10/410 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	5.0% 32/638 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.

Additional Information

VP, Scientific Affairs

MAP Pharmaceuticals Inc., a wholly owned subsidiary of Allergan

Phone: 650-386-3100

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee A disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 90 days from the time submitted to the sponsor for review. The sponsor cannot require changes to the communication and cannot extend the embargo.
Publication restrictions are in place

Restriction type: OTHER

Measure	Double-blind Placebo n=404 participants at risk Placebo 1.0mg inhaled to treat a qualifying migraine up to 8 weeks followed by MAP0004 1.0mg inhaled to treat a qualifying migraine for up to an additional 52 weeks.	Double-blind MAP0004 n=410 participants at risk MAP0004 1.0mg inhaled to treat a qualifying migraine up to 8 weeks followed by MAP0004 1.0mg inhaled to treat qualifying migraines for up to an additional 52 weeks.	Open-label MAP0004 n=638 participants at risk MAP0004 1.0mg inhaled to treat a qualifying migraine for up to an additional 52 weeks.
Blood and lymphatic system disorders Aplastic anemia	0.00% 0/404 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.00% 0/410 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.16% 1/638 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.
Cardiac disorders Acute myocardial infarction	0.00% 0/404 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.00% 0/410 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.16% 1/638 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.
Gastrointestinal disorders Inguinal hernia	0.00% 0/404 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.00% 0/410 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.16% 1/638 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.
Gastrointestinal disorders Rectal haemorrhage	0.00% 0/404 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.00% 0/410 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.16% 1/638 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.
Gastrointestinal disorders Umbilical hernia	0.00% 0/404 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.00% 0/410 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.16% 1/638 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.
Infections and infestations Gastroenteritis	0.00% 0/404 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.00% 0/410 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.16% 1/638 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.
Infections and infestations Appendicitis	0.00% 0/404 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.00% 0/410 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.16% 1/638 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.
Infections and infestations Septic shock	0.00% 0/404 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.00% 0/410 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.16% 1/638 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.
Injury, poisoning and procedural complications Decompression sickness	0.00% 0/404 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.00% 0/410 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.16% 1/638 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.
Injury, poisoning and procedural complications Testicular injury	0.00% 0/404 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.00% 0/410 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.16% 1/638 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.
Metabolism and nutrition disorders Hypokalaemia	0.00% 0/404 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.00% 0/410 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.16% 1/638 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.
Musculoskeletal and connective tissue disorders Muscular weakness	0.00% 0/404 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.00% 0/410 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.16% 1/638 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer female	0.00% 0/404 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.00% 0/410 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.16% 1/638 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.
Nervous system disorders Encephalopathy	0.00% 0/404 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.00% 0/410 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.16% 1/638 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.
Pregnancy, puerperium and perinatal conditions Pregnancy	0.00% 0/404 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.00% 0/410 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.16% 1/638 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.
Psychiatric disorders Suicide attempt	0.00% 0/404 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.00% 0/410 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.31% 2/638 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.
Renal and urinary disorders Nephrolithiasis	0.00% 0/404 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.00% 0/410 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.16% 1/638 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.
Reproductive system and breast disorders Menorrhagia	0.00% 0/404 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.00% 0/410 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.16% 1/638 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.
Reproductive system and breast disorders Uterine haemorrhage	0.00% 0/404 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.00% 0/410 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.16% 1/638 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/404 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.00% 0/410 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.	0.16% 1/638 All subjects who received any dose of study treatment in the double-blind or open-label study period and had at least one post-dose safety evaluation were included in the adverse events analysis.