MUSIC: Macitentan Use in an Idiopathic Pulmonary Fibrosis Clinical Study

• Sponsor: Actelion (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00903331
• Collaborator: (none)
• Enrollment: 178
• Locations: 53
• Arms: 2
• Duration (Months): 27
• Patients Per Site: 3.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The AC-055B201/MUSIC study is a Phase II study, comparing one dose of ACT-064922 (macitentan) 10 mg with placebo in patients with idiopathic pulmonary fibrosis (IPF). The main study objective is to demonstrate that macitentan positively affects the forced vital capacity (FVC) in comparison with placebo in patients with idiopathic pulmonary fibrosis (IPF).

The secondary objectives are to evaluate the effect of macitentan on the time to disease worsening or death in patients with IPF, and to evaluate the benefit/risk profile of macitentan in the treatment of patients with IPF.

Condition or Disease	Intervention/Treatment	Phase
Idiopathic Pulmonary Fibrosis	Drug: ACT-064992 (macitentan); Drug: Placebo	Phase 2

Detailed Description

The study included two treatment periods: Period 1 (fixed duration) from randomization up to the primary endpoint evaluation (Month 12 or earlier in case of premature discontinuation of study drug) and Period 2 (variable duration) from the primary endpoint evaluation visit up to the end of study (EOS). EOS occurred when the last patient randomized and not prematurely discontinued completed Period 1.

Study Design

• Study Type: Interventional
• Actual Enrollment: 178 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Double-blind, Randomized, Placebo-controlled, Multicenter, Parallel Group Study to Evaluate the Efficacy, Safety, and Tolerability of Macitentan in Patients With Idiopathic Pulmonary Fibrosis
• Study Start Date: May 1, 2009
• Actual Primary Completion Date: Jun 1, 2011
• Actual Study Completion Date: Aug 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ACT-064922 ACT-064922 tablet (macitentan), 10 mg, once daily	Drug: ACT-064992 (macitentan); ACT-064992 (macitentan) tablet, 10 mg, once daily; Other Names: macitentan
Placebo Comparator: Placebo Matching placebo, once daily	Drug: Placebo; matching placebo, once daily

Outcome Measures

Primary Outcome Measures

1. Forced Vital Capacity (FVC) at Baseline and End of Period 1 [12 months]

   FVC was measured at baseline and at the end of Period 1. The same equipment and tester were used during the course of the study. The equipment was calibrated and the calibration documented prior to each patient's measurement. The person responsible for conducting the pulmonary function tests was required to comply with the study guidelines and the American Thoracic Society/European Respiratory Society joint criteria on lung function testing.

Secondary Outcome Measures

1. Number of Patients at Risk of Event of Disease Worsening or Death up to the End of Study [Up to end of study (Up to 24 months)]

   Disease worsening was indicated by pulmonary function test/idiopathic pulmonary fibrosis worsening (PFT/IPF) or acute respiratory decompensation of IPF. PFT/IPF worsening was indicated by the occurrence of both of the following: confirmed by two tests at least 4 weeks apart, as defined by the occurrence of both of the following: decrease from baseline ≥ 10% in forced vital capacity and decrease from baseline ≥ 15% in corrected diffusing capacity of the lung for carbon monoxide. Acute respiratory decompensation of IPF was defined as an unexplained rapid deterioration (over a period of less than 4 weeks) of the patient's condition with increasing shortness of breath requiring oxygen supplementation ≥ 5 L/min to maintain a resting oxygen saturation ≥ 90% or arterial oxygen pressure ≥ 55 mmHg (sea level) or 50 mmHg (high altitude).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Signed informed consent.

2. Male or female patients of at least 18 years of age (females of child-bearing potential must use a reliable method of contraception).

3. IPF diagnosis within 3 years prior to randomization, proven according to the American Thoracic Society/European Respiratory Society consensus conference criteria, with surgical lung biopsy.

Exclusion Criteria:

1. Interstitial lung disease due to conditions other than IPF.

2. Presence of extensive honeycombing on Baseline high-resolution computed tomography (HRCT) scan performed within 3 months prior to randomization.

3. Severe concomitant illness limiting life expectancy (< 1 year).

4. Severe restrictive lung disease: forced vital capacity (FVC) < 50% predicted, or FVC < 1.2 liter.

5. Diffusing capacity of the lung for carbon monoxide (DLCO) < 30% predicted.

6. Residual volume ≥ 120% predicted.

7. Obstructive lung disease: forced expiratory volume in 1 second (FEV1)/FVC) < 0.70.

8. Documented sustained improvement of the patient's IPF condition up to 12 months prior to randomization with or without IPF-specific therapy.

9. Recent pulmonary or upper respiratory tract infection (up to 4 weeks prior to randomization).

10. Acute or chronic impairment (other than dyspnea) limiting the ability to comply with study requirements (e.g., pulmonary function tests).

11. Chronic heart failure with New York Heart Association class III/IV or known left ventricular ejection fraction < 25%.

12. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C.

13. Estimated creatinine clearance < 30 mL/min.

14. Aspartate aminotransferase (AST) and/or alanine aminotransferase > 1.5 x upper limit of normal.

15. Hemoglobin < 75% of the lower limit of the normal range.

16. Systolic blood pressure < 100 mmHg.

17. Pregnant or breast-feeding.

18. Current drug or alcohol dependence.

19. Chronic treatment with the following drugs (within 4 weeks of randomization):

• Oral corticosteroids (> 20 mg/day of prednisone or equivalent),

• Immunosuppressive or cytotoxic drugs including cyclophosphamide and azathioprine,

• Antifibrotic drugs including pirfenidone, D penicillamine, colchicine, tumor necrosis factor α blockers, imatinib and interferon γ,

• Chronic use of N-acetylcysteine prescribed for IPF (> 600 mg/day).

• Oral anticoagulants prescribed for IPF.

1. Treatment with endothelin receptor antagonists within 4 weeks prior to randomization.

2. Systemic treatment within 4 weeks prior to randomization with cyclosporine A or tacrolimus, everolimus, sirolimus (calcineurin or mammalian target of rapamycin (mTOR) inhibitors).

3. Treatment with Cytochrome P450 3A inducers within 4 weeks prior to randomization.

4. Known hypersensitivity to drugs of the same class as the study drug, or any of their excipients.

5. Planned treatment, or treatment with another investigational drug within 4 weeks prior to randomization.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
2	Pulmonary Associates, P.A.	Phoenix	Arizona	United States	85006
3	Mayo Clinic - Arizona	Scottsdale	Arizona	United States	85259
4	U.C. Davis University of California	Sacramento	California	United States	95817
5	UCSD Pulmonary Critical Care	San Diego	California	United States	92103
6	University of California - San Francisco	San Francisco	California	United States	94143
7	Stanford University Medical Center - Chest Clinic	Stanford	California	United States	94305
8	National Jewish Medical & Research Center	Denver	Colorado	United States	80206
9	Yale University School of Medicine	New Haven	Connecticut	United States	06520
10	Wichita Clinic P.A	Wichita	Kansas	United States	67208
11	St. Luke's Medical Group	Chesterfield	Missouri	United States	63017
12	The Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
13	Temple University Hospital - Lung Center	Philadelphia	Pennsylvania	United States	19140
14	Baylor College of Medicine - Baylor Clinic	Houston	Texas	United States	77030
15	University of Wisconsin - Madison	Madison	Wisconsin	United States	53792
16	Prince Charles Hospital Lung Transplant	Chermside		Australia
17	St. Vincent's Public Hospital	Darlinghurst		Australia
18	The Alfred Hospital	Melbourne		Australia
19	Royal Perth Hospital	Perth		Australia
20	University of Alberta - Health Sciences Center	Edmonton	Alberta	Canada	T6G2B7
21	Kelowna General Hospital	Kelowna	British Columbia	Canada	V1W3T1
22	St. Paul's Hospital	Vancouver	British Columbia	Canada	V6Z1Y6
23	St. Joseph's Healthcare	Hamilton	Ontario	Canada	L8N4A6
24	Toronto General Hospital	Toronto	Ontario	Canada	M5G2N2
25	Hospital Notre-Dame du CHUM	Montreal	Quebec	Canada	H2L4M1
26	Hopital Avicenne	Bobigny		France
27	Hôpital Cardiologique et Pneumologique Louis Pradel	Bron		France
28	CHRU - Hopital Calmette Clinique des Maladies Respiratoires	Lille		France
29	Helios Klinikum Emil von Behring	Berlin		Germany
30	Justus-Liebig-Universität Gießen	Giessen		Germany
31	Fachklinik fur Lungenerkrankungen	Immenhausen		Germany
32	Universität zu Köln	Koln		Germany
33	Ludwig-Maximilian-Universität München	Munchen		Germany
34	Hadassah Ein Kerem Medical Center	Jerusalem		Israel
35	Rabin Medical Center, Beilinson Hospital	Petach Tikvah		Israel
36	Kaplan Medical Center	Rehovot		Israel
37	Tel-Aviv Sourasky Medical Center	Tel Aviv		Israel
38	The Chaim Sheba Medical Center	Tel Hashomer		Israel
39	Ospedale San Giuseppe Milanocuore	Milan		Italy
40	Università degli Studi di Torino Clinica di Malattie dell'Apparato Respiratorio	Orbassano		Italy
41	A.O.U Policlinico Tor Vergata	Roma		Italy
42	Ospedale di Cattinara	Trieste		Italy
43	Bolnišnica Golnik	Golnik		Slovenia
44	Centre for Chest Diseases, Milpark Hospital	Johannesburg		South Africa
45	Pretoria East Hospital	Pretoria		South Africa
46	Hospital Clinic I Provincial de Barcelona	Barcelona		Spain
47	Hospital General Vall d'Hebron	Barcelona		Spain
48	Fundación Hospital Alcorcón	Madrid		Spain
49	Hospital Clinico San Carlos	Madrid		Spain
50	Hospital Universitario Ramón y Cajal	Madrid		Spain
51	Karolinska Universitetssjukhuset Lung Allergi kliniken	Stockholm		Sweden
52	Ankara University School of Medicine	Ankara		Turkey
53	Ege University School of Medicine	Izmir		Turkey

Sponsors and Collaborators

• Actelion

Investigators

• Study Chair: Loic Perchenet, Ph.D., Actelion

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Actelion
• ClinicalTrials.gov Identifier: NCT00903331
• Other Study ID Numbers: AC-055B201
• First Posted: May 18, 2009
• Last Update Posted: Feb 17, 2014
• Last Verified: Jan 1, 2014

• Keywords provided by Actelion: idiopathic pulmonary fibrosis; MUSIC
• Additional relevant MeSH terms: Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Fibrosis; Macitentan

Study Results

Participant Flow

Recruitment Details	The study was conducted at 48 centers in Australia, Canada, France, Germany, Israel, Italy, Slovenia, South Africa, Spain, Sweden, Turkey, and the USA.
Pre-assignment Detail	The study included a screening period of up to 28 days followed by a double-blind treatment phase that was further divided into two periods. 300 patients were screened and 178 randomized in a 2:1 ratio to study treatment with ACT-064922 or placebo

Arm/Group Title	Placebo	ACT-064922
Arm/Group Description	Matching placebo, once daily Placebo : matching placebo, once daily	ACT-064922 tablet, 10 mg, once daily ACT-064992 (macitentan) : tablet, 10 mg, once daily
Period Title: Overall Study
STARTED	59	119
COMPLETED	54	101
NOT COMPLETED	5	18

Baseline Characteristics

Arm/Group Title	Placebo	ACT-064922	Total
Arm/Group Description	Matching placebo, once daily Placebo : matching placebo, once daily	ACT-064922 tablet, 10 mg, once daily ACT-064992 (macitentan) : tablet, 10 mg, once daily	Total of all reporting groups
Overall Participants	59	119	178
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.5 (6.32)	65.1 (7.85)	64.9 (7.37)
Sex: Female, Male (Count of Participants)
Female	22 37.3%	35 29.4%	57 32%
Male	37 62.7%	84 70.6%	121 68%
Region of Enrollment (participants) [Number]
Australia	9 15.3%	18 15.1%	27 15.2%
Canada	5 8.5%	10 8.4%	15 8.4%
France	10 16.9%	16 13.4%	26 14.6%
Germany	5 8.5%	8 6.7%	13 7.3%
Israel	2 3.4%	5 4.2%	7 3.9%
Italy	1 1.7%	7 5.9%	8 4.5%
Slovenia	1 1.7%	1 0.8%	2 1.1%
South Africa	1 1.7%	1 0.8%	2 1.1%
Spain	4 6.8%	7 5.9%	11 6.2%
Sweden	0 0%	1 0.8%	1 0.6%
Turkey	3 5.1%	8 6.7%	11 6.2%
United States	18 30.5%	37 31.1%	55 30.9%

Outcome Measures

1. Primary Outcome

Title	Forced Vital Capacity (FVC) at Baseline and End of Period 1
Description	FVC was measured at baseline and at the end of Period 1. The same equipment and tester were used during the course of the study. The equipment was calibrated and the calibration documented prior to each patient's measurement. The person responsible for conducting the pulmonary function tests was required to comply with the study guidelines and the American Thoracic Society/European Respiratory Society joint criteria on lung function testing.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

All randomized patients

Arm/Group Title	Placebo	ACT-064922
Arm/Group Description	Matching placebo, once daily Placebo : matching placebo, once daily	ACT-064922 tablet, 10 mg, once daily ACT-064992 (macitentan) : tablet, 10 mg, once daily
Measure Participants	59	119
Baseline	2.74 (0.776)	2.83 (0.834)
End of Period 1	2.40 (0.918)	2.57 (1.012)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, ACT-064922
	Comments	The null hypothesis was that there was no difference between ACT-064922 and placebo for the change in FVC from baseline to the end of Period 1. The aim was to detect a placebo-corrected change in FVC of ≥ 0.1 L (Standard Deviation = 0.2 L) at a two-sided 0.05 type 1 error level and 80% power.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9631
	Comments
	Method	Wilcoxon Rank Sum
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 95%; -0.09 to 0.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Patients at Risk of Event of Disease Worsening or Death up to the End of Study
Description	Disease worsening was indicated by pulmonary function test/idiopathic pulmonary fibrosis worsening (PFT/IPF) or acute respiratory decompensation of IPF. PFT/IPF worsening was indicated by the occurrence of both of the following: confirmed by two tests at least 4 weeks apart, as defined by the occurrence of both of the following: decrease from baseline ≥ 10% in forced vital capacity and decrease from baseline ≥ 15% in corrected diffusing capacity of the lung for carbon monoxide. Acute respiratory decompensation of IPF was defined as an unexplained rapid deterioration (over a period of less than 4 weeks) of the patient's condition with increasing shortness of breath requiring oxygen supplementation ≥ 5 L/min to maintain a resting oxygen saturation ≥ 90% or arterial oxygen pressure ≥ 55 mmHg (sea level) or 50 mmHg (high altitude).
Time Frame	Up to end of study (Up to 24 months)

Outcome Measure Data

Analysis Population Description

All randomized patients

Arm/Group Title	Placebo	ACT-064922
Arm/Group Description	Matching placebo, once daily Placebo : matching placebo, once daily	ACT-064922 tablet, 10 mg, once daily ACT-064992 (macitentan) : tablet, 10 mg, once daily
Measure Participants	59	119
Patients at Risk of Event at Month 4	59 100%	112 94.1%
Patients at Risk of Event at Month 8	57 96.6%	103 86.6%
Patients at Risk of Event at Month 12	44 74.6%	81 68.1%
Patients at Risk of Event at Month 16	22 37.3%	43 36.1%
Patients at Risk of Event at Month 20	8 13.6%	14 11.8%
Patients at Risk of Event at Month 24	2 3.4%	1 0.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, ACT-064922
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7056
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.118
	Confidence Interval	(2-Sided) 95%; 0.626 to 1.996
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Up to 28 days after treatment discontinuation, approximately 2 years
Arm/Group Title	Placebo		ACT-064922
Arm/Group Description	Matching placebo, once daily Placebo : matching placebo, once daily		ACT-064922 tablet, 10 mg, once daily ACT-064992 (macitentan) : tablet, 10 mg, once daily
All Cause Mortality
	Placebo		ACT-064922
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		ACT-064922
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/59 (33.9%)		37/119 (31.1%)
Blood and lymphatic system disorders
THROMBOCYTOPENIA	0/59 (0%)		2/119 (1.7%)
Cardiac disorders
ANGINA PECTORIS	1/59 (1.7%)		1/119 (0.8%)
ACUTE MYOCARDIAL INFARCTION	0/59 (0%)		1/119 (0.8%)
ARTERIOSPASM CORONARY	0/59 (0%)		1/119 (0.8%)
ATRIAL FLUTTER	0/59 (0%)		1/119 (0.8%)
CORONARY ARTERY DISEASE	0/59 (0%)		1/119 (0.8%)
DIASTOLIC DYSFUNCTION	0/59 (0%)		1/119 (0.8%)
ANGINA UNSTABLE	1/59 (1.7%)		0/119 (0%)
CARDIAC ARREST	1/59 (1.7%)		0/119 (0%)
SINUS BRADYCARDIA	1/59 (1.7%)		0/119 (0%)
Gastrointestinal disorders
GASTRIC MUCOSAL HYPERTROPHY	0/59 (0%)		1/119 (0.8%)
HIATUS HERNIA	0/59 (0%)		1/119 (0.8%)
SMALL INTESTINAL OBSTRUCTION	0/59 (0%)		1/119 (0.8%)
UMBILICAL HERNIA	0/59 (0%)		1/119 (0.8%)
VOMITING	1/59 (1.7%)		0/119 (0%)
General disorders
CHEST PAIN	0/59 (0%)		1/119 (0.8%)
DEVICE MALFUNCTION	0/59 (0%)		1/119 (0.8%)
HERNIA OBSTRUCTIVE	0/59 (0%)		1/119 (0.8%)
PYREXIA	0/59 (0%)		1/119 (0.8%)
Hepatobiliary disorders
CHOLELITHIASIS	1/59 (1.7%)		1/119 (0.8%)
Immune system disorders
ALLERGY TO ARTHROPOD BITE	0/59 (0%)		1/119 (0.8%)
Infections and infestations
PNEUMONIA	2/59 (3.4%)		6/119 (5%)
LOWER RESPIRATORY TRACT INFECTION	2/59 (3.4%)		1/119 (0.8%)
COMMUNITY ACQUIRED INFECTION	0/59 (0%)		1/119 (0.8%)
LOWER RESPIRATORY TRACT INFECTION BACTERIAL	0/59 (0%)		1/119 (0.8%)
Injury, poisoning and procedural complications
CYSTITIS RADIATION	0/59 (0%)		1/119 (0.8%)
INCISIONAL HERNIA	0/59 (0%)		1/119 (0.8%)
LACERATION	0/59 (0%)		1/119 (0.8%)
POST PROCEDURAL HAEMORRHAGE	0/59 (0%)		1/119 (0.8%)
JOINT DISLOCATION	1/59 (1.7%)		0/119 (0%)
SNAKE BITE	1/59 (1.7%)		0/119 (0%)
TRAUMATIC BRAIN INJURY	1/59 (1.7%)		0/119 (0%)
Metabolism and nutrition disorders
FLUID RETENTION	0/59 (0%)		1/119 (0.8%)
Musculoskeletal and connective tissue disorders
PAIN IN EXTREMITY	0/59 (0%)		1/119 (0.8%)
BACK PAIN	1/59 (1.7%)		0/119 (0%)
OSTEONECROSIS	1/59 (1.7%)		0/119 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
HEAD AND NECK CANCER	0/59 (0%)		1/119 (0.8%)
MALIGNANT MEDIASTINAL NEOPLASM	0/59 (0%)		1/119 (0.8%)
MYELODYSPLASTIC SYNDROME	0/59 (0%)		1/119 (0.8%)
RECTAL CANCER	0/59 (0%)		1/119 (0.8%)
SQUAMOUS CELL CARCINOMA	0/59 (0%)		1/119 (0.8%)
LUNG NEOPLASM	1/59 (1.7%)		0/119 (0%)
LUNG SQUAMOUS CELL CARCINOMA STAGE UNSPECIFIED	1/59 (1.7%)		0/119 (0%)
Nervous system disorders
CEREBROVASCULAR ACCIDENT	0/59 (0%)		1/119 (0.8%)
TRANSIENT ISCHAEMIC ATTACK	0/59 (0%)		1/119 (0.8%)
DIZZINESS	1/59 (1.7%)		0/119 (0%)
PARAESTHESIA	1/59 (1.7%)		0/119 (0%)
Renal and urinary disorders
RENAL FAILURE ACUTE	0/59 (0%)		1/119 (0.8%)
Respiratory, thoracic and mediastinal disorders
IDIOPATHIC PULMONARY FIBROSIS	6/59 (10.2%)		10/119 (8.4%)
RESPIRATORY FAILURE	2/59 (3.4%)		4/119 (3.4%)
HYPOXIA	2/59 (3.4%)		3/119 (2.5%)
ACUTE RESPIRATORY FAILURE	1/59 (1.7%)		2/119 (1.7%)
PULMONARY EMBOLISM	2/59 (3.4%)		1/119 (0.8%)
ACUTE RESPIRATORY DISTRESS SYNDROME	0/59 (0%)		1/119 (0.8%)
PNEUMONIA ASPIRATION	0/59 (0%)		1/119 (0.8%)
HAEMOPTYSIS	1/59 (1.7%)		0/119 (0%)
PLEURAL EFFUSION	1/59 (1.7%)		0/119 (0%)
PULMONARY ARTERIAL HYPERTENSION	1/59 (1.7%)		0/119 (0%)
PULMONARY HYPERTENSION	1/59 (1.7%)		0/119 (0%)
Skin and subcutaneous tissue disorders
SKIN HAEMORRHAGE	0/59 (0%)		1/119 (0.8%)
Surgical and medical procedures
INTESTINAL OPERATION	0/59 (0%)		1/119 (0.8%)
MALIGNANT TUMOUR EXCISION	0/59 (0%)		1/119 (0.8%)
SKIN LESION EXCISION	0/59 (0%)		1/119 (0.8%)
HIP ARTHROPLASTY	2/59 (3.4%)		0/119 (0%)
Vascular disorders
AORTIC ANEURYSM	1/59 (1.7%)		1/119 (0.8%)
HYPOTENSION	0/59 (0%)		1/119 (0.8%)
HYPERTENSION	1/59 (1.7%)		0/119 (0%)
WEGENER'S GRANULOMATOSIS	1/59 (1.7%)		0/119 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		ACT-064922
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	57/59 (96.6%)		114/119 (95.8%)
Blood and lymphatic system disorders
ANAEMIA	0/59 (0%)		13/119 (10.9%)
Cardiac disorders
ANGINA PECTORIS	3/59 (5.1%)		3/119 (2.5%)
MITRAL VALVE INCOMPETENCE	3/59 (5.1%)		2/119 (1.7%)
Ear and labyrinth disorders
VERTIGO	3/59 (5.1%)		1/119 (0.8%)
Gastrointestinal disorders
NAUSEA	2/59 (3.4%)		9/119 (7.6%)
DIARRHOEA	5/59 (8.5%)		8/119 (6.7%)
CONSTIPATION	3/59 (5.1%)		5/119 (4.2%)
GASTROOESOPHAGEAL REFLUX DISEASE	4/59 (6.8%)		1/119 (0.8%)
General disorders
OEDEMA PERIPHERAL	4/59 (6.8%)		14/119 (11.8%)
CHEST PAIN	3/59 (5.1%)		7/119 (5.9%)
FATIGUE	2/59 (3.4%)		6/119 (5%)
PYREXIA	5/59 (8.5%)		3/119 (2.5%)
ASTHENIA	4/59 (6.8%)		1/119 (0.8%)
Infections and infestations
UPPER RESPIRATORY TRACT INFECTION	12/59 (20.3%)		20/119 (16.8%)
BRONCHITIS	9/59 (15.3%)		16/119 (13.4%)
LOWER RESPIRATORY TRACT INFECTION	5/59 (8.5%)		7/119 (5.9%)
Investigations
PULMONARY FUNCTION TEST DECREASED	5/59 (8.5%)		9/119 (7.6%)
ALANINE AMINOTRANSFERASE INCREASED	4/59 (6.8%)		9/119 (7.6%)
ASPARTATE AMINOTRANSFERASE INCREASED	4/59 (6.8%)		8/119 (6.7%)
WEIGHT DECREASED	2/59 (3.4%)		6/119 (5%)
Metabolism and nutrition disorders
DIABETES MELLITUS	3/59 (5.1%)		2/119 (1.7%)
Musculoskeletal and connective tissue disorders
ARTHRALGIA	2/59 (3.4%)		6/119 (5%)
BACK PAIN	6/59 (10.2%)		3/119 (2.5%)
NECK PAIN	4/59 (6.8%)		2/119 (1.7%)
Nervous system disorders
DIZZINESS	5/59 (8.5%)		11/119 (9.2%)
HEADACHE	8/59 (13.6%)		7/119 (5.9%)
Psychiatric disorders
INSOMNIA	3/59 (5.1%)		8/119 (6.7%)
Respiratory, thoracic and mediastinal disorders
DYSPNOEA	9/59 (15.3%)		24/119 (20.2%)
COUGH	21/59 (35.6%)		22/119 (18.5%)
IDIOPATHIC PULMONARY FIBROSIS	10/59 (16.9%)		17/119 (14.3%)
Skin and subcutaneous tissue disorders
RASH	3/59 (5.1%)		4/119 (3.4%)
Vascular disorders
HYPERTENSION	5/59 (8.5%)		4/119 (3.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only 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 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.