ORCHESTRA: A Pulmonary Arterial Hypertension Study With Macitentan to Validate the PAH-SYMPACT™ in France, Italy and Spain

• Sponsor: Actelion (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02081690
• Collaborator: (none)
• Enrollment: 160
• Locations: 39
• Arm: 1
• Actual Duration (Months): 20
• Patients Per Site: 4.1
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

Prospective, multi-center, open-label, single-arm, Phase 3b psychometric validation study.

Primary objectives: To evaluate the psychometric characteristics of reliability and construct validity of the French, Italian and Spanish versions of the PAH-SYMPACT™.

To evaluate the ability of the French, Italian and Spanish versions of the PAH SYMPACT™ to detect change.

Secondary objective: To assess the safety of macitentan in patients with pulmonary arterial hypertension (PAH).

Exploratory objective: To explore the effects of macitentan on PAH symptoms and their impact (as measured by the PAH-SYMPACT™) in patients with PAH in France, Italy and Spain.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Arterial Hypertension	Drug: Macitentan	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 160 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multi-center, Open-label, Single-arm, Phase 3b Study of Macitentan in Patients With Pulmonary Arterial Hypertension to Psychometrically Validate the French, Italian and Spanish Versions of the PAH-SYMPACT™
• Actual Study Start Date: Mar 1, 2014
• Actual Primary Completion Date: Oct 1, 2015
• Actual Study Completion Date: Nov 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Macitentan Macitentan tablet, dose of 10 mg, once daily	Drug: Macitentan; Macitentan tablet, dose of 10 mg, once daily

Outcome Measures

Primary Outcome Measures

1. Evaluation of the Reliability and the Construct Validity of the Cardiopulmonary Symptoms Domain of the PAH-SYMPACT [From Screening Visit (Visit 1) to End of Treatment (EOT) Visit (Visit 4, Week 16)]

   The Cardiopulmonary Symptoms domain consists of 6 items reported on a 5-point Likert scale (from 0 to 4). The value 0 means "no symptom" and value 4 corresponds to "very severe symptoms".The symptoms part of the PAH-SYMPACT was administered daily over a 7 day period. The recall period of symptom items is the last 24 hours. An average Cardiopulmonary Symptoms domain score is determined based on the daily scores of the 6 items. It was administered two times (daily during 7 days each time) prior to administration of Macitentan (Visit 2, Baseline) and daily during the 7-day period in the treatment period prior to Visit 3 (Week 8) and Visit 4 (Week 16).

2. Evaluation of the Reliability and the Construct Validity of the Cardiovascular Symptoms Domain of the PAH-SYMPACT [From Screening Visit (Visit 1) to End of Treatment (EOT) Visit (Visit 4, Week 16)]

   The Cardiovascular Symptoms domain consists of 5 items reported on a 5-point Likert scale (from 0 to 4). The value 0 corresponds to "no symptoms" and value 4 corresponds to "very severe symptoms". The symptoms part of the PAH-SYMPACT was administered daily over a 7 day period. The recall period of symptom items is the last 24 hours. An average Cardiovascular Symptoms domain score is determined based on the daily scores of the 5 items. It was administered two times (daily during 7 days each time) prior to administration of Macitentan (Visit 2, Baseline) and daily during the 7-day period in the treatment period prior to Visit 3 (Week 8) and Visit 4 (Week 16).

3. Evaluation of the Reliability and the Construct Validity of the Physical Impacts Domain of the PAH-SYMPACT [From Screening Visit (Visit 1) to End of Treatment (EOT) Visit (Visit 4, Week 16)]

   The Physical Impacts domain consists of 7 items reported on a 5-point Likert scale (from 0 to 4). The value 0 corresponds to "not at all"/"with no difficulty at all" and value 4 corresponds to "very much"/"extremely"/ "not able at all". The impacts part of the PAH-SYMACT was administered on Day 7 of the symptoms part administration. Items in the impact part have a 7 day recall period. An average Physical Impacts domain score is determined based on the 7 items in the domain. It was administered two times prior to administration of Macitentan (Visit 2, Baseline) and during the 7-day period in the treatment period prior to Visit 3 (Week 8) and Visit 4 (Week 16).

4. Evaluation of the Reliability and the Construct Validity of the Cognitive/Emotional Impacts Domain of the PAH-SYMPACT [From Screening Visit (Visit 1) to End of Treatment (EOT) Visit (Visit 4, Week 16)]

   The Cognitive/Emotional Impacts domain consists of 4 items reported on a 5-point Likert scale (from 0 to 4). The value 0 corresponds to "not at all"/"with no difficulty at all" and value 4 corresponds to "very much"/"extremely"/ "not able at all". The impacts part of the PAH-SYMACT was administered on Day 7 of the symptoms part administration. Items in the impact part have a 7 day recall period. An average Cognitive/Emotional Impacts domain score is determined based on the 4 items in the domain. It was administered two times prior to administration of Macitentan (Visit 2, Baseline) and during the 7-day period in the treatment period prior to Visit 3 (Week 8) and Visit 4 (Week 16)."

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Signed informed consent prior to initiation of any study-mandated procedure.

2. Patients with symptomatic PAH in WHO Functional Class (FC) II or III.

3. Patients with PAH belonging to one of the following subgroups of the Dana Point

Clinical Classification Group 1:

1. Idiopathic, or,

2. Heritable, or,

3. Drug or toxin induced, or,

4. Associated with one of the following:

1. Connective tissue disease, ii. Congenital heart disease with simple systemic-to-pulmonary shunt at least 1 year after surgical repair, iii. HIV infection.

1. Documented hemodynamic diagnosis of PAH by right heart catheterization - performed at any time prior to Screening showing:

2. Resting mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg and,

3. Resting pulmonary vascular resitance (PVR) > 240 dyn.s.cm-5 and,

4. Pulmonary capillary wede pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) ≤ 15 mmHg.

5. 6-minute walk distance (6MWD) ≥ 150 m at Screening.

6. Able to fluently speak and read the local language.

7. Men or women aged 18-80; women of childbearing potential (as defined below) must:

8. Have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Baseline and agree to perform monthly serum pregnancy tests, and,

9. Agree to use two reliable methods of contraception in parallel, from Screening Visit 1 until 1 month after study drug discontinuation (see details below).

• A female is considered to have childbearing potential unless she meets at least one of the following criteria:

• Previous bilateral salpingo and/or oophorectomy, or hysterectomy.

• Premature ovarian failure confirmed by a specialist.

• Pre-pubescence, XY genotype, Turner syndrome, uterine agenesis.

• Postmenopausal, defined as 12 consecutive months with no menses without an alternative medical cause.

• Of the two contraceptive methods that must be used, one must be from Group 1, and one must be from Group 2, defined as follows:

• Group 1: Oral, implantable, transdermal or injectable hormonal contraceptives, intrauterine devices, female sterilization (tubal ligation or non surgical sterilization, e.g., permanent contraception with Essure procedure), or partner's sterilization (vasectomy). If a hormonal contraceptive is chosen from this group, it must be taken for at least 1 month prior to enrollment. Alternatively, if the Essure procedure is chosen as a contraceptive method, a hysterosalpingogram must have been performed to confirm correct location of the microinserts and tubal occlusion (as per manufacturer's recommendations).

• Group 2: Female or male condoms, diaphragm or cervical cap, any of them in combination with a spermicide.

• Sexual abstinence, rhythm methods, or contraception by the partner alone are not considered as acceptable methods of contraception for this study.

Exclusion Criteria:

1. Known moderate-to-severe obstructive lung disease (i.e., forced expiratory volume in one second [FEV1] < 80 % of predicted, with FEV1 / forced vital capacity [FVC] < 70%) or known significant chronic lung disease diagnosed by chest imaging (e.g., interstitial lung disease, emphysema).

2. Known moderate-to-severe restrictive lung disease (i.e., total lung capacity [TLC] < 60% of predicted value).

3. Hemoglobin < 100g/L at Screening.

4. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 3 X upper limit of the normal range (ULN) at Screening.

5. Patients undergoing dialysis.

6. Systolic blood pressure (SBP) < 90 mmHg at Screening.

7. Body weight < 40 kg at Screening.

8. Known concomitant life-threatening diseases with a life expectancy of < 12 months.

9. Treatment with ERAs within 3 months prior to Visit 2, or scheduled to receive any of these compounds, other than macitentan, during the trial.

10. Treatment with intravenous or subcutaneous prostacyclin or prostacyclin analogs within 3 months prior to Visit 2, or scheduled to receive any of these compounds during the trial.

11. Treatment with soluble guanylate cyclase stimulator (riociguat) within 3 months prior to Visit 2, or scheduled to receive riociguat during the trial.

12. Patients who changed the dose of or discontinued phosphodiesterase type-5 inhibitor (PDE5i), inhaled prostacyclin analogues, or calcium channel blockers within 3 months prior to Visit 2.

13. Initiation of diuretics within 1 week prior to the Baseline period.

14. Patients on oral diuretics in whom the dose has not been stable for at least 1 week prior to the Baseline period.

15. Treatment with cytochrome P4500 (CYP) 3A inducers within 4 weeks prior to Visit 2.

16. Recently started (< 8 weeks prior to Visit 2) or planned cardio-pulmonary rehabilitation program based on exercise.

17. Females who are lactating or pregnant (positive Screening or Baseline pregnancy test) or plan to become pregnant during the study.

18. Known hypersensitivity to macitentan or its excipients or drugs of the same class.

19. Treatment with another investigational drug within 3 months prior to Visit 2.

20. Any known factor or disease that might interfere with treatment compliance, study conduct or interpretation of the results such as drug or alcohol dependence or psychiatric disease.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hôpital de Haut Levêque	Bordeaux		France	33604
2	Hôpital Côte de Nacre	Caen		France	14033
3	Hôpital Albert Michallon	Grenoble		France	38700
4	CHU de Bicêtre	Le Kremlin-Bicêtre		France	94270
5	CHRU Lille - Hôpital Cardiologique	Lille		France	59037
6	Hôpital Louis Pradel	Lyon		France	69677
7	Hôpital Arnaud de Villeneuve	Montpellier		France	34295
8	Hôpitaux de Brabois	Nancy		France	54511
9	Hôpital Pontchaillou	Rennes		France	35033
10	Hôpital Charles Nicolle	Rouen		France	76031
11	Hôpital Nord	Saint-Etienne		France	42227
12	Hôpital Civil	Strasbourg		France	67091
13	Hôpital Larrey	Toulouse		France	31059
14	Universita degli Studi di Bari	Bari		Italy	70124
15	Ospedale di Venere	Bari		Italy	70131
16	Ospedale Sant'Orsola	Bologna		Italy	40138
17	A.O.U.C. Careggi	Firenze		Italy	50124
18	Milan Sacco Hospital	Milan		Italy	20157
19	AORN Azienda Ospedaliera dei Colli	Naples		Italy	80131
20	Ambulatorio Scompenso Cardiaco e Trapiant	Pavia		Italy	27100
21	Istituto di Fisiologia clinica - CNR	Pisa		Italy	56126
22	Centro Per La Diagnosi E La Cura Dell'Ipertensione Polmonare	Roma		Italy	00186
23	UOC Immunologia Clinica B-PGRM Centro di Riferimento per la Sclerosi Sistemica	Rome		Italy	00161
24	Ospedale "S. Maria di Cà Foncello"	Treviso		Italy	31100
25	Policlinico G.B. Rossi	Verona		Italy	37134
26	Hospital Universitario Insular Gran Canarias	Las Palmas de Gran Canaria	Islas Canarias	Spain	35016
27	Hospital General de Alicante	Alicante		Spain	03010
28	Hospital Val Hebron	Barcelona		Spain	08035
29	Hospital Clinic	Barcelona		Spain	08036
30	Hospital de Cruces	Bilbao		Spain	48903
31	Hospital Reina Sofia	Córdoba		Spain	14004
32	Hospital Dr Negrin	Las Palmas de Gran Canaria		Spain	35010
33	Hospital 12 Octubre	Madrid		Spain	28041
34	Hospital La Paz	Madrid		Spain	28046
35	Hospital Carlos Haya	Malaga		Spain	29010
36	Hospital Son Espases	Palma de Mallorca		Spain	7010
37	Hospital de Valdecilla	Santander		Spain	39008
38	Hospital Virgen del Rocio	Sevilla		Spain	41013
39	Hospita General U. Valencia	Valencia		Spain	46014

Sponsors and Collaborators

• Actelion

Investigators

• Study Director: Loïc Perchene, Actelion

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Actelion
• ClinicalTrials.gov Identifier: NCT02081690
• Other Study ID Numbers: AC-055-310
• First Posted: Mar 7, 2014
• Last Update Posted: Mar 21, 2018
• Last Verified: Feb 1, 2018

• Keywords provided by Actelion: PAH-SYMPACT; psychometric instrument
• Additional relevant MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension; Macitentan

Study Results

Participant Flow

Recruitment Details	The study was designed to recruit 160 male and female patients aged 18 to 80 years (inclusive) with PAH. A total of 93 patients were screened and 88 patients were enrolled at 37 recruitment sites. Due to slow recruitment, the sponsor decided to prematurely stop the study.

Arm/Group Title	Macitentan
Arm/Group Description	Subjects received Macitentan at a 10 mg oral dose, once daily during 16 weeks
Period Title: Overall Study
STARTED	88
COMPLETED	81
NOT COMPLETED	7

Baseline Characteristics

Arm/Group Title	Macitentan
Arm/Group Description	Macitentan tablet, dose of 10 mg, once daily
Overall Participants	88
Age (Years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Years]	57.5
Sex: Female, Male (Count of Participants)
Female	58 65.9%
Male	30 34.1%

Outcome Measures

1. Primary Outcome

Title	Evaluation of the Reliability and the Construct Validity of the Cardiopulmonary Symptoms Domain of the PAH-SYMPACT
Description	The Cardiopulmonary Symptoms domain consists of 6 items reported on a 5-point Likert scale (from 0 to 4). The value 0 means "no symptom" and value 4 corresponds to "very severe symptoms".The symptoms part of the PAH-SYMPACT was administered daily over a 7 day period. The recall period of symptom items is the last 24 hours. An average Cardiopulmonary Symptoms domain score is determined based on the daily scores of the 6 items. It was administered two times (daily during 7 days each time) prior to administration of Macitentan (Visit 2, Baseline) and daily during the 7-day period in the treatment period prior to Visit 3 (Week 8) and Visit 4 (Week 16).
Time Frame	From Screening Visit (Visit 1) to End of Treatment (EOT) Visit (Visit 4, Week 16)

Outcome Measure Data

Analysis Population Description

Validation set

Arm/Group Title	Macitentan
Arm/Group Description	Macitentan tablet, dose of 10 mg, once daily
Measure Participants	87
Cardiopulmonary Symptoms domain score at baseline	0.90 (0.58)
Cardiopulmonary Symptoms domain score at week 8	0.89 (0.63)
Cardiopulmonary Symptoms domain score at week 16	0.89 (0.68)

2. Primary Outcome

Title	Evaluation of the Reliability and the Construct Validity of the Cardiovascular Symptoms Domain of the PAH-SYMPACT
Description	The Cardiovascular Symptoms domain consists of 5 items reported on a 5-point Likert scale (from 0 to 4). The value 0 corresponds to "no symptoms" and value 4 corresponds to "very severe symptoms". The symptoms part of the PAH-SYMPACT was administered daily over a 7 day period. The recall period of symptom items is the last 24 hours. An average Cardiovascular Symptoms domain score is determined based on the daily scores of the 5 items. It was administered two times (daily during 7 days each time) prior to administration of Macitentan (Visit 2, Baseline) and daily during the 7-day period in the treatment period prior to Visit 3 (Week 8) and Visit 4 (Week 16).
Time Frame	From Screening Visit (Visit 1) to End of Treatment (EOT) Visit (Visit 4, Week 16)

Outcome Measure Data

Analysis Population Description

Validation set

Arm/Group Title	Macitentan
Arm/Group Description	Macitentan tablet, dose of 10 mg, once daily
Measure Participants	87
Cardiovascular Symptoms domain score at baseline	0.58 (0.62)
Cardiovascular Symptoms domain score at week 8	0.54 (0.62)
Cardiovascular Symptoms domain score at week 16	0.54 (0.65)

3. Primary Outcome

Title	Evaluation of the Reliability and the Construct Validity of the Physical Impacts Domain of the PAH-SYMPACT
Description	The Physical Impacts domain consists of 7 items reported on a 5-point Likert scale (from 0 to 4). The value 0 corresponds to "not at all"/"with no difficulty at all" and value 4 corresponds to "very much"/"extremely"/ "not able at all". The impacts part of the PAH-SYMACT was administered on Day 7 of the symptoms part administration. Items in the impact part have a 7 day recall period. An average Physical Impacts domain score is determined based on the 7 items in the domain. It was administered two times prior to administration of Macitentan (Visit 2, Baseline) and during the 7-day period in the treatment period prior to Visit 3 (Week 8) and Visit 4 (Week 16).
Time Frame	From Screening Visit (Visit 1) to End of Treatment (EOT) Visit (Visit 4, Week 16)

Outcome Measure Data

Analysis Population Description

Validation set

Arm/Group Title	Macitentan
Arm/Group Description	Macitentan tablet, dose of 10 mg, once daily
Measure Participants	87
Physical Impacts domain score at baseline	1.13 (0.88)
Physical Impacts domain score at week 8	1.15 (0.97)
Physical Impacts domain score at week 16	1.25 (1.00)

4. Primary Outcome

Title	Evaluation of the Reliability and the Construct Validity of the Cognitive/Emotional Impacts Domain of the PAH-SYMPACT
Description	The Cognitive/Emotional Impacts domain consists of 4 items reported on a 5-point Likert scale (from 0 to 4). The value 0 corresponds to "not at all"/"with no difficulty at all" and value 4 corresponds to "very much"/"extremely"/ "not able at all". The impacts part of the PAH-SYMACT was administered on Day 7 of the symptoms part administration. Items in the impact part have a 7 day recall period. An average Cognitive/Emotional Impacts domain score is determined based on the 4 items in the domain. It was administered two times prior to administration of Macitentan (Visit 2, Baseline) and during the 7-day period in the treatment period prior to Visit 3 (Week 8) and Visit 4 (Week 16)."
Time Frame	From Screening Visit (Visit 1) to End of Treatment (EOT) Visit (Visit 4, Week 16)

Outcome Measure Data

Analysis Population Description

Validation set

Arm/Group Title	Macitentan
Arm/Group Description	Macitentan tablet, dose of 10 mg, once daily
Measure Participants	83
Cogn/Emotional Impacts domain score at baseline	0.87 (0.77)
Cogn/Emotional Impacts domain score at week 8	0.88 (0.91)
Cogn/Emotional Impacts domain score at week 16	0.91 (0.96)

Adverse Events

Time Frame	From study treatment initiation up to 30 days after study treatment discontinuation
Arm/Group Title	Macitentan
Arm/Group Description	Macitentan tablet, dose of 10 mg, once daily
All Cause Mortality
	Macitentan
	Affected / at Risk (%)	# Events
Total	3/88 (3.4%)
Serious Adverse Events
	Macitentan
	Affected / at Risk (%)	# Events
Total	13/88 (14.8%)
Cardiac disorders
Cardiac arrest	1/88 (1.1%)	1
Cardio-respiratory arrest	1/88 (1.1%)	1
Coronary artery stenosis	1/88 (1.1%)	1
Right ventricular failure	4/88 (4.5%)	5
General disorders
Chest discomfort	1/88 (1.1%)	1
Oedema peripheral	1/88 (1.1%)	1
Infections and infestations
Pneumonia	1/88 (1.1%)	1
Investigations
Investigation	1/88 (1.1%)	1
Metabolism and nutrition disorders
Hyperglycaemia	1/88 (1.1%)	1
Musculoskeletal and connective tissue disorders
Arthritis	1/88 (1.1%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
B-cell lymphoma	1/88 (1.1%)	1
Renal and urinary disorders
Chronic kidney disease	1/88 (1.1%)	1
Renal failure	1/88 (1.1%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea	3/88 (3.4%)	4
Epistaxis	1/88 (1.1%)	1
Pulmonary oedema	1/88 (1.1%)	1
Surgical and medical procedures
Sympathectomy	1/88 (1.1%)	1
Vascular disorders
Arteriovenous fistula	1/88 (1.1%)	1
Haemorrhage	1/88 (1.1%)	1
Other (Not Including Serious) Adverse Events
	Macitentan
	Affected / at Risk (%)	# Events
Total	21/88 (23.9%)
General disorders
Oedema peripheral	8/88 (9.1%)	8
Nervous system disorders
Headache	11/88 (12.5%)	12
Vascular disorders
Hypotension	5/88 (5.7%)	6

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Any study-related publication written independently by investigators must be submitted to Actelion for review at least 30 days prior to submission for publication or presentation. Upon review, Actelion may provide comments, and may also request alterations and/or deletions for the sole purpose of protecting its confidential information and/or patent rights.