Clinical Trials Register

Summary
EudraCT Number:	2005-006192-13
Sponsor's Protocol Code Number:	C200-006
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2006-05-12
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2005-006192-13

A.3

Full title of the trial

Estudio aleatorio, doble-ciego, controlado con placebo para evaluar la seguridad y eficacia de la adición de Iloprost inhalado en pacientes con hipertensión arterial pulmonar que reciben Sildenafilo por vía oral

A.3.2

Name or abbreviated title of the trial where available

VISION

A.4.1

Sponsor's protocol code number

C200-006

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	CoTherix, Inc
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Information not present in EudraCT
D.2.1.1.1	Trade name	Comment- IMP inhalation solution identical to ventavis inhalation solution, but IMP is in a different volume presentation. Please see covering letter.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/00/014
D.3 Description of the IMP
D.3.1	Product name	Iloprost (Ventavis®)
D.3.4	Pharmaceutical form	Inhalation vapour, solution
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Inhalation use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Iloprost
D.3.9.1	CAS number	78919-13-8
D.3.10	Strength
D.3.10.1	Concentration unit	µg/ml microgram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Information not present in EudraCT
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	Information not present in EudraCT
D.3.11.8	Extractive medicinal product	Information not present in EudraCT
D.3.11.9	Recombinant medicinal product	Information not present in EudraCT
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	Yes
D.3.11.13.1	Other medicinal product type	Chemical Inhalation solution

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Inhalation vapour, solution
D.8.4	Route of administration of the placebo	Inhalation use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Spanish: hipertensión arterial pulmonar

English: Pulmonary Arterial Hypertension (PAH) is a condition that is characterized by increased pulmonary arterial pressure and vascular resistance that can lead to right ventricular failure and death.

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	8.1
E.1.2	Classification code	10037400

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this study is to assess the efficacy of the addition of inhaled iloprost vs. placebo in patients with PAH receiving sildenafil. The primary measure will be the change in 6-Minute Walk Distance (6-MWD) from baseline, measured after inhalation, following 16 weeks of combination therapy with inhaled iloprost (administered 6 times per day) and sildenafil vs. inhaled placebo plus sildenafil.

E.2.2

Secondary objectives of the trial

1.Change from baseline in 6-MWD measured after inhalation at Week 16 of inhaled iloprost (4 x/day) plus sildenafil vs. placebo plus sildenafil
2.Change from baseline in NYHA/WHO class assessed at Week16 of inhaled iloprost (6x/day) plus sildenafil vs. placebo plus sildenafil
3.Time to clinical worsening with inhaled iloprost (6x/day) plus sildenafil vs. placebo plus sildenafil, where clinical worsening is defined by: death due to PAH, hospitalization by worsening PAH, or any early discontinuation due to worsening PAH, initiation of additional PAH-specific therapy (such as systemic prostanoids), or performance of lung or heart-lung transplantation or atrial septostomy
4.Change from baseline in NYHA/WHO class assessed at Week16 with inhaled iloprost (4x/day) plus sildenafil vs. placebo plus sildenafil
5.Time to clinical worsening with inhaled iloprost (4x/day) plus sildenafil vs. placebo plus sildenafil, (clinical worsening is defined above)

E.2.3

Trial contains a sub-study

Information not present in EudraCT

E.3

Principal inclusion criteria

Patients may be included in the study only if they meet all of the following:
1. Able and willing to give written informed consent and comply with study requirements.
2. Male or female patients aged 18-80 years
3. Have a current diagnosis of symptomatic PAH classified by one of the following: a) IPAH or FPAH; b) PAH associated with one of the following connective tissue diseases and mild or no lung parenchymal disease: scleroderma spectrum of disease, systemic lupus erythematosis, or mixed connective tissue disease, c) PAH associated with repaired atrial septal defect (ASD), ventricular septal defect (VSD), or patent ductus arteriosus (PDA) ≥ 1 year post-operative from Screening, d) PAH associated with HIV, or e) PAH associated with the use of anorexigens (e.g. fenfluramine-phentermine)
4. On a stable dose regimen of sildenafil, at doses between 20 mg TID and 80 mg TID, for at least 12 weeks prior to screening, and tolerating sildenafil without clinically significant side effects
5. Screening 6-MWD of 100-425 meters
6. Have a cardiac catheterization either at baseline or within the previous 3 years consistent with PAH, with the following values: a) mean pulmonary artery pressure (mPAP) at rest > 25 mm Hg, b) pulmonary capillary wedge pressure (PCWP) or left ventricular end-diastolic pressure ≤ 15 mm Hg, and c) pulmonary vascular resistance (PVR) ≥ 240 dynes·sec·cm-5
7. Have pulmonary function tests showing FEV1/FVC ratio > 50% AND either a) total lung capacity > 70% predicted, or b) total lung capacity between 60% and 70% predicted, with no more than mild patchy interstitial lung disease
8. If HIV-seropositive, must have been stable with a) no concomitant active opportunistic infections and an undetectable viral load for the 6 months prior to screening, b) CD4+ T cell count > 200/mm3 and no change in antiviral regimen for the 3 months prior to screening, c) no change in antiviral regimen anticipated during the course of the study, and d) no use of inhaled pentamidine
9. Documented evidence of absence of thromboembolic disease (i.e., low probability for pulmonary embolism) using methodology such as pulmonary angiogram, ventilation perfusion scan, or chest CT scan within 3 years of screening
10. If on corticosteroids, be receiving a stable dose of ≤ 20 mg/day of prednisone or equivalent for at least 1 month prior to screening
11. Women of childbearing potential must agree to use an adequate method of contraception

E.4

Principal exclusion criteria

Patients meeting any of the following criteria are not eligible to participate in the study:
1. Pulmonary arterial hypertension related to any etiology other than those specified in the inclusion criteria (including portopulmonary)
2. Receipt of any prostacyclin or prostacyclin analogue within 12 weeks before screening
3. Receipt of bosentan or other endothelin antagonist within 12 weeks before screening
4. Change in sildenafil dose within 12 weeks before screening
5. Any clinically significant ocular abnormality during screening examination that could be potentially related to sildenafil use (e.g. retinal abnormalities or visual defects)
6. History of poor tolerability to sildenafil
7. Untreated or inadequately treated obstructive sleep apnea
8. History of left-sided heart disease, including any of the following:
- aortic or mitral valve disease;
- pericardial constriction;
- restrictive or congestive cardiomyopathy;
- diastolic dysfunction syndrome;
- left ventricular ejection fraction < 40% by multigated radionucleotide angiogram
(MUGA), angiography, or echocardiography;
- left ventricular shortening fraction < 22% by echocardiography;
- symptomatic coronary disease with demonstrable ischemia;
- life-threatening cardiac arrhythmias
9. Cerebrovascular events (e.g. transient ischemic attack or stroke) within 6 months of screening
10. Chest X-Ray showing medically relevant disease other than findings consistent with PAH
11. Receipt of atrial septostomy within 6 months of screening

12. Any condition other than PAH which might affect the patient’s ability to perform a 6-MWT
13. Clinically relevant obstructive lung disease (e.g. asthma or COPD)
14. Clinically relevant abnormal laboratory values at screening that, in the opinion of the investigator, would compromise the evaluation of efficacy and/or safety of the study drug
15. Treatment with an investigational drug or device which has not received regulatory approval within 120 days before screening
16. Uncontrolled systemic hypertension as evidenced by systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg on repeated measurement
17. Systemic hypotension with systolic BP < 95 mmHg
18. Chronic renal insufficiency as defined by a creatinine of > 2.5 mg/dL or the requirement for dialysis
19. Chronic liver disease or cirrhosis, including porto-pulmonary hypertension
20. Clinically relevant bleeding disorder or active bleeding
21. Psychiatric, addictive, or other disorder that compromises the ability to give informed consent for participating in this study
22. Pregnant or breastfeeding
23. The addition or discontinuation of any new type of chronic treatment for PAH including, but not limited to calcium channel blockers within 12 weeks before screening; or vasodilators, digitalis, diuretics, oxygen, or investigational treatments within 30 days before screening; for all of these except diuretics, the dose must have been stable for 7 days prior to baseline. Anti-coagulant therapy may be modified at any time.
24. Concomitant use of medications that are contraindicated with sildenafil, including regular or intermittent use of organic nitrates
25. Are study investigators, study staff, or their immediate families

E.5 End points

E.5.1

Primary end point(s)

The primary measure will be the change in 6-Minute Walk Distance (6-MWD) from baseline, measured after inhalation, following 16 weeks of combination therapy with inhaled iloprost (administered 6 times per day) and sildenafil vs. inhaled placebo plus sildenafil

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Information not present in EudraCT

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

E.8.7

Trial has a data monitoring committee

Information not present in EudraCT

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

When last patient, last visit occurs.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects
F.1 Age Range
F.1.1	Trial has subjects under 18	No
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
F.1.2	Adults (18-64 years)	Yes
F.1.3	Elderly (>=65 years)	Yes
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Information not present in EudraCT
F.3.3.1	Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2006-05-12.	Yes
F.3.3.2	Women of child-bearing potential using contraception	Information not present in EudraCT
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	10
F.4.2	For a multinational trial
F.4.2.1	In the EEA	100
F.4.2.2	In the whole clinical trial	180

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2006-06-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2006-05-30

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2008-07-01

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