A multi-center, multinational, randomized, double-blind, placebo-controlled, proof of concept trial to assess the effects of a subject-optimized dose of UK-369,003 Modified Release on exercise capacity in subjects with pulmonary hypertension associated with chronic obstructive pulmonary disease. - Not Applicable

• Register: EUCTR
• Last refreshed on: 14 August 2012
• Main ID: EUCTR2004-002216-28-GB
• Date of registration: 23/02/2005
• Prospective Registration: No
• Primary sponsor: Pfizer Limited
• Public title: A multi-center, multinational, randomized, double-blind, placebo-controlled, proof of concept trial to assess the effects of a subject-optimized dose of UK-369,003 Modified Release on exercise capacity in subjects with pulmonary hypertension associated with chronic obstructive pulmonary disease. - Not Applicable
• Scientific title: A multi-center, multinational, randomized, double-blind, placebo-controlled, proof of concept trial to assess the effects of a subject-optimized dose of UK-369,003 Modified Release on exercise capacity in subjects with pulmonary hypertension associated with chronic obstructive pulmonary disease. - Not Applicable
• Date of first enrolment: 13/01/2005
• Target sample size: 272
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2004-002216-28
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no

Countries of recruitment

Germany, United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:
1. Subjects aged > 40 and < 75 years.
2. Subjects who have COPD as defined by the GOLD criteria with the condition being stable for the preceding 6 weeks prior to the screening visit (no worsening of their COPD symptoms leading to change in class of medication used to treat their COPD or leading to hospital admissions or treatment with antibiotics for a presumed pulmonary infection).
3. Subjects will have FEV1 < 80% predicted and FEV1/FVC<70% at screening post 400mcg salbutamol (or equivalent) delivered via a spacing device.
4. Smokers or ex-smokers with a smoking history greater than 10 pack years (a pack year is equivalent to 20 cigarettes per day for 1 year equivalent).
5. Subjects who have symptom limited exercise capacity with a 6 minute Walk distance of >100m and < 450m and who do not desaturate to a SaO2 <75% during or 5 minutes after this walk at screening visit.
6. Subjects whose resting TTPG is = 30 mmHg or mPAP measurement is > 20mmHg by right heart catheter during screening or within 3 months prior to the baseline visit (V1) (as long as these subjects with measurements before baseline visit (V1) have been stable with no worsening of their COPD that has resulted in changes in class of medication or treatment with antibiotics for a presumed pulmonary infection, or hospitalization since their catheter).
7. Subjects who are capable of giving written informed consent to participate in the study.
8. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests and other trial procedures.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. Subjects with a history of asthma, allergic rhinitis or atopy
2. Subjects with a history of other chronic pulmonary disease eg tuberculosis, lung cancer, cystic fibrosis, interstitial lung disease, known obstructive sleep apnoea or with significant restrictive lung disease (with a FEV1/FVC>70% post nebuliser) eg respiratory muscle weakness, or lung fibrosis
3. Subjects who have had previous lung volume reduction surgery
4. Subjects on continuous long term oxygen therapy for >15 hours per day
5. Subjects with primary PH or PH associated with other lung disease other than COPD eg thromboembolism, HIV, congestive heart failure or schistosomiasis, sarcoid, tuberculosis or bronchiectasis, connective tissue disease etc
6. Subjects who have had a new class of COPD or cardiopulmonary medication (eg diuretic, steroids) or change in class of these medications initiated within 6 weeks prior to entering the study at screening visit
7. Subjects with a history of pulmonary embolism verified by ventilation/perfusion scan, angiogram or spiral chest CT scan within 6 months of randomization
8. Subjects with congenital heart disease
9. Subjects with significant (ie > 2+) valvular disease other than tricuspid regurgitation or pulmonary regurgitation, or subjects with previous valvular surgery
10. Subjects with a left ventricular ejection fraction (LVEF) less than 45% or LV shortening fraction <0.2 on echocardiogram at screening or within 3 months prior to study enrolment at screening visit
11. Subjects with an episode of heart failure within the previous 30 days at screening visit
12. Subjects with acute myocardial infarction or Cerebral Vascular Accident (CVA) within 3 months prior to study enrolment at screening visit
13. Subjects with uncontrolled brady- or tachyarrhythmias (e.g., sinus arrest, complete heart block, atrial fibrillation or flutter, frequent runs of ventricular tachycardia); placement of dual chamber pacemakers and/or implantable defibrillators <60 days prior to screening
14. Subjects whose 6-Minute Walk Test might be limited by conditions other than PH-associated dyspnea or fatigue, e.g., claudication from vascular insufficiency, significant arthritis or amputation of a lower limb without a suitable prosthesis
15. Subjects with creatinine clearance <30 mL/min as determined by the Cockroft-Gault formula (Appendix 6 of the protocol) measured at screening visit
16. Subjects with symptomatic postural hypotension
17. Subjects who are obese with a BMI>35kg/m2
18. Subjects with severe impairment of hepatic function, Child-Pugh Class C (Appendix 7 of the protocol), or portal PH
19. Pregnant or lactating women or women of child bearing potential (i.e those who are not post-menopausal or surgically sterilised). Women who have undergone tubal ligation should be excluded.
20. Subjects who have previously received chronic oral sildenafil or any other PDE5 inhibitor for any reason for a period exceeding 5 days
21. Subjects who have taken sildenafil or any other PDE5 inhibitor in the 48 hours prior to screening and who are unwilling to cease taking this therapy for the duration of the study. Subjects who have received any PDE4 inhibitor in the 48 hours prior to screening (see exclusion 23)
22. Subjects who are currently receiving any form of nitrates or nitric oxide donors (including nicorandil) in any form, protease inhibitors such as ritonavir and saquinavir, ketoconazole, itraconazole, alpha blockers, [Subjects previously receiving any of the

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Pulmonary hypertension associated with chronic obstructive pulmonary disease

Intervention(s)

Product Name: Not Applicable - Name not assigned
Product Code: UK-369,003
Pharmaceutical Form: Tablet
INN or Proposed INN: N/A
CAS Number: N/A
Current Sponsor code: UK-369,03
Other descriptive name: N/A
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50 and 100-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Primary end point(s): Change from baseline in total distance walked during a 6MWT at week 12 of the study

Main Objective: To evaluate the effects of UK-369,003MR on exercise capacity as measured by change frombaseline in distance walked during the 6 Minute Walk Test (6MWT) after 12 weeks of treatment in subjects with PH associated with COPD.

Secondary Objective: 1. To evaluate the effects of UK-369,003MR on health related quality of life as measured by the St George’s Respiratory Questionnaire.
2. To evaluate the effects of UK-369,003MR on exertional dyspnea as measured by the Borg dyspnea score.
3. To evaluate the safety and tolerability of UK-369,003MR in subjects with COPD associated PH.
4. To evaluate the effects of UK-369,003MR on resting PaO2.
5. To evaluate the effects of UK-369,003MR on the maximum oxygen desaturation during the 6MWT
6. To evaluate the effects of UK-369,003MR on spirometry.
7. To investigate the population pharmacokinetic parameters in these subjects.
8. To investigate the effects of UK-369,003MR on time to clinical worsening.

Secondary ID(s)

Not Applicable

A3711028