Clinical trial NCT02626182: Evaluation and Treatment of Pulmonary Vascular Disease in Moderate to Severe CF
Official title: Evaluation and Treatment of Pulmonary Vascular Disease in Moderate to Severe Cystic Fibrosis Lung Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Cystic Fibrosis
Lead sponsor: National Jewish Health
Sponsor class: OTHER
First posted: 2015-12-10
Enrollment: 14
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study evaluates the ability of the drug sildenafil to improved exercise capacity, cardiac performance during exercise, and quality of life in patients with moderate to severe CF lung disease. 3/4 of the subjects will receive sildenafil and 1/4 will receive placebo.

Detailed description: Over time, patients with Cystic Fibrosis (CF) develop disabling lung disease that progresses to chronic respiratory failure, exercise intolerance with marked limitation of physical activity, and premature death. Despite substantial improvements in care, patients with CF often develop pulmonary vascular disease (PVD) that leads to pulmonary hypertension. Previous studies have clearly linked severe pulmonary hypertension and right heart failure with high mortality in CF. Early clinical manifestations of PVD prior to the development of cor pulmonale include shortness of breath and dyspnea with exertion, but the extent to which PVD contributes to the decline in exercise tolerance and quality of life in patients with CF is not known. Early evidence of PVD could be recognized in CF patients through standardized exercise testing and echocardiographic evaluation. Identifying those CF patients with PVD prior to the onset of right ventricular dysfunction may allow pharmacologic intervention to attenuate the progression of cardiovascular disease and improve quality of life. Clinical trials have demonstrated that treatment with the phosphodiesterase type 5 inhibitor, sildenafil, can decrease pulmonary vascular resistance and improve exercise tolerance in non-CF patients with pulmonary hypertension. Because experimental and clinical studies have implicated impaired NO-cGMP signaling in the pathophysiology of lung disease in CF, sildenafil may provide a novel pharmacological approach for treating PVD in patients with CF lung disease.

Eligibility criteria: Inclusion Criteria:

1. Confirmed diagnosis of CF based on the following criteria: Positive sweat chloride ≥60mEq/liter (by pilocarpine iontophoresis) and/or Genotype with two identifiable mutations consistent with CF, and accompanied by one or more clinical features consistent with the CF phenotype
2. Male or female patients ≥ 18 years of age
3. FEV1 ≥ 20% predicted and ≤ 70% predicted (Hankinson)
4. Clinically stable without evidence of acute upper or lower respiratory tract infection or current pulmonary exacerbation within the 14 days prior to the screening visit
5. Ability to reproducibly perform spirometry (according to ATS criteria)
6. Ability to understand and sign a written informed consent or assent and comply with the requirements of the study
7. Willingness to maintain chronic CF medication schedule (e.g. alternating month inhaled antibiotics)

Exclusion Criteria:

1. History of hypersensitivity to sildenafil
2. Use of an investigational agent within the 4-week period prior to Visit 1 (Day 0)
3. Breastfeeding, pregnant, or verbal expression of unwillingness to practice an acceptable birth control method (abstinence, hormonal or barrier methods, partner sterilization or intrauterine device) during participation in the study for women of child-bearing potential.
4. History of significant hepatic disease (AST or ALT \> 5 times the upper limit of normal at screening, documented biliary cirrhosis, or portal hypertension),
5. History of significant cardiovascular disease (history of aortic stenosis, coronary artery disease, or life-threatening arrhythmia),
6. History of severe neurological disease (e.g. history of stroke),
7. History of severe hematologic disease (e.g. history of bleeding diathesis; current INR \> 2.0
8. History of severe ophthalmologic disease (e.g. history of retinal impairment or non-arteritic ischemic optic neuritis)
9. History of severe renal impairment (creatinine \>1.8 mg/dL.)
10. Inability to swallow pills
11. Previous organ transplantation
12. Use of concomitant nitrates, α-blocker, or Ca channel blocker (currently or within one month of Visit 1)
13. Use of concomitant medications known to be potent inhibitors of CYP3A4 \[e.g. ketoconazole, itraconazole, ritonavir, clarithromycin, erythromycin, rifampin (currently or within one month of initiation of study drug)\] NOTE: use of azithromycin is NOT a cause for exclusion
14. History of sputum or throat swab culture yielding Burkholderia cepacia or Mycobacterium massiliense within 2 years of screening
15. Weight less than 40 kg at Screening
16. History of migraine headaches.
17. Resting room air oxygen saturation \<80% without supplemental oxygen
18. Presence of a condition or abnormality that in the opinion of the investigator would compromise the safety of the subject or the quality of the data
19. Start of CFTR modulator therapy less than 1 month prior to first dose of sildenafil or placebo
20. Use of anticoagulants
21. Frank pulmonary hypertension (RVSP \>40 mmHg by ECHO)

Primary outcomes:
measure: 6 Minute Walk Distance
timeFrame: Weeks 1, 13
measure: Cardiopulmonary Exercise Test Work Rate
timeFrame: Weeks 1 and 13
Secondary outcomes:
measure: Cystic Fibrosis Quality of Life-Revised Respiratory Domain Score
timeFrame: Assessed at weeks 1 and 13
Other outcomes:
Locations:
city: Denver
country: United States
facility: National Jewish Health
state: Colorado
Study officials:
affiliation: National Jewish Health
name: Jennifer L Taylor-Cousar, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Orenstein DM, Higgins LW. Update on the role of exercise in cystic fibrosis. Curr Opin Pulm Med. 2005 Nov;11(6):519-23. doi: 10.1097/01.mcp.0000181476.92810.07.
citation: Pianosi P, Leblanc J, Almudevar A. Peak oxygen uptake and mortality in children with cystic fibrosis. Thorax. 2005 Jan;60(1):50-4. doi: 10.1136/thx.2003.008102.
citation: Almajed A, Lands LC. The evolution of exercise capacity and its limiting factors in cystic fibrosis. Paediatr Respir Rev. 2012 Dec;13(4):195-9. doi: 10.1016/j.prrv.2012.01.001. Epub 2012 Feb 10.
citation: Jiang K, Jiao S, Vitko M, Darrah R, Flask CA, Hodges CA, Yu X. The impact of Cystic Fibrosis Transmembrane Regulator Disruption on cardiac function and stress response. J Cyst Fibros. 2016 Jan;15(1):34-42. doi: 10.1016/j.jcf.2015.06.003. Epub 2015 Jun 25.
citation: Galie N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, Fleming T, Parpia T, Burgess G, Branzi A, Grimminger F, Kurzyna M, Simonneau G; Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005 Nov 17;353(20):2148-57. doi: 10.1056/NEJMoa050010.
citation: Mourani PM, Sontag MK, Ivy DD, Abman SH. Effects of long-term sildenafil treatment for pulmonary hypertension in infants with chronic lung disease. J Pediatr. 2009 Mar;154(3):379-84, 384.e1-2. doi: 10.1016/j.jpeds.2008.09.021. Epub 2008 Oct 31.
citation: Montgomery GS, Sagel SD, Taylor AL, Abman SH. Effects of sildenafil on pulmonary hypertension and exercise tolerance in severe cystic fibrosis-related lung disease. Pediatr Pulmonol. 2006 Apr;41(4):383-5. doi: 10.1002/ppul.20393.
citation: Lubamba B, Lecourt H, Lebacq J, Lebecque P, De Jonge H, Wallemacq P, Leal T. Preclinical evidence that sildenafil and vardenafil activate chloride transport in cystic fibrosis. Am J Respir Crit Care Med. 2008 Mar 1;177(5):506-15. doi: 10.1164/rccm.200703-344OC. Epub 2007 Nov 15.
citation: Taylor-Cousar JL, Wiley C, Felton LA, St Clair C, Jones M, Curran-Everett D, Poch K, Nichols DP, Solomon GM, Saavedra MT, Accurso FJ, Nick JA. Pharmacokinetics and tolerability of oral sildenafil in adults with cystic fibrosis lung disease. J Cyst Fibros. 2015 Mar;14(2):228-36. doi: 10.1016/j.jcf.2014.10.006. Epub 2014 Nov 13.