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Chronic Left Ventricular FailurePhase 2BRIDGENCT02482402

Iloprost for Bridging to Heart Transplantation in PH

A Phase 2 study testing Inhaled Iloprost in people with Chronic Left Ventricular Failure and Pulmonary Hypertension, run by Heidelberg University at 2 sites in Germany.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial summary

Trial Rationale/ Justification To assess efficacy and safety of inhaled Iloprost in treatment naïve patients with left heart failure and pulmonary hypertension, who are on the waiting list for orthotopic heart transplantation. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Inhaled Iloprost
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
0 participants
Where
2 sitesGermany
Study dates
Feb 2015to 17 Mar 2015
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Female and male patients of any ethnic origin with left heart insufficiency and secondary PH
  • Having fulfilled his/her 18th birthday on Visit 1 (Day -7 to -1) of the study
  • Written informed consent (must be available before enrollment in the trial)
  • Modified WHO functional class III-IV
  • PH diagnosed by right heart catheter showing:
  • Baseline mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg
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  • Baseline pulmonary vascular resistance (PVR) > 230 dyn x s x cm-5
  • Baseline transpulmonary gradient (TPG) > 15 mm Hg
  • Echocardiogram on Visit 1/Day -7 to -1 consistent with secondary PH, specifically evidence of right ventricular hypertrophy or dilation, and absence of mitral valve stenosis
  • Patients receiving maximal conventional left heart failure therapy according to current guidelines (ISHLT Guidelines 2006) including intensified treatment with diuretics and have been stable for at least 2 months before entering the study (i.e. no acute decompensations requiring i.v. diuretic treatment).
  • Except for diuretics, vasodilators and antihypertensives, medical treatment should not be expected to change during the entire 12-week study period.
  • Negative pregnancy test (β-HCG or urine dipstick) at the start of the trial and appropriate contraception throughout the study for women with child-bearing potential.
  • Able to understand and sign the Informed Consent Form
  • Ability of subject to understand character and individual consequences of the clinical trial

Who cannot join

  • PH of any cause other than permitted in the entry criteria, e.g. concomitantly to portal hypertension, complex congenital heart disease, reversed shunt, anamestic HIV infection, suspected pulmonary veno-occlusive disease based on pulmonary oedema during a previous vasoreactivity test or on abnormal findings compatible with that diagnosis (septal lines or pulmonary edema detected previously at high resolution computer tomography), congenital or acquired valvular defects with clinically relevant myocardial function disorders not related to pulmonary hypertension
  • Contraindication for right heart catheterization
  • Severe lung disease: FEV1/FVC <0.5 and total lung capacity < 70% of the normal value
  • Any subject who had received any investigational medication within 4 weeks prior to the start of this study or who is scheduled to receive another investigational drug during the course of this study
  • Any PAH-specific medication (ERAs, PDE-5-I, Prostacyclins) during the last 30 days prior to inclusion (randomization).
  • Known intolerance to inhalation treatment
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  • Conditions where the effects of inhaled Iloprost on platelets might increase the risk of haemorrhage (e.g. active peptic ulcers, trauma, and intracranial haemorrhage).
  • Severe coronary heart disease or unstable angina, myocardial infarction within the last six months
  • Cerebrovascular events (e.g. stroke) within the last 3 months
  • Active liver disease, porphyria or elevations of serum transaminases >3 x ULN (upper limit of normal) or bilirubin > 1.5 x ULN
  • Hemoglobin concentration of less than 75 % of the lower limit of normal
  • Systolic blood pressure < 85 mmHg
  • History or suspicion of inability to cooperate adequately
  • Pregnancy and lactation
  • History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal product

Trial locations and contacts

2 sites in 1 country.

Germany2 sites
  • Klinik für Thorax- und Kardiovaskularchirurgie

    Bad Oeynhausen, 32545

  • Thoraxclinic at the University of Heidelberg

    Heidelberg, 69126

Other trials in Germany

About this study

Official title: Iloprost for Bridging to Heart Transplantation in Patients With Pulmonary Hypertension and Left Heart Failure A Randomized, Controlled, Double-blind, Parallel Group, Proof-of-concept Trial

Trial Rationale/ Justification To assess efficacy and safety of inhaled Iloprost in treatment naïve patients with left heart failure and pulmonary hypertension, who are on the waiting list for orthotopic heart transplantation. As patients often show increasing hemodynamic values while waiting for a donor organ, the transplantation becomes infeasible at the time of identification of an appropriate donor organ when reaching the exclusion limits. Therefore, there is a high need of improvement and stabilisation of the patients' hemodynamic values as PVR, PAP and TPG. In a retrospective, non-controlled study inhaled Iloprost has already shown a beneficial effect on the hemodynamics as reduction of PVR, TPG and CI (Schulz 2010). Treatment with inhaled Iloprost could stabilize the hemodynamics and prevent the patients from being classified as ineligible by the time an appropriate donor organ is identified.

However, the adverse event profile regarding frequency, time-dependency has to be further validated to show safety and tolerability of inhaled Iloprost in this indication.

All patients can be transferred to a long-term medically supervised observation period with inhaled Iloprost therapy.

Read the detailed description

Scientific Background In many patients with severe left heart failure (LHF) a chronic pulmonary hypertension (PH) occurs during follow-up leading to a remodeling of pulmonary arteries with an increase in pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR) and transpulmonary gradient (TPG). According to the International Society for Heart and Lung Transplantation and the German Standing Committee on Organ Transplantation, cardiac transplantation is contraindicated if values of PAP, PVR, and/or TPG are above 40 mmHg, 240 dyn x s x cm-5, and 15 mmHg, respectively. Even if the patients show only slightly elevated hemodynamic values at the time of application for transplantation, values most often reach the respective exclusion limits during the waiting period. Patients signed in for transplantation partially are not any longer electable for orthotopic heart transplantation (OHT) at the time of identification of an appropriate donor organ. In the meantime the time on the waiting list for heart transplantation is increasing. In 2001, patients being on the waiting list were undergoing heart transplantation within one year. In contrast, 972 patients were on the waiting list while only 325 heart transplantations were performed in Germany in 2011 (www.eurotransplant.nl).

At present, no specific therapy for PH due to left heart disease is available (Galie 2009), treatment with PAH agents is not recommended due to lack of data (Rosenkranz 2011).

There are only few studies with PH-targeted medication within this indication. Phosphodiesterase inhibitors (e.g. Sildenafil), Endothelin-receptor antagonists and Prostacyclin are potential agents for the treatment of PH during the waiting period for a heart transplantation.

Iloprost is a synthetic analogue of Prostacyclin PGI2. Iloprost dilates systemic and pulmonary arterial vascular beds leading to a reduction of blood pressure.

In a previous study the investigators administered aerosolized Iloprost (ILO) in 14 patients with pulmonary hypertension due to chronic cardiac failure on the waiting list for heart transplantation. Iloprost caused a significant reduction in pulmonary arterial pressure and pulmonary vascular resistance without severe side effects and was more effective than nitric oxide (Sablotzky, Grünig et al. 2002, 2003). In a retrospective non-controlled study in 51 patients awaiting orthotopic heart transplantation Iloprost inhalation caused a significant decrease in PVR (from 458 dyn x s x cm-5 to 345 dyn x s x cm-5), a significant decrease in TPG (21 mmHg to 17 mmHg), and a significant improvement in Cardiac Index (CI) from 2,09 l/min/m2 to 2,23 l/min/m2 (Schulz et al., 2010). In a retrospective non-controlled study low-dose Bosentan improved hemodynamic parameters and 1-year survival rate in 82 end-stage heart failure patients on the waiting list for cardiac transplantation (Hefke et al., 2011).

Randomized-controlled trials are missing within this indication. Sildenafil is not a medication of first choice due to contraindications and as well as many patients waiting for OHT are treated with nitrate (medication due to coronary heart disease). In contrast, inhaled Iloprost has advantageous effects on coronary perfusion. However, in this indication the adverse event profile of inhaled Iloprost regarding frequency and time-dependency is not yet clear. In Germany inhaled Iloprost is administered by the I-Neb AAD-System which allows precise, reproducible dose of the drug.

Due to the positive results in retrospective analyses and in the treatment of patients with pulmonary hypertension, the initiation of this proof-of-concept study seems to be justified.

Being tested
Inhaled Iloprost, Placebo
Medical subject headings
Hypertension, Pulmonary

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Inhaled IloprostDrug

    Also called Ilomedin

    Treatment effect will be controlled at each study visit and the dose and/or inhalation frequency will be adapted.

  • PlaceboDrug

    Also called inhaled placebo

    inhalation solution placebo

Study groups in NCT02482402
Study groupRoleWhat they receive
Inhaled IloprostExperimental2 inhalations per day of 2.5 µg Iloprost [Ventavis®] per inhalation to a maximum of 6 inhalations per day of 5 µg Iloprost per inhalation (total daily dose 5 - 30 µg) will be performed according to each patient's health condition.
Receives: Drug: Inhaled Iloprost
Placebo inhaledPlacebo comparator2 to a maximum of 6 inhalations per day of placebo solution (PLA) will be performed. Study medication will be inhaled using the portable, hand-held I-Neb AAD vibrating mesh technology nebulizer system.
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. safety and tolerability measured by adverse events rates

    The primary objective of the clinical trial is to acquire first data on safety and tolerability of inhaled Ilorpost in patients with left heart failure on the waiting list for orthotopic heart transplantation.. This proof-of-concept trial aims to evaluate the safety profile of inhaled Iloprost in this indication.

    Measured: baseline until end of study after 12 weeks

Secondary outcomes (54)
  1. hemodynamics right atrial pressure

    Right heart catheterization will be performed at trough level, at least 4 hours after last study drug inhalation, according to 4-8 half-life periods.

    Measured: baseline vs. 12 weeks

  2. hemodynamics pulmonary arterial pressure

    Right heart catheterization will be performed at trough level, at least 4 hours after last study drug inhalation, according to 4-8 half-life periods.

    Measured: baseline vs. 12 weeks

  3. hemodynamics pulmonary arterial wedge pressure

    Right heart catheterization will be performed at trough level, at least 4 hours after last study drug inhalation, according to 4-8 half-life periods.

    Measured: baseline vs. 12 weeks

  4. hemodynamics Cardiac output

    Right heart catheterization will be performed at trough level, at least 4 hours after last study drug inhalation, according to 4-8 half-life periods.

    Measured: baseline vs. 12 weeks

  5. hemodynamics Cardiac index

    Right heart catheterization will be performed at trough level, at least 4 hours after last study drug inhalation, according to 4-8 half-life periods.

    Measured: baseline vs. 12 weeks

  6. hemodynamics venuous oxygen saturation

    Right heart catheterization will be performed at trough level, at least 4 hours after last study drug inhalation, according to 4-8 half-life periods.

    Measured: baseline vs. 12 weeks

  7. Echocardiography systolic pulmonary arterial pressure

    Measured: baseline vs. 12 weeks

  8. Echocardiography Tei index

    Measured: baseline vs. 12 weeks

  9. Echocardiography right atrial area

    Measured: baseline vs. 12 weeks

  10. Echocardiography right ventricular area

    Measured: baseline vs. 12 weeks

  11. Echocardiography tricuspid annular plane systolic excursion

    Measured: baseline vs. 12 weeks

  12. Echocardiography left ventricular pump function

    Measured: baseline vs. 12 weeks

  13. WHO functional class

    Measured: baseline vs. 12 weeks

  14. Lung function tests and Blood Gas analysis

    Lung function test: Bodyplethysmography (preferred method) including forced vital capacity, forced expiratory volume in one second, FEV1 percent, peak expiratory flow rate, forced expiratory flow, lung volume, diffusion-limited carbon monoxide, Blood gas analysis: capillary or arterial blood gas analysis; partial pressure of oxygen and carbon dioxide, oxygen saturation, supplemental oxygen "yes" or "no" (if the patient receives supplemental oxygen the amount will be recorded in the CRF in litres/minute)

    Measured: baseline vs. 12 weeks

  15. 6-minute walking distance and Borg dyspnea Score (CR 10)

    will be performed according to ATS guidelines. Blood pressure, heart rate and oxygen saturation will be measured before and after the test.

    Measured: baseline vs. 12 weeks

  16. Quality of Life SF 36- questionnaire

    Measured: baseline vs. 12 weeks

  17. Quality of Life CAMPHOR

    Measured: baseline vs. 12 weeks

  18. Blood pressure

    blood pressure and heart rate will be measured after the patient has been at rest for at least 5 minutes.

    Measured: baseline vs. 12 weeks

  19. heart rate measurements

    blood pressure and heart rate will be measured after the patient has been at rest for at least 5 minutes.

    Measured: baseline vs. 12 weeks

  20. Electrocardiography

    For deriving the ECGs the patients should always be in supine position. The ECGs should be derived after a resting period of at least 10 minutes. The investigator will review the ECGs for potential AEs.

    Measured: baseline to 12 weeks

  21. Clinical laboratory Haematology

    Measured: baseline to 12 weeks

  22. Clinical laboratory Leucocytes

    Measured: baseline to 12 weeks

  23. Clinical laboratory erythrocytes

    haemoglobin, haematocrit, platelets Substrates Bilirubin, LDL/HDL, cholesterol, triglycerides, creatinine, uric acid, urea, total protein, albumin, glucose Electrolytes Sodium, potassium, calcium, chloride Enzymes SGOT/ASAT, SGPT/ALAT, Gamma-GT, GLDH, AP, LDH, CK Others INR, PTT, β-HCG test for women with childbearing potential at V1; V5 and V6 Biomarkers CRP, NT-proBNP

    Measured: baseline to 12 weeks

  24. Clinical laboratory haemoglobin

    Measured: baseline to 12 weeks

  25. Clinical laboratory haematocrit

    Measured: baseline to 12 weeks

  26. Clinical laboratory platelets

    Measured: baseline to 12 weeks

  27. Clinical laboratory Substrates

    Measured: baseline to 12 weeks

  28. Clinical laboratory Bilirubin

    Measured: baseline to 12 weeks

  29. Clinical laboratory LDL/HDL

    Measured: baseline to 12 weeks

  30. Clinical laboratory cholesterol

    Measured: baseline to 12 weeks

  31. Clinical laboratory triglycerides

    Measured: baseline to 12 weeks

  32. Clinical laboratory creatinine

    Measured: baseline to 12 weeks

  33. Clinical laboratory uric acid

    Measured: baseline to 12 weeks

  34. Clinical laboratory urea

    Measured: baseline to 12 weeks

  35. Clinical laboratory total protein

    Measured: baseline to 12 weeks

  36. Clinical laboratory albumin

    Measured: baseline to 12 weeks

  37. Clinical laboratory glucose

    Measured: baseline to 12 weeks

  38. Clinical laboratory Electrolytes

    Measured: baseline to 12 weeks

  39. Clinical laboratory sodium

    Measured: baseline to 12 weeks

  40. Clinical laboratory potassium

    Measured: baseline to 12 weeks

  41. Clinical laboratory calcium

    Measured: baseline to 12 weeks

  42. Clinical laboratory chloride

    Measured: baseline to 12 weeks

  43. Clinical laboratory SGOT/ASAT

    Measured: baseline to 12 weeks

  44. Clinical laboratory SGPT/ALAT

    Measured: baseline to 12 weeks

  45. Clinical laboratory Gamma-GT

    Measured: baseline to 12 weeks

  46. Clinical laboratory GLDH

    Measured: baseline to 12 weeks

  47. Clinical laboratory AP

    Measured: baseline to 12 weeks

  48. Clinical laboratory LDH

    Measured: baseline to 12 weeks

  49. Clinical laboratory CK

    Measured: baseline to 12 weeks

  50. Clinical laboratory INR

    Measured: baseline to 12 weeks

  51. Clinical laboratory PTT

    Measured: baseline to 12 weeks

  52. Clinical laboratory β-HCG test for women with childbearing potential at

    Measured: V1; V5 and V6

  53. Clinical laboratory CRP

    Measured: baseline to 12 weeks

  54. Clinical laboratory NT-proBNP

    Measured: baseline to 12 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted26 Jun 2015 (estimated)
  2. Study startFeb 2015
  3. Primary completion17 Mar 2015
  4. Study completion17 Mar 2015

Why it stopped: Delay in recruitment

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02482402
Sponsor's protocol ID
IG 43
Other IDs
2013-001613-33
Acronym
BRIDGE
Status last verified
Dec 2019
First submitted
31 Oct 2014
Last updated
23 Dec 2019
Results posted
No
Data monitoring committee
Yes

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Inhaled Iloprost in people with Chronic Left Ventricular Failure and Pulmonary Hypertension, run by Heidelberg University at 2 sites in Germany.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 14 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 23 Dec 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

safety and tolerability measured by adverse events rates (time frame: baseline until end of study after 12 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Dec 2019.

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