Clinical trial NCT02847260: Safety and Tolerability of Rapid Dose Titration of Subcutaneous Remodulin® Therapy in PAH Subjects (RAPID)
Official title: A 16 Week, Open Label, Multi-centre, Study to Evaluate the Safety, Tolerability and Pharmacodynamic Effects of a Rapid Dose Titration Regimen of Subcutaneous Remodulin® Therapy in Subjects With Pulmonary Arterial Hypertension (PAH)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Pulmonary Arterial Hypertension
Lead sponsor: United Therapeutics
Sponsor class: INDUSTRY
First posted: 2016-07-28
Enrollment: 39
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of the study is to evaluate the safety and tolerability of a rapid dose titration regimen of subcutaneous Remodulin® therapy in patients with PAH.

Detailed description: This is an open label, single territory, multi-centre study in subjects with pulmonary arterial.

hypertension (PAH). Subjects were treatment naïve or receiving an approved endothelin receptor antagonist (ERA) and / or phosphodiesterase (PDE)-5 inhibitor for at least 60 days prior to screening and maintained on a stable dose for at least 30 days.

Eligibility criteria: Inclusion Criteria:

1. The subject is at least 18 years of age at screening.
2. The subject weigh a minimum of 40 kg with a body mass index less than 40 kg/m\^2 at screening.
3. Sexually active women of childbearing potential must use two different forms of highly effective contraception. Males participating in the study must use a condom during the length of the study, and for at least 64 days after discontinuing study drug.
4. The subject has a diagnosis of symptomatic idiopathic or heritable PAH (IPAH or HPAH).
5. A Baseline 6MWD between 150 and 550 metres is required, in the absence of a concurrent injury, illness (other than PAH or a PAH related condition), or other confounding factors that would effect the subject's exercise capacity.
6. The subject is either treatment naïve or receiving an approved PDE-5 inhibitor and / or an approved ERA for at least 60 days prior to screening and is on a stable dose for 30 days and is willing to remain on a PDE-5 inhibitor and / or an ERA at the same dose for the duration of the 16-week treatment phase.
7. The subject must be optimally treated with conventional pulmonary hypertension therapy (e.g., oral vasodilators, oxygen, digoxin, etc.) with no additions, discontinuations, or dose changes for at least 14 days prior to screening (excluding diuretics and anticoagulant dose adjustments).
8. The subject has undergone right heart catheterisation at screening (or within 8 weeks before screening) and has been documented to have a mean pulmonary artery pressure (PAPm) of greater than or equal to 25 mmHg, a pulmonary capillary wedge pressure (PCWP) of less than or equal to 15 mmHg, and pulmonary vascular resistance (PVR) of more than 3 Wood units.
9. The subject has undergone echocardiography at screening with evidence of clinically normal left systolic and diastolic ventricular function, absence of any clinically significant left sided heart disease (e.g., mitral valve stenosis) and absence of unrepaired congenital heart disease.
10. The subject has a previous ventilation perfusion lung scan and / or high resolution computerised tomography scan of the chest and / or pulmonary angiography that is consistent with the diagnosis of PAH (e.g., low probability of pulmonary embolism; absence of major perfusion defects).
11. The subject has pulmonary function tests done within 9 months of screening with the following:

    * Total lung capacity (TLC) was at least 60% (of predicted value)
    * Forced expiratory volume in one second/forced vital capacity (FEV1/FVC) ratio is at least 50%
12. In the opinion of the Principal Investigator, the subject is able to communicate effectively with study personnel, was considered reliable, willing and likely to be cooperative with protocol requirements.
13. The subject voluntarily gives written informed consent to participate in the study.

Exclusion Criteria:

1. The subject is pregnant or lactating.
2. The subject has received epoprostenol, treprostinil, intravenous iloprost, or beraprost within 30 days prior to screening (except if used during acute vasoreactivity testing).
3. The subject has had previous intolerance or significant lack of efficacy to prostacyclin or a prostacyclin analogue that resulted in discontinuation or inability to titrate that therapy effectively.
4. The subject has any disease associated with PH other than idiopathic PAH or heritable PAH or had had an atrial septostomy.
5. The subject is in WHO functional class IV.
6. The subject has a current diagnosis of uncontrolled sleep apnoea as defined by their physician.
7. The subject has liver function tests (aspartate transaminase (AST) or alanine transaminase (ALT)) greater than three times the upper limit of the laboratory reference range and / or an international normalised ratio (INR) greater than 3 units at screening.
8. The subject has a history of active gastro-intestinal ulcer, intracranial haemorrhage, injury or other cause of clinically significant bleeding episode within 6 months before screening, or has any other disease / condition that would either jeopardise the safety of the subject and / or interfere with the interpretation of study assessments in the opinion of the Investigator.
9. The subject has a history of ischemic heart disease including previous myocardial infarction or symptomatic coronary artery disease within 6 months of screening, or history of left sided myocardial disease as evidenced by a PCWP (or Left Ventricular End-Diastolic Pressure (LVEDP)) greater than 15 mmHg or left ventricular ejection fraction (LVEF) less than 40%.
10. The subject has uncontrolled systemic hypertension as evidenced by systolic blood pressure greater than 160 mmHg or diastolic blood pressure greater than 100 mmHg.
11. The subject has a musculoskeletal disorder (e.g., arthritis affecting the lower limbs, recent hip or knee joint replacement, artificial leg) or any other disease that is likely to limit ambulation, or is connected to a machine that is not portable.
12. The subject has an unstable psychiatric condition or is mentally incapable of understanding the objectives, nature, or consequences of the trial.
13. The subject is receiving an investigational drug, has an investigational device in place or has participated in an investigational drug or device study within 30 days prior to screening.

Primary outcomes:
measure: Number of Participants With Successful Completion of the 16 Week Treatment Period.
timeFrame: Baseline to week 16
Secondary outcomes:
measure: Change From Baseline in Six Minute Walk Distance at Week 16.
timeFrame: Baseline to week 16
measure: Change in Borg Dyspnea Score (Following 6MWT) From Baseline to Week 16
timeFrame: Baseline to week 16
measure: Change in N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Concentrations From Baseline to Week 16.
timeFrame: Baseline to week 16
measure: Number of Participants With a Change From Baseline World Health Organization (WHO) Functional Classification at Week 16.
timeFrame: Baseline to week 16
measure: Change in Quality of Life (QoL) Assessment: Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) From Baseline to Week 16.
timeFrame: Baseline to week 16
measure: Change From Baseline to Week 16 in Hemodynamic Parameters: Mean Pulmonary Artery Pressure (PAPm), Mean Right Atrial Pressure (RAPm) and Mean Pulmonary Capillary Wedge Pressure (PCWPm).
timeFrame: Baseline to week 16
measure: Change From Baseline to Week 16 in Hemodynamic Parameters: Cardiac Index (CI) (L/Min/m^2)
timeFrame: Baseline to week 16
measure: Change From Baseline to Week 16 in HemodynamicParameters: Pulmonary Vascular Resistance Index (PVRI) (mmHg*Min*m^2/L)
timeFrame: Baseline to week 16
Other outcomes:
Locations:
Study officials:
affiliation: Thoraxklinik am Universitätsklinikum, Heidelberg, Germany
name: Grünig
role: PRINCIPAL_INVESTIGATOR
affiliation: Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
name: Klose
role: PRINCIPAL_INVESTIGATOR
affiliation: Universitätsklinikum Köln, Köln, Germany
name: Rosenkranz
role: PRINCIPAL_INVESTIGATOR
affiliation: Universitaetsklinikum Dresden, Dresden, Germany
name: Höffken
role: PRINCIPAL_INVESTIGATOR
affiliation: Universitätsklinikum Regensburg, Regensburg, Germany
name: Lange
role: PRINCIPAL_INVESTIGATOR
affiliation: Universitätsklinikum Leipzig, Leipzig, Germany
name: Wirtz
role: PRINCIPAL_INVESTIGATOR
affiliation: Klinikum Großhadern der LMU, Munich, Germany
name: Neurohr
role: PRINCIPAL_INVESTIGATOR
affiliation: Universitätsklinikum Klinik, Homburg, Germany
name: Wilkens
role: PRINCIPAL_INVESTIGATOR
affiliation: Missionsärztliche Klinik, Würzburg, Germany
name: Held
role: PRINCIPAL_INVESTIGATOR
affiliation: Herzzentrum Duisburg, Duisburg, Germany
name: Krüger
role: PRINCIPAL_INVESTIGATOR
References: