Safety, Tolerability, Pharmacokinetics and Efficacy of Two Different Rates of Subcutanous Remodulin® Dose Titration in Pulmonary Arterial Hypertension

• Register: ClinicalTrials.gov
• Last refreshed on: 16 December 2017
• Main ID: NCT02893995
• Date of registration: 24/08/2016
• Prospective Registration: Yes
• Primary sponsor: United Therapeutics
• Public title: Safety, Tolerability, Pharmacokinetics and Efficacy of Two Different Rates of Subcutanous Remodulin® Dose Titration in Pulmonary Arterial Hypertension
• Scientific title: A 16-Week, Open-Label, Multi-Center, Parallel, Randomized Controlled Study to Compare the Safety, Tolerability, Pharmacokinetics and Efficacy of Slow and Rapid Dose Titration Regimens of Subcutaneous Remodulin Therapy in Subjects With Pulmonary Arterial Hypertension
• Date of first enrolment: February 2017
• Target sample size: 0
• Recruitment status: Withdrawn
• URL: https://clinicaltrials.gov/show/NCT02893995
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 4

Countries of recruitment

China

Contacts

• Name: Junbo Ge
• Affiliation: Zhongshan Hospital affiliated with Fudan University

Key inclusion & exclusion criteria

Inclusion Criteria:

A subject is eligible for inclusion in this study if all of the following criteria apply:

1. The subject voluntarily gives written informed consent to participate in the study.

2. The subject is at least 18 years of age at screening.

3. The subject weighs a minimum of 40 kg with a body mass index less than 40 kg/m2 at
screening.

4. The subject has a diagnosis of idiopathic or heritable PAH, PAH associated with
repaired congenital systemic-to-pulmonary shunts (at least one year since repair with
respect to the date of providing informed consent), or PAH associated with connective
tissue diseases.

5. The subject must have a baseline 6MWD between 150 and 550 meters, inclusive, in the
absence of a concurrent injury, illness (other than PAH or a PAH related condition),
or other confounding factor that would prevent the accurate assessment of the
subject's exercise capacity.

6. The subject is either treatment naïve or is receiving a PDE-5 inhibitor and/or an ERA
for at least 60 days prior to screening and on a stable dose for at least 30 days
prior to screening 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 catheterization during the screening period (or
within 3 years before screening) and been documented to have a mean pulmonary artery
pressure (PAPm) of greater than or equal to 25 mmHg, a pulmonary arterial wedge
pressure (PAWP) 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 within 7 days prior to randomisation 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. Subjects with clinically
insignificant left ventricular diastolic dysfunction due to the effects of right
ventricular overload (i.e., right ventricular hypertrophy and/or dilatation) will not
be excluded.

10. The subject has a previous ventilation perfusion lung scan and/or high resolution
computerized tomography scan of the chest and/or pulmonary angiography that are
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 prior to or during the
screening period with the following:

1. Total lung capacity (TLC) is at least 60% (of predicted value)

2. Forced expiratory volume in one second/forced vital capacity (FEV1/FVC) ratio is
at least 50%

12. Sexually active women of childbearing potential must practice true abstinence from
intercourse when it is in line with their preferred and usual lifestyle, or use two
different forms of highly effective contraception. Medically acceptable forms of
effective contraception include: (1) approved hormonal contraceptive (such as birth
control pills), (2) barrier methods (such as a condom or diaphragm) used with a
spermicide, (3) an intrauterine device (IUD), or (4) partner vasectomy. For women of
childbearing potential, a negative serum pregnancy test is required at screening and a
negative hCG urine pregnancy test is required at baseline visit. Women of child
bearing potential include any females who have experienced menarche and who have not
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or
bilateral oophorectomy) or are not postmenopausal (defined as amenorrhea for at least
12 consecutive months).

Males participating in the study must use a condom during the length of the study, and
for at least 48 hours after discontinuing study medication.

13. In the opinion of the Principal Investigator, the subject is able to communicate
effectively with study personnel, is considered reliable, willing and likely to be
cooperative with protocol requirements, including attending all study visits, and is
mentally and physically capable of learning to administer Remodulin by continuous SC
infusion using a micro infusion pump.

Exclusion Criteria:

A subject is not eligible for inclusion in this study if any of the following criteria
apply:

1. The subject is pregnant or lactating.

2. The subject has received epoprostenol, treprostinil, iloprost or beraprost within 90
days prior to screening (except if used during acute vasoreactivity testing).

3. The subject has had previous intolerance or 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 or heritable PAH,
or PAH associated with repaired (for at least one year) congenital
systemic-to-pulmonary shunts or connective tissue diseases or has had an atrial
septostomy.

5. The subject is in WHO functional class IV.

6. The subject has a current diagnosis of uncontrolled sleep apnea as defined by their
physician.

7. The subject has liver function tests (AST or ALT) greater than three times the upper
limit of the laboratory reference range.

8. The subject has a history of active gastro-intestinal ulcer, intracranial hemorrhage,
injury or other cause of clinically significant bleeding episode within 6 months
before screening, or any other disease / condition that would either jeopardize 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 before screening, or
history of left sided myocardial disease as evidenced by a PAWP (or left ventricular
end-diastolic pressure) 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 mm


Age minimum: 18 Years
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

Pulmonary Arterial Hypertension

Intervention(s)

Drug: Slow Dose Titration Group of Subcutaneous Treprostinil

Drug: Rapid Dose Titration Group of Subcutaneous Treprostinil

Primary Outcome(s)

Change in Patient Reported Site Pain from Baseline to Week 16 [Time Frame: Baseline and Week 16]

Incidence of Subject Discontinuations Among Participants through 16 Weeks [Time Frame: 16 Weeks]

Incidence of Adverse Events Among Subjects through 16 Weeks [Time Frame: 16 Weeks]

Secondary Outcome(s)

Change in 6-minute Walk Distance (6MWD) from Baseline to Week 16 [Time Frame: Baseline and Week 16]

Change in Borg Dyspnea Score (following 6MWT) from Baseline to Week 16 [Time Frame: Baseline and Week 16]

Number of Participants with a Change from Baseline World Health Organization (WHO) Functional Classification at Week 16 [Time Frame: Change from Baseline at Week 16]

Change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations from Baseline to Week 16 [Time Frame: Baseline and Week 16]

Change in PAH Symptoms from Baseline to Week 16 [Time Frame: Change from Baseline at 16 Weeks]

Measure treprostinil plasma concentration from Week 4 to Week 16 [Time Frame: Week 4, Week 8, Week 12, and Week 16]

Change in Measured Tricuspid Annular Plane Systolic Excursion (TAPSE) from Baseline to Week 16 [Time Frame: Baseline and Week 16]

Change in Measured Tricuspid Regurgitant Jet Velocity (TRJV) from Baseline to Week 16 [Time Frame: Baseline and Week 16]

Incidence of Pericardial Effusion from Baseline to Week 16 [Time Frame: Baseline and Week 16]

Secondary ID(s)

CVT-CV-003

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Secondary Sponsor(s)

CVie Therapeutics Co. Ltd.