A Study to Assess the Safety, Tolerability, and Hemodynamic Response of PB1046 in Subjects With PAH

An Open-Label, Dose Titration Study to Assess the Safety, Tolerability, and Hemodynamic Response of PB1046, A Sustained-Release Analogue of Vasoactive Intestinal Peptide, In Adult Subjects With Pulmonary Arterial Hypertension

PB1046-PT-CL-0005 is an open-label, dose-titration study to assess the safety, tolerability, and hemodynamic effects of individually dose-titrated PB1046 administered by weekly subcutaneous injection for 8 weeks in adult subjects with PAH who have a permanently implanted hemodynamic monitor in the distal pulmonary artery. The primary objectives of the study are to assess the overall safety, tolerability, and hemodynamic profile of a PB1046 across an individually titrated dose range.

Study Overview

• Status: Completed
• Conditions: Pulmonary Arterial Hypertension
• Intervention / Treatment: Drug: PB1046 Subcutaneous Injection

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University Wexner Medical Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Willing and able to provide written informed consent and follow all study-related procedures;
• Confirmed diagnosis of Pulmonary Arterial Hypertension (WHO Group 1) and WHO Functional Class II or III by clinical diagnostic criteria assessed by the Investigator and have a permanently implanted pulmonary artery hemodynamic monitor (IHM);
• Adult subjects ≥18 years of age willing and able to utilize contraception as needed for 30 days after their last dose of study drug;
• Body mass index ≥ 18 kg/m2 and ≤ 47 kg/m2;
• Receipt of Investigator-directed stable (no change in dose or addition or removal of a therapy) medical-therapy in accordance with local standard of care for the management of PAH for 30 days prior to screening and between screening and first dose and are in stable clinical condition;
• Screening hemoglobin ≥ 9.0 g/dL secondary to the volume of blood to be collected during the study period;
• Willing and able to return to the study unit for specified study visits, or accommodate home visits;
• Willing and able to transmit hemodynamics via IHM and monitor systemic blood pressure while at home and record results.

Exclusion Criteria:

• Concomitant medical disorder, condition, or history, that in the opinion of the Investigator would impair the subject's ability to participate in or complete the requirements of the study;
• Concomitant medical disorder that is expected to limit the subject's life-expectancy to ≤ 1 year;
• Pregnant or lactating female subjects;
• First positive result from serology testing at visit 1 (screening labs) for human immunodeficiency virus, hepatitis B surface antigen, or hepatitis C virus prior to first dose;
• Participation in another investigational study within 30 days prior to screening or are taking part in a non-medication study which, in the opinion of the Investigator, would interfere with the study compliance or outcome assessments;
• Use of bosentan therapy for PAH within 30 days prior to screening or during study participation;
• Sustained systolic blood pressure (SBP) < 95 mmHg and/or diastolic blood pressure (DBP) < 50 mmHg (confirmed by a duplicate seated reading) on at least 3 consecutive readings (self-monitored or office) prior to first dose, or overt symptomatic hypotension;
• Sustained resting heart rate >110 beats per minute (BPM) at screening (V1) or prior to first dose (confirmed by duplicate assessments of office vital signs or consecutive ECG assessments) on at least 3 consecutive readings prior to first dose;
• Clinically significant renal dysfunction as measured by the estimated glomerular filtration rate (eGFR) of < 40 mL/min/1.73m2 as calculated by the MDRD equation: eGFR = 175 x (Creat / 88.4)-1.154 x (Age)-0.203 x (0.742 if female) x (1.212 if African American) (conventional units);
• Clinically significant liver dysfunction as measured by any one of the following: a. alanine aminotransferase (ALT) >3.0 time ULN or; b. aspartate aminotransferase (AST) >3.0 time ULN or; c. serum bilirubin ≥ 1.6 mg/dL;
• Known history of substance abuse that in the opinion of the Investigator would impair the subject's ability to participate in or complete the requirements of the study;
• Any major surgical procedure within 30 days prior to screening or planned surgical procedure during the study period;
• In-patient hospitalization (defined as greater than 23 hours) within 30 days of subject dosing;
• Enrollment within the past 3 months prior to screening or plans to enroll during the study into a cardiopulmonary rehabilitation program;
• Other medical or psychiatric condition which, in the opinion of the Investigator, would place the subject at increased risk or would preclude obtaining voluntary consent or would confound the objectives of study;
• Known hypersensitivity to study drug or any of the excipients of the drug formulation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PB1046 Injection; PB1046 Subcutaneous Injection	Drug: PB1046 Subcutaneous Injection; Eight weekly doses of PB1046.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events	Incidence and severity of AEs (described descriptively) and their relationship to study drug	Pre-dose to 28 days after last dose
Vital Signs (Blood pressure)	Changes from baseline in blood pressure and their relationship to study drug	Prior to eight weekly doses and 1 and 3 hours after the final dose and 1, 2, 3, 5, 7 and 28 days after final dose.
Vital Signs (Heart rate)	Changes from baseline in heart rate and their relationship to study drug	Prior to eight weekly doses and 1 and 3 hours after the final dose and 1, 2, 3, 5, 7 and 28 days after final dose.
Laboratory Parameters (Lipids)	Changes from baseline in lipids and their relationship to study drug	Pre-dose and 7 and 28 days after last dose
Laboratory Parameters (Serum chemistry)	Changes from baseline in serum chemistry and their relationship to study drug	Pre-dose and prior to doses 2-8 and 7 and 28 days after last dose
Laboratory Parameters (Urinalysis)	Changes from baseline in urinalysis and their relationship to study drug	Pre-dose and prior to doses 2-8 and 7 and 28 days after last dose
Laboratory Parameters (NT-pro-BNP)	Changes from baseline in NT-pro-BNP and their relationship to study drug	Prior to doses 1-8 and 7 and 28 days after last dose
Mean Pulmonary Artery Pressure	Change from baseline in mean pulmonary artery pressure	Prior to eight weekly doses and 1 and 3 hours after the final dose and 1, 2, 3, 5, 7, 8 and 28 days after final dose
Cardiac Index	Change from baseline in cardiac index	Prior to eight weekly doses and 1 and 3 hours after the final dose and 1, 2, 3, 5, 7, 8 and 28 days after final dose
Total pulmonary resistance	Change from baseline in total pulmonary resistance	Prior to eight weekly doses and 1 and 3 hours after the final dose and 1, 2, 3, 5, 7, 8 and 28 days after final dose
Laboratory Parameters (Fasting Plasma Glucose)	Changes from baseline in fasting plasma glucose and their relationship to study drug	Pre-dose and 7 and 28 days after last dose
Laboratory Parameters (Hematology)	Changes from baseline in hematology and their relationship to study drug	Pre-dose and prior to doses 2-8 and 7 and 28 days after last dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic Dose Exposures (AUC (0-t))	Area under the curve over the dosing interval (AUC(0-t))	Prior to eight weekly doses and at 1, 3, 24, 48, 72,120, 168 and 192 hours after final dose.
Pharmacokinetic Dose Exposures (AUC (0-tmax))	Area under the curve concentration-time profile (AUC(0-tmax))	Prior to eight weekly doses and at 1, 3, 24, 48, 72,120, 168 and 192 hours after final dose.
Pharmacokinetic Dose Exposures (Cmax)	Maximum serum concentration (Cmax)	Prior to eight weekly doses and at 1, 3, 24, 48, 72,120, 168 and 192 hours after final dose.
Pharmacokinetic Dose Exposures (Tmax)	Time to Cmax (Tmax)	Prior to eight weekly doses and at 1, 3, 24, 48, 72,120, 168 and 192 hours after final dose.
Pharmacokinetic Dose Exposures (Ctrough)	Pre-dose serum concentrations at Weeks 1 through 7 and the concentrations after the last dose	Prior to eight weekly doses and at 1, 3, 24, 48, 72,120, 168 and 192 hours after final dose.
Pharmacokinetic Dose Exposures (t1/2)	Half-life (t1/2)	Prior to eight weekly doses and at 1, 3, 24, 48, 72,120, 168 and 192 hours after final dose.
Pharmacokinetic Dose Exposures (Lambda z)	Lambda z	Prior to eight weekly doses and at 1, 3, 24, 48, 72,120, 168 and 192 hours after final dose.
Pharmacokinetic Dose Exposures (Cl/F)	Apparent clearance (Cl/F)	Prior to eight weekly doses and at 1, 3, 24, 48, 72,120, 168 and 192 hours after final dose.
Pharmacokinetic Dose Exposures (Vd/F)	Volume of distribution (Vd/F)	Prior to eight weekly doses and at 1, 3, 24, 48, 72,120, 168 and 192 hours after final dose.
Immunogenicity	Incidence of immunogenicity	Prior to eight weekly doses and on study days 59, 77 and 105.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
6 Minute Walk Distance Test (6MWD)	Change from baseline in 6MWD	Pre-dose and 7 days after final dose
Borg Dyspnea Index (BDI)	Change from baseline in BDI	Pre-dose and 7 days after final dose
PAH Related Biomarkers	Change from baseline in PAH related biomarkers	Prior to Dose 1, prior to Dose 5 and 7 days after final dose

Collaborators and Investigators

• Sponsor: PhaseBio Pharmaceuticals Inc.

Study record dates

Study Major Dates

• Study Start (Actual): October 20, 2017
• Primary Completion (Actual): August 8, 2019
• Study Completion (Actual): August 8, 2019

Study Registration Dates

• First Submitted: October 2, 2017
• First Submitted That Met QC Criteria: October 16, 2017
• First Posted (Actual): October 20, 2017

Study Record Updates

• Last Update Posted (Actual): October 8, 2019
• Last Update Submitted That Met QC Criteria: October 7, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Hypertension; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Vasodilator Agents; VIP-ELP fusion molecule PB1046
• Other Study ID Numbers: PB1046-PT-CL-0005

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No