Phase 2 Study to Assess Safety, Tolerability and Efficacy of Once Weekly SC Pemziviptadil (PB1046) in Subjects With Symptomatic PAH

Pulmonary Arterial Hypertension Clinical Trial

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Official title:

A Randomized, Double-Blind, Parallel Group, Phase 2 Study to Assess the Safety, Tolerability, and Efficacy of Once Weekly Subcutaneous (SC) Injections of a Sustained-Release Vasoactive Intestinal Peptide (VIP) Analogue, Pemziviptadil (PB1046), in Adult Subjects With Symptomatic Pulmonary Arterial Hypertension (PAH)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03556020
• Other study ID #: PB1046-PT-CL-0004
• Status: Terminated
• Phase: Phase 2
• Start date: July 15, 2018
• Est. completion date: January 7, 2022

Study information

• Verified date: August 2022
• Source: PhaseBio Pharmaceuticals Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a multi-center, randomized, double-blind, controlled, Phase 2 study to assess the safety, tolerability, and efficacy of pemziviptadil (PB1046) at the optimally titrated dose after 16 weeks of treatment. Subjects will be randomized in a 2:1 ratio to one of two parallel dose groups: a) high-dose group where PB1046 will be up-titrated from a 0.2 mg/kg minimally effective starting dose to a target high dose level of at least 1.2 mg/kg or higher to a maximally tolerated dose (MTD), or b) a low-dose group that will start at 0.2 mg/kg and remain at this minimally effective dose (MED) level with sham up-titration. The total treatment period will be comprised of 2 phases: 1) an initial 10 week dose titration phase in which weekly doses of PB1046 will be titrated (or sham titrated) up to a target dose level of at least 1.2 mg/kg or higher to the MTD, and 2) a maintenance of treatment phase that begins when subjects reach week 11 and continues for 6 weeks during which no further up-titration should occur.

Description:

The primary safety and tolerability objectives will be assessed by investigating the incidence and severity of adverse events (AEs) as well as changes from baseline in vital signs, laboratory parameters, ECGs and their relationship to pemziviptadil (PB1046). The primary efficacy objective will be assessed by investigating the change in PVR derived from right heart catheterization (RHC). Secondary efficacy objectives will be assessed by investigating the impact of pemziviptadil (PB1046) on change from baseline in 6 minute walk distance (6MWD) test and NT-proBNP, a prognostic biomarker for PAH, in the two groups (comparing the MTD and MED groups) at the end of the treatment period. In addition, the effect of pemziviptadil (PB1046) on other cardiopulmonary hemodynamic parameters (e.g. CI, mPAP, mRAP, wedge pressure and SvO2) as measured by RHC will be assessed. Changes in BDI, HRQoL, and NYHA/WHO (New York Heart Association/World Health Organization) FC will also be assessed.

An independent Data Safety Monitoring Board (DSMB) will periodically assess safety, efficacy and biomarker data to independently assess the overall safety profile of pemziviptadil (PB1046), to help adjudicate potential dose-limiting toxicities, and to monitor the overall benefit risk profile of pemziviptadil (PB1046) during the study. The DSMB will review the safety and tolerability data after the first 10 subjects while recruitment is ongoing.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 35
• Est. completion date: January 7, 2022
• Est. primary completion date: January 7, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 79 Years

Eligibility

Inclusion Criteria:

• Male and female subjects with PAH, =18 and = 79 years of age, who are symptomatic and have reduced exercise capacity due primarily to their PAH diagnosis and have been assessed by a qualified individual (i.e. physician, physician assistant, nurse practitioner) to be in NYHA/WHO functional class II or III;

• Willing and able to sign a written informed consent prior to all study-related procedures;

• Subjects with PAH belonging to one of the following subgroups of the Nice Clinical Classification of Pulmonary Hypertension Group 1: a. Idiopathic, b. Heritable, c. Drug or toxin-induced, d. Associated with connective tissue disease, HIV infection, portal hypertension, congenital heart disease (pulmonary-to-systemic shunt;

• Two 6MWD test results > 50 m and < 550 m prior to randomization with results +/- 10% of each other. Note: Up to four tests may be conducted between Screening and Randomization for eligibility purposes;

• Hemodynamic assessment of PAH demonstrating elevated mPAP and PVR as indicated below during the Screening Period: a. mean pulmonary artery pressure (mPAP) of = 25 mmHg; and, b. pulmonary vascular resistance (PVR) = 400 dyne•sec/cm5; and, c. pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) of = 12 mmHg if PVR = 400 and < 500 dynes•sec/cm5; or PCWP/LVEDP = 15 mmHg if PVR = 500 dynes•sec/cm5;

• Body mass index = 18 kg/m2 and = 40 kg/m2 at screening;

• Meet the following criteria determined by pulmonary function tests completed no more than 24 weeks prior to screening: a. Forced expiratory volume in one second (FEV1) = 55% of predicted normal, b. FEV1: FVC (forced vital capacity) ratio = 0.60;

• Agrees to use a medically acceptable method of contraception (both male and female patients) throughout the entire study period and continuing for 30 days after their last dose of study drug;

• Stable background medical regimen of up to 3 oral PAH therapies for at least 30 days prior to Screening and having been on PAH therapy for at least 3 months;

• If a subject has historical diagnosis (prior to screening visit) of being positive for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV), must be clinically stable and if on therapy, must be on stable therapy for HIV or HCV for at least 3 months; Willing and able to understand and follow instructions; return to the study unit for specified study visits; and able to participate in the study for the entire period.

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 HIV, HBsAg, or HCV prior to randomization;

• Participation in another investigational drug study within 30 days prior to screening or participating in a non-medication study which, in the opinion of the Investigator, would interfere with the study compliance or outcome assessments;

• Use of chronic subcutaneous prostanoid/prostacyclin therapy for PAH within 30 days prior to screening, including prostacyclin receptor agonists;

• More than mild mitral or aortic valve disease, left ventricular ejection fraction < 50%, or left ventricular regional wall motion abnormality suggestive of active coronary artery disease on documented 2D-echocardiography occurring within 12 months of Screening;

• 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) at screening and prior to dosing, or overt symptomatic hypotension;

• Sustained resting heart rate >110 beats per minute (BPM) (confirmed by duplicate assessments of office vital signs or consecutive ECG assessments) on at least 3 consecutive readings at screening and prior to dosing;

• Clinically significant renal dysfunction at the Screening Visit as measured by the estimated glomerular filtration rate (eGFR)

• Significant liver dysfunction as measured by any one of the following at screening: a. alanine aminotransferase (ALT) >3.0 times upper limit of normal (ULN) or; b. aspartate aminotransferase (AST) >3.0 times ULN or; c. serum bilirubin = 1.6 mg/dL;

• Known history of substance abuse within the past 1 year 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 90 days prior to screening or planned surgical procedure during the study period;

• Any in-patient hospitalization (defined as greater than 23 hours) within 30 days of subject screening;

• 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;

• More than two of the following: a. BMI > 35; b. Current atrial fibrillation; c. Current Diabetes Mellitus; d. Current hypertension; e. History of clinically significant coronary artery disease in prior 3 years.

Related Conditions & MeSH terms

• Familial Primary Pulmonary Hypertension
• Hypertension
• Pulmonary Arterial Hypertension

Intervention

Drug:
• Pemziviptadil (PB1046)
Pemziviptadil (PB1046), Once Weekly Subcutaneous Injection

Locations

Country	Name	City	State
United States	The Emory Clinic	Atlanta	Georgia
United States	University of Colorado Denver	Aurora	Colorado
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Tufts University	Boston	Massachusetts
United States	University of Chicago	Chicago	Illinois
United States	The Linder Center for Resarch and Education at The Christ Hospital	Cincinnati	Ohio
United States	University of Cincinnati	Cincinnati	Ohio
United States	UT Southwestern Medical Center	Dallas	Texas
United States	University of Florida	Gainesville	Florida
United States	Memorial Hermann Hospital CRU affiliated with University of Texas Health Science Center at Houston - McGovern Medical School	Houston	Texas
United States	University of Iowa Hospitals & Clinics, Dept of Internal Medicine	Iowa City	Iowa
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	University of California, San Diego (UCSD)	La Jolla	California
United States	University of Southern California, Keck School of Medicine	Los Angeles	California
United States	VA Greater Los Angeles Healthcare System	Los Angeles	California
United States	The University Miami Health Hospital	Miami	Florida
United States	IMC - Diagnostic & Medical Clinic, LLC	Mobile	Alabama
United States	NYU Langone Health	New York	New York
United States	INTEGRIS Baptist Medical Center	Oklahoma City	Oklahoma
United States	AdventHealth Orlando	Orlando	Florida
United States	Allegheny General Hospital	Pittsburgh	Pennsylvania
United States	UPMC Presbyterian Hospital	Pittsburgh	Pennsylvania
United States	University of Rochester Medical Center	Rochester	New York
United States	University of California-Davis	Sacramento	California
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Banner University Medical Center	Tucson	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
PhaseBio Pharmaceuticals Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change from baseline in Borg Dyspnea Index (BDI) at the end of treatment		142 days - Pre-dose (up to 30 days prior to first dose) and one week post-dose 16.
Other	Change from baseline in emPHasis-10 (HRQoL) score at the end of treatment		142 days - Pre-dose (up to 30 days prior to first dose) and one week post-dose 16.
Other	Change in NYHA/WHO Functional Class (FC) at the end of treatment		142 days - Pre-dose (up to 30 days prior to first dose) and one week post-dose 16.
Other	Incidence of clinical worsening over 16 weeks as defined by any one of the following (See description):	All-cause mortality, Hospitalization due to worsening of PAH, Initiation of parenteral prostacyclin, Worsening of PAH either by >15% decrease in 6MWD or new or worsening right heart failure (RHF), or worsening of symptoms requiring escalation of PAH therapy	142 days - Pre-dose (up to 30 days prior to first dose) and post-dose 16.
Other	Time to clinical worsening with data censored at the end of treatment		142 days - Pre-dose (up to 30 days prior to first dose) and post-dose 16.
Other	Change from baseline in other PAH biomarkers at the end of treatment		142 days - Pre-dose (up to 30 days prior to first dose) and post-dose 16.
Other	Multi-dose pharmacokinetic (PK) profile of individually dose-titrated pemziviptadil (PB1046) administered once-weekly for 16 weeks - Cmax		Pre-dose (Dose 1), day 28 pre-dose, day 70 pre-dose, day 77 pre-dose, day 84 pre-dose, day 91 pre-dose, day 98 pre-dose, day 105 pre-dose, 1 and 3 hours post-dose, day 106, day 107, day 108, day 110 and day 112.
Other	Multi-dose pharmacokinetic (PK) profile of individually dose-titrated PB1046 administered once-weekly for 16 weeks - Tmax		Pre-dose (Dose 1), day 28 pre-dose, day 70 pre-dose, day 77 pre-dose, day 84 pre-dose, day 91 pre-dose, day 98 pre-dose, day 105 pre-dose, 1 and 3 hours post-dose, day 106, day 107, day 108, day 110 and day 112.
Other	Multi-dose pharmacokinetic (PK) profile of individually dose-titrated pemziviptadil (PB1046) administered once-weekly for 16 weeks - Ctrough		Pre-dose (Dose 1), day 28 pre-dose, day 70 pre-dose, day 77 pre-dose, day 84 pre-dose, day 91 pre-dose, day 98 pre-dose, day 105 pre-dose, 1 and 3 hours post-dose, day 106, day 107, day 108, day 110 and day 112.
Other	Multi-dose pharmacokinetic (PK) profile of individually dose-titrated pemziviptadil (PB1046) administered once-weekly for 16 weeks - Area Under Curve(0-t) [AUC(0-t)]		Pre-dose (Dose 1), day 28 pre-dose, day 70 pre-dose, day 77 pre-dose, day 84 pre-dose, day 91 pre-dose, day 98 pre-dose, day 105 pre-dose, 1 and 3 hours post-dose, day 106, day 107, day 108, day 110 and day 112.
Other	Multi-dose pharmacokinetic (PK) profile of individually dose-titrated pemziviptadil (PB1046) administered once-weekly for 16 weeks - AUC(0-tmax)		Pre-dose (Dose 1), day 28 pre-dose, day 70 pre-dose, day 77 pre-dose, day 84 pre-dose, day 91 pre-dose, day 98 pre-dose, day 105 pre-dose, 1 and 3 hours post-dose, day 106, day 107, day 108, day 110 and day 112.
Other	Multi-dose pharmacokinetic (PK) profile of individually dose-titrated pemziviptadil (PB1046) administered once-weekly for 16 weeks - AUC(tmax-t)		Pre-dose (Dose 1), day 28 pre-dose, day 70 pre-dose, day 77 pre-dose, day 84 pre-dose, day 91 pre-dose, day 98 pre-dose, day 105 pre-dose, 1 and 3 hours post-dose, day 106, day 107, day 108, day 110 and day 112.
Primary	Incidence and severity of AEs		172 days - Starting up to 30 days prior to first dose and completing 28 days after last dose.
Primary	Incidence of Clinical Laboratory Abnormalities		172 days - Starting up to 30 days prior to first dose and completing 28 days after last dose.
Primary	Changes in Diastolic Blood Pressure		172 days - Starting up to 30 days prior to first dose and completing 28 days after last dose.
Primary	Changes in Systolic Blood Pressure		172 days - Starting up to 30 days prior to first dose and completing 28 days after last dose.
Primary	Changes in Oral Body Temperature		172 days - Starting up to 30 days prior to first dose and completing 28 days after last dose.
Primary	Changes in Respiratory Rate		172 days - Starting up to 30 days prior to first dose and completing 28 days after last dose.
Primary	Changes in Heart Rate		172 days - Starting up to 30 days prior to first dose and completing 28 days after last dose.
Primary	12-Lead ECG - Incidence of clinically significant findings		172 days - Starting up to 30 days prior to first dose and completing 28 days after last dose.
Primary	Immunogenicity		172 days - Starting up to 30 days prior to first dose and completing 8 weeks after last dose. May be extended in the event that result does not return to baseline in time allotted.
Primary	Change in baseline in pulmonary vascular resistance (PVR)		142 days - Pre-dose (up to 30 days prior to first dose) and post-dose 16.
Secondary	Change from baseline in 6MWD		142 days - Pre-dose (up to 30 days prior to first dose) and one week post-dose 16.
Secondary	Change from baseline in NT-proBNP		142 days - Pre-dose (up to 30 days prior to first dose) and one week post-dose 16.
Secondary	Change from baseline in cardiac index (CI)		142 days - Pre-dose (up to 30 days prior to first dose) and one week post-dose 16.
Secondary	Change from baseline in mean pulmonary artery pressure (mPAP)		142 days - Pre-dose (up to 30 days prior to first dose) and one week post-dose 16.
Secondary	Change from baseline in mean right atrial pressure (mRAP)		142 days - Pre-dose (up to 30 days prior to first dose) and one week post-dose 16.
Secondary	Change from baseline in wedge pressure		142 days - Pre-dose (up to 30 days prior to first dose) and one week post-dose 16.
Secondary	Change from baseline in mixed venous oxygen saturation (SvO2)		142 days - Pre-dose (up to 30 days prior to first dose) and one week post-dose 16.
Secondary	Change from baseline in pulmonary artery compliance		142 days - Pre-dose (up to 30 days prior to first dose) and one week post-dose 16.