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

Study Description

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Brief Summary:

This is a multi-center, randomized, double-blind, controlled, Phase 2 study to assess the safety, tolerability, and efficacy of 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.

Condition or disease	Intervention/treatment	Phase
Pulmonary Arterial Hypertension	Drug: PB1046	Phase 2

Detailed 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 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 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 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 PB1046, to help adjudicate potential dose-limiting toxicities, and to monitor the overall benefit risk profile of PB1046 during the study. The DSMB will review the safety and tolerability data after the first 10 subjects while recruitment is ongoing.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	63 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
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, PB1046, in Adult Subjects With Symptomatic Pulmonary Arterial Hypertension (PAH)
Actual Study Start Date :	July 15, 2018
Estimated Primary Completion Date :	January 31, 2020
Estimated Study Completion Date :	January 31, 2020

Arms and Interventions

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Arm	Intervention/treatment
Experimental: High Dose Group; Maximally tolerated dose Drug: PB1046, Once Weekly Subcutaneous Injection	Drug: PB1046; PB1046, Once Weekly Subcutaneous Injection
Experimental: Low Dose Group; Minimally effective dose Drug: PB1046, Once Weekly Subcutaneous Injection	Drug: PB1046; PB1046, Once Weekly Subcutaneous Injection

Outcome Measures

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Primary Outcome Measures :

1. Incidence and severity of AEs [ Time Frame: 172 days - Starting up to 30 days prior to first dose and completing 28 days after last dose. ]
2. Incidence of Clinical Laboratory Abnormalities [ Time Frame: 172 days - Starting up to 30 days prior to first dose and completing 28 days after last dose. ]
3. Changes in Diastolic Blood Pressure [ Time Frame: 172 days - Starting up to 30 days prior to first dose and completing 28 days after last dose. ]
4. Changes in Systolic Blood Pressure [ Time Frame: 172 days - Starting up to 30 days prior to first dose and completing 28 days after last dose. ]
5. Changes in Oral Body Temperature [ Time Frame: 172 days - Starting up to 30 days prior to first dose and completing 28 days after last dose. ]
6. Changes in Respiratory Rate [ Time Frame: 172 days - Starting up to 30 days prior to first dose and completing 28 days after last dose. ]
7. Changes in Heart Rate [ Time Frame: 172 days - Starting up to 30 days prior to first dose and completing 28 days after last dose. ]
8. 12-Lead ECG - Incidence of clinically significant findings [ Time Frame: 172 days - Starting up to 30 days prior to first dose and completing 28 days after last dose. ]
9. Immunogenicity [ Time Frame: 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. ]
10. Change in baseline in pulmonary vascular resistance (PVR) [ Time Frame: 142 days - Pre-dose (up to 30 days prior to first dose) and post-dose 16. ]

Secondary Outcome Measures :

1. Change from baseline in 6MWD [ Time Frame: 142 days - Pre-dose (up to 30 days prior to first dose) and one week post-dose 16. ]
2. Change from baseline in NT-proBNP [ Time Frame: 142 days - Pre-dose (up to 30 days prior to first dose) and one week post-dose 16. ]
3. Change from baseline in cardiac index (CI) [ Time Frame: 142 days - Pre-dose (up to 30 days prior to first dose) and one week post-dose 16. ]
4. Change from baseline in mean pulmonary artery pressure (mPAP) [ Time Frame: 142 days - Pre-dose (up to 30 days prior to first dose) and one week post-dose 16. ]
5. Change from baseline in mean right atrial pressure (mRAP) [ Time Frame: 142 days - Pre-dose (up to 30 days prior to first dose) and one week post-dose 16. ]
6. Change from baseline in wedge pressure [ Time Frame: 142 days - Pre-dose (up to 30 days prior to first dose) and one week post-dose 16. ]
7. Change from baseline in mixed venous oxygen saturation (SvO2) [ Time Frame: 142 days - Pre-dose (up to 30 days prior to first dose) and one week post-dose 16. ]
8. Change from baseline in pulmonary artery compliance [ Time Frame: 142 days - Pre-dose (up to 30 days prior to first dose) and one week post-dose 16. ]

Other Outcome Measures:

1. Change from baseline in Borg Dyspnea Index (BDI) at the end of treatment [ Time Frame: 142 days - Pre-dose (up to 30 days prior to first dose) and one week post-dose 16. ]
2. Change from baseline in emPHasis-10 (HRQoL) score at the end of treatment [ Time Frame: 142 days - Pre-dose (up to 30 days prior to first dose) and one week post-dose 16. ]
3. Change in NYHA/WHO Functional Class (FC) at the end of treatment [ Time Frame: 142 days - Pre-dose (up to 30 days prior to first dose) and one week post-dose 16. ]
4. Incidence of clinical worsening over 16 weeks as defined by any one of the following (See description): [ Time Frame: 142 days - Pre-dose (up to 30 days prior to first dose) and post-dose 16. ]
   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
5. Time to clinical worsening with data censored at the end of treatment [ Time Frame: 142 days - Pre-dose (up to 30 days prior to first dose) and post-dose 16. ]
6. Change from baseline in other PAH biomarkers at the end of treatment [ Time Frame: 142 days - Pre-dose (up to 30 days prior to first dose) and post-dose 16. ]
7. Multi-dose pharmacokinetic (PK) profile of individually dose-titrated PB1046 administered once-weekly for 16 weeks - Cmax [ Time Frame: 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. ]
8. Multi-dose pharmacokinetic (PK) profile of individually dose-titrated PB1046 administered once-weekly for 16 weeks - Tmax [ Time Frame: 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. ]
9. Multi-dose pharmacokinetic (PK) profile of individually dose-titrated PB1046 administered once-weekly for 16 weeks - Ctrough [ Time Frame: 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. ]
10. Multi-dose pharmacokinetic (PK) profile of individually dose-titrated PB1046 administered once-weekly for 16 weeks - Area Under Curve(0-t) [AUC(0-t)] [ Time Frame: 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. ]
11. Multi-dose pharmacokinetic (PK) profile of individually dose-titrated PB1046 administered once-weekly for 16 weeks - AUC(0-tmax) [ Time Frame: 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. ]
12. Multi-dose pharmacokinetic (PK) profile of individually dose-titrated PB1046 administered once-weekly for 16 weeks - AUC(tmax-t) [ Time Frame: 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. ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 79 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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, e.g., atrial septal defect (ASD) or patent ductus arteriosus (PDA), at least 1 year after surgical repair);
• Two 6MWD test results > 50 m and < 525 m prior to dosing with results +/- 10% of each other. Note: Up to four tests may be conducted between Screening and Baseline for eligibility purposes (no more than two 6MWD tests may be performed on the same day, and must be completed at least two hours apart);
• Hemodynamic assessment of PAH by right heart catheterization (RHC) 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;
• Male subjects and female subjects of childbearing potential willing and able to practice effective contraception during the study and continuing contraception for 30 days after their last dose of study drug. Female subjects of non-childbearing potential are defined as being surgically sterile by bilateral tubal ligation, bilateral oophorectomy, or hysterectomy. A female subject 45 to 60 year of age, inclusive who is post-menopausal for at least 1 year and has a follicle-stimulating hormone level confirmation indicating post-menopausal status will be considered of non-childbearing potential. Female subjects >60 years of age are considered post-menopausal and of non-childbearing potential;
• Stable background medical regimen of up to 2 oral PAH therapies for at least 30 days prior to Screening and having been on PAH therapy for at least 4 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 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) of < 40 mL/min/1.73m2 as calculated by the MDRD equation: eGFR = 186 x (Creat / 88.4)-1.154 x (Age)-0.203 x (0.742 if female) x (1.210 if black)
• 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.

Contacts and Locations

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Locations

United States, Colorado
University of Colorado Denver	Recruiting
Aurora, Colorado, United States, 80045
Contact: Cheri Abbott, RN, CCRP 303-724-7466 Cheryl.Abbott@ucdenver.edu
Principal Investigator: Todd Bull, MD
United States, Georgia
The Emory Clinic	Recruiting
Atlanta, Georgia, United States, 30322
Contact: Jane Gillespie, RN 404-712-8204 jane.gillespie@emory.edu
Principal Investigator: Micah Fisher, MD
United States, Missouri
Washington University School of Medicine	Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Ellen Newton-Lovato, RN 314-454-8717 elovato@wustl.edu
Principal Investigator: Murali Chakinala, MD
United States, New York
University of Rochester Medical Center	Recruiting
Rochester, New York, United States, 14642
Contact: Andrew Mintz, RN 585-486-0869 urmc_pahresearch@urmc.rochester.edu
Principal Investigator: R. James White, MD
United States, Ohio
The Linder Center for Resarch and Education at The Christ Hospital	Recruiting
Cincinnati, Ohio, United States, 45219
Contact: Patricia Padgett, RN 513-585-1777 patricia.padgett@thechristhospital.com
Principal Investigator: Peter Engel, MD
University of Cincinnati	Recruiting
Cincinnati, Ohio, United States, 45219
Contact: Jean Elwing, MD 513-558-4831 ext 5135584831 jean.elwing@uc.edu
Contact: Tammy Roads 5135582148 ext 5135584831 tammy.roads@uc.edu
Principal Investigator: Jean Elwing, MD
United States, Pennsylvania
Allegheny General Hospital	Recruiting
Pittsburgh, Pennsylvania, United States, 15212
Contact: Raymond Benza, MD 412-359-4760 raymond.benza@ahn.org
Principal Investigator: Raymond Benza, MD
UPMC Presbyterian Hospital	Recruiting
Pittsburgh, Pennsylvania, United States, 15213
Contact: Janel Giovannelli, RN BSN 412-647-8305 giovannellij@upmc.edu
Contact: Mary Kunkel, RN BSN 4126474463 kunkelme@upmc.edu
Principal Investigator: Marc Simon, MD

Sponsors and Collaborators

PhaseBio Pharmaceuticals Inc.

More Information

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Responsible Party:	PhaseBio Pharmaceuticals Inc.
ClinicalTrials.gov Identifier:	NCT03556020 History of Changes
Other Study ID Numbers:	PB1046-PT-CL-0004
First Posted:	June 14, 2018
Last Update Posted:	November 2, 2018
Last Verified:	November 2018

Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Additional relevant MeSH terms:

Hypertension; Familial Primary Pulmonary Hypertension; Vascular Diseases; Cardiovascular Diseases; Hypertension, Pulmonary; Lung Diseases; Respiratory Tract Diseases	Vasoactive Intestinal Peptide; Gastrointestinal Agents; Vasodilator Agents; Neuroprotective Agents; Protective Agents; Physiological Effects of Drugs