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A Phase 2b, Randomized, Double-Blind, Multicenter, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Treprostinil Palmitil Inhalation Powder in Participants with Pulmonary Arterial Hypertension

PHRR220520-004684

20220223152849

2022-CT0674

Protocol Title: A Phase 2b, Randomized, Double-Blind, Multicenter, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Treprostinil Palmitil Inhalation Powder in Participants with Pulmonary Arterial Hypertension

Brief Title: A Randomized, Double-Blind, Placebo-Controlled Study of Treprostinil Palmitil Inhalation Powder in Participants with Pulmonary Arterial Hypertension

This is a Phase 2b, randomized, double-blind, multicenter, placebo-controlled study to evaluate the efficacy, safety, and PK of TPIP in participants diagnosed with PAH.

This is the first placebo-controlled study of TPIP in participants with PAH.

For individual participants, the study will consist of a Screening Period of up to 30 days, a Treatment Period of 16 weeks (includes a 3-week Titration Period) and a 4-week Follow-Up Period after the Week 16 visit. At the Investigator’s discretion, participants may undergo a study drug taper for up to 2 weeks after the Week 16 visit to help facilitate a safe withdrawal from study drug.

Including the Screening, Treatment, and Follow-Up Periods, the study participation period is expected to be approximately up to 24 weeks.

Participants will self-administer study drug. Study drug administration will be overseen by study site personnel at all in-clinic visits.

The study will include 2 sub-studies (1 each for transthoracic echocardiogram and pulmonary vascular volume assessment). These assessments are considered optional at the participant’s discretion (ie, a participant may choose to not have the assessment) and may not be performed at all study sites. Participants will be informed by the Investigator which sub-studies, if any, are available at their study site and a specific sub-study ICF will be provided.

Regime Classification Priority
2017 - 2022 Research in equity and health Drug Discovery and Development
Start Date Duration in Months Target Completion Date Actual Completion Date
2022-07-14 26 2024-09-14 2024-09-16

Ongoing

Institution Classification Region LTO #
Insmed Incorporated Private Business United States of America
Institution Classification Region LTO #
PPD Pharmaceutical Development Philippines Corporation Private Business NCR 3000000780190
Institution Region
Insmed Incorporated United States of America
Name E-Mail Institution and Institution Address
Mary Francesca Athena Ocampo MaryFrancescaAthena.Ocampo@ppd.com PPD, part of Thermo Fischer Scientific 22/F Seven/NEO Building (formerly Net Park) 5th Avenue, E-Square, Crescent Park West BGC, Taguig, Philippines 1634
Name E-Mail Institution and Institution Address
Branislav Gvozdenovic Branislav.Gvozdenovic@ppd.com PPD, part of Thermo Fischer Scientific, Belgrade RS Omladinskih Brigad, Serbia
Name Expertise Affiliation
Andrei Rhoniel M. Rodriguez, MD Internal Medicine and Rheumatology Makati Medical Center
Teresita S. de Guia, MD Pulmonary Medicine Philippine Heart Center
Project Location Institutional Ethics Review Board
Makati Medical Center Makati Medical Center Institutional Review Board
Philippine Heart Center Philippine Heart Center Ethics Review Committee

Pulmonary Arterial Hypertension (PAH)

Primary:

  • To assess the effect of TPIP compared with placebo on PVR

 

Secondary:

  • To assess the effect of TPIP compared with placebo on exercise capacity
  • To assess the safety and tolerability of TPIP compared with placebo
  • To evaluate the PK of TP and TRE in plasma
  • To evaluate the efficacy of TPIP compared with placebo on the concentration of NT-proBNP in blood

Exploratory:

  • To evaluate the effect of TPIP compared with placebo on hemodynamic variables
  • To evaluate the efficacy of TPIP compared to placebo on the change in WHO functional status
  • To evaluate the effect of TPIP compared to placebo on clinical worsening
  • To evaluate the efficacy of TPIP compared with placebo on heart rate
  • To evaluate the efficacy effects of TPIP compared with placebo on systemic blood pressure
  • To evaluate the effect of TPIP compared with placebo on QOL
  • To evaluate the effect of TPIP compared with placebo on right ventricular function as assessed by transthoracic echocardiogram
  • To evaluate the effect of TPIP compared with placebo on pulmonary vasculature blood flow
  • To evaluate PK/PD relationships
  • To characterize population PK and PK covariates

Recruiting

  • Argentina
  • Australia
  • Austria
  • Belgium
  • Brazil
  • Denmark
  • France
  • Germany
  • Italy
  • Japan
  • Malaysia
  • Mexico
  • Peru
  • Philippines
  • Serbia
  • Spain
  • Switzerland
  • United Kingdom
  • United States

Clinical Trial

20220223152849

20220223152849

2022-04-22

2022-03-04

4

Unspecified

Unspecified

2022-08-15

Inclusion Criteria

Participants are eligible to be included in the study only if all the following criteria apply:

Age

  1. Participants must be ≥ 18 to ≤ 75 years at the time of signing the ICF. Participants in Japan must be ≥ 20 years of age at the time of signing the ICF.

Type of Participant and Disease Characteristics

  1. Participants must have a diagnosis of WHO Group 1 PH (PAH) in any of the following subtypes (Galie et al., 2016):
  • idiopathic
  • heritable
  • drug/toxin-induced or CTD-associated PAH
  1. PAH diagnosis for at least 1 year.
  2. New York Heart Association (NYHA)/WHO functional class II or III.
  3. Medical history, physical examination, vital signs, ECG, and clinical laboratory results consistent with their degree of PAH and treatment.
  4. Participants must be on stable PH therapy consisting of up to 2 medications from the following classes:
  • Endothelin receptor antagonists (eg, ambrisentan, bosentan, macitentan)
  • Phosphoesterase type 5 inhibitors (eg, sildenafil, tadalafil)
  • Guanylate cyclase stimulator (eg, riociguat)
  1. No change in PH medications (eg, ambrisentan, bosentan, macitentan, sildenafil, tadalafil, riociguat) or dosage for at least 60 days prior to Screening.
  2. No change in diuretic use or dosage for at least 30 days prior to Screening.
  3. Documented pre-bronchodilator predicted FEV1 ≥70% and FEV1/FVC ratio ≥ 70% within 1 year of Screening. If documented spirometry is not available, pulmonary function testing will be performed during Screening.
  4. At least two 6MWTs during Screening with a 6MWT distance between 150 and 450 meters in length where both values are within 15% of each other.
  5. Right heart catheterization at Screening (or within 30 days prior to Screening, if available) with all the following hemodynamic findings:
  • Mean PAP ≥ 25 mmHg at rest
  • PCWP ≤ 15 mmHg
  • PVR of ≥ 5 WU

Weight

  1. BMI within the range 19.0-32.0 kg/m2 (inclusive).

Sex and Contraceptive/Barrier Requirements

  1. Male and female participants must use contraceptives that are consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
  • Male participants:

Male participants who are not sterile, with female partners of childbearing potential, must be using effective contraception from Day 1 to at least 90 days after the last dose of study drug. Such methods include true abstinence (refraining from heterosexual intercourse during the study), combined (estrogen and progestogen containing) or progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine devices, intrauterine hormone-releasing systems.

  • Female participants:

Women must be postmenopausal (defined as no menses for 12 months without an alternative medical cause), surgically sterile, (ie, post-tubal ligation for at least 12 months) or using highly effective contraception methods (ie, methods that alone or in combination achieve <1% unintended pregnancy rates per year when used consistently and correctly) from Day 1 to at least 90 days after the last dose of study drug. Such methods include true abstinence (refraining from heterosexual intercourse during the study), combined (estrogen and progestogen containing) or progestogen-only hormonal contraception associated with inhibition of ovulation and supplemented with a double barrier (preferably male condom), intrauterine devices, intrauterine hormone-releasing systems, or vasectomized partner. For WOCBBP ≤45 years, an additional confirmatory testing of FSH level with a threshold of >40 mIU/mL should be performed to be considered infertile.

 All WOCBP must have a negative urine pregnancy test prior to randomization

Note: Abstinence is only considered to be a highly effective method of contraception when this is the preferred and usual lifestyle of a participant. Periodic abstinence (calendar, symptothermal, post ovulation methods), withdrawal (coitus interruptus), spermicides only, and LAM are not acceptable methods of contraception. Male condom and female condom should not be used together (due to risk to failure from friction).

  1. Female participants of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Baseline.
  2. Male participants with pregnant or non-pregnant WOCBP partner must use a condom in order to avoid potential exposure to embryo/fetus.

Informed Consent Section

  1. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
  2. Able to understand and comply with protocol requirements, restrictions, and instructions, and likely to complete the study as planned, as judged by the Investigator.

Exclusion Criteria

Participants are excluded from the study if any of the following criteria apply:

Medical Conditions

  1. History of PH other than idiopathic, hereditary, drug/toxin-induced, or CTD-associated PAH (eg, congenital heart disease-associated PAH, portal hypertension-associated PAH, PH belonging to Groups 2 through 5).
  2. Allergy, or documented hypersensitivity or contraindication, to TPIP or TRE or mannitol (an excipient of the TPIP formulation).
  3. Per the Investigator’s discretion, previous intolerance to prostacyclin analogues or receptor agonists (eg, selexipag) or previous chronic use (>30 days) of a prostacyclin or prostacyclin analogue within 60 days of the Screening Visit.
  4. QTcF interval > 480 ms on resting ECG at Screening.
  5. Any known ventricular or supraventricular tachyarrhythmia except for paroxysmal atrial fibrillation and any symptomatic bradycardia.
  6. History of heart disease including left ventricular ejection fraction (LVEF) ≤ 40% or clinically significant valvular, constrictive, or symptomatic atherosclerotic heart disease (eg, stable angina, myocardial infarction, etc).
  7. Systolic BP < 90 mm Hg at Screening
  8. Participation in a cardio-pulmonary rehabilitation program within 1 month of Screening Visit.
  9. Evidence of thromboembolic disease as assessed by VQ scan, pulmonary angiography, or pulmonary CT scan.
  10. Acutely decompensated heart failure within 1 month of Screening Visit.
  11. Abnormal renal function (estimated glomerular filtration rate < 30 mL/min/1.73m2) at Screening.
  12. Active liver disease or hepatic dysfunction manifested as: in
  • Elevated liver function test results (ALT or AST > 2 × ULN) at Screening
  • Bilirubin > 1.5 × ULN (isolated bilirubin > 1.5 × ULN; ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%) at Screening
  • Known hepatic or biliary abnormalities, not including Gilbert's syndrome or asymptomatic gallstones at Screening
  1. History of HIV infection or positive HIV serology at Screening.
  2. Established diagnosis of hepatitis B viral infection, or positive for HBsAg at the time of Screening.
  • Participants who have gained immunity for hepatitis B virus infection after vaccination (ie, participants who are HBsAg-negative, HBsAb-positive, and HBcAb-negative) are eligible for the study.
  • Participants with positive HBcAbs are eligible for the study only if the hepatitis B virus DNA level is undetectable.
  1. Established diagnosis of hepatitis C viral infection at the time of screening. Participants positive for hepatitis C antibody are eligible for the study only if hepatitis C virus RNA is negative.
  2. Active and current symptomatic COVID-19 or previous severe disease and/or hospitalization due to COVID-19
  3. Use of live attenuated vaccines within 4 weeks of the Screening Visit.
  4. Participants with Down’s Syndrome.
  5. History of abnormal bleeding or bruising with a platelet count of <50,000/μL at Screening.
  6. History of solid organ transplantation.
  7. Known or suspected immunodeficiency disorder, including history of invasive opportunistic infections (eg, tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, aspergillosis) despite infection resolution, or otherwise recurrent infections of abnormal frequency, or prolonged infections suggesting an immune-compromised status, as judged by the Investigator.
  8. Severe concomitant illness(es) that, in the Investigator's judgment, would adversely affect the participant’s participation in the study. Examples include but are not limited to short life expectancy, uncontrolled diabetes, cardiovascular conditions (eg, NYHA Class III or IV cardiac failure), severe renal conditions (eg, severe nephrotic syndrome), hepatobiliary conditions (eg, Child-Pugh class B or C), neurological conditions (eg, demyelinating diseases), active major autoimmune diseases (eg, lupus, inflammatory bowel disease, rheumatoid arthritis, etc.), other severe endocrinologic, gastrointestinal, metabolic, pulmonary, or lymphatic diseases. The specific justification for participants excluded under this criterion will be noted in study documents (chart notes, CRF, etc.).
  9. Any clinically significant abnormal laboratory values at Screening or diseases or disorders (eg, cardiovascular, pulmonary, gastrointestinal, liver, kidney, neurological, musculoskeletal, endocrine, metabolic, psychiatric, physical impairment) that, in the opinion of the Investigator, may put the participant at risk by participating in the study, or interfere with the participant’s treatment, assessment, or influence the results of the study, or have compliance issues with the study or have a planned or anticipated major surgical procedure during the study.
  10. History of alcohol or drug abuse within 6 months prior to Screening.
  11. Any other medical or psychological condition including relevant laboratory abnormalities at Screening that, in the opinion of the Investigator, suggest a new and/or insufficiently understood disease, may present an unreasonable risk to the study participant as a result of his/her participation in this clinical trial, may make participant’s participation unreliable, or may interfere with study assessments. The specific justification for participants excluded under this criterion will be noted in study documents.
  12. Acute or chronic impairment (other than dyspnea), limiting the ability to comply with study requirements, in particular with 6MWT (eg, angina pectoris, claudication, musculoskeletal disorder, need for walking aids).
  13. Participants with current or recent (past 4 weeks) lower respiratory tract infection (may be re-screened at appropriate time (Section 5.4).
  14. History of malignancy in the past 5 years, with exception of completely treated in situ carcinoma of the cervix and completely treated non-metastatic squamous or basal cell carcinoma of the skin.

Prior/Concomitant Therapy

  1. Change in PH medication (endothelin receptor agonists, phosphoesterase type 5 inhibitors, and guanylate cyclase stimulators or diuretics) between Screening and Baseline.

Prior/Concurrent Clinical Study Experience

  1. Have participated in any other interventional clinical studies within 30 days of Baseline.

Other Exclusions

  1. Current use of cigarettes (as defined by CDC) or e-cigarettes.
  2. Participants who currently inhale marijuana (recreational or medical).
  3. Pregnant or breastfeeding.

Interventional

Treprostinil Palmitil Inhalation Powder (INS1009)

Treprostinil palmitil (TP) is an inactive prodrug of treprostinil (TRE), which is widely used in the treatment of pulmonary hypertension (PH). Treprostinil palmitil inhalation powder (TPIP) is a dry powder formulation for inhalation of TP that is being developed for the treatment of pulmonary arterial hypertension (PAH; World Health Organization [WHO] Group 1 PH). TPIP is expected to provide extended release of TRE in the lung with the goals of less frequent, more convenient dosing while reducing the frequency and severity of dose-limiting side effects associated with the currently approved forms of TRE.

Date Amendment Classification Reason
2022-07-12 Amendments related to the protocol Informed consent

Randomized

Double Blind

Randomized, Double-Blind, Placebo-Controlled Study

Not Applicable

TP is an inactive prodrug of TRE. TPIP is a dry powder for inhalation formulation of TP that is being developed for the treatment of PAH. TPIP is expected to provide extended release of TRE in the lung with the goals of providing prolonged vasodilation of the pulmonary vasculature with less frequent and more convenient dosing while reducing the frequency and severity of dose-limiting side effects associated with the currently approved forms of TRE. TP has been previously studied in healthy volunteers as a nebulized inhalation suspension (TPIS) in single doses up to 340 μg (Study INS1009-101) and as TPIP single doses up to 675 μg, and multiple doses up to 225 μg QD in healthy volunteers (Study INS1009-102).


A Phase 2a, open-label, single-dose study of TPIP to evaluate the safety, PK, and PD of TPIP in participants with PAH is being conducted in parallel with the present study. Study INS1009-201 will include up to 10 participants with PAH.


This is the first placebo-controlled study of TPIP in participants with PAH. Evaluation of pulmonary vascular physiology, particularly PVR via RHC, is essential to understand how TPIP affects cardio-pulmonary hemodynamics and to elucidate dose-and PK-effect relationships. This study will inform future stages in the development program for TPIP, potentially addressing the significant remaining unmet need for patients with PAH by offering them a new, effective treatment option.

Phase II

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