Pulmonary Arterial Hypertension
Conditions
Keywords
prostacyclin
Brief summary
This was a Phase 1b safety and tolerability single-sequence study in which PAH subjects on a stable regimen of Tyvaso switched to a corresponding dose of TreT.
Detailed description
United Therapeutics Corporation (UTC) developed a combination drug-device product comprised of a dry powder formulation of Treprostinil Inhalation Powder (TreT) and a small, portable, dry powder inhaler. In this Phase 1b safety and tolerability study, patients with PAH on a stable dose of Tyvaso (6 to 12 breaths 4 times daily \[QID\]) were evaluated after switching to a corresponding dose of TreT. Patients underwent PK assessments, safety assessments, a 6-Minute Walk Test (6MWT), and questionnaires for satisfaction/preference for inhaled devices and patient-reported PAH symptoms and impact. Following 3 weeks of treatment with TreT, patients were offered the opportunity to participate in the Optional Extension Phase until the drug/device became commercially available.
Interventions
Treprostinil inhalation powder single-use cartridges containing either 32 or 48 micrograms of treprostinil per cartridge (QID)
Sponsors
United Therapeutics
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Single-sequence in which subjects on a stable regimen of Tyvaso switched to a corresponding dose of TreT
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Subject voluntarily gave informed consent to participate in the study. 2. Subject was aged 18 years or older at the time of signing informed consent. 3. Women of childbearing potential were those who had experienced menarche and who had not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or were not postmenopausal (defined as amenorrhea for at least 12 consecutive months). WOCBP must have been nonpregnant (as confirmed by a urine pregnancy test at Screening prior to initiating study medication), nonlactating, and did 1 of the following: 1. Abstained from intercourse (when it was in line with their preferred and usual lifestyle), or 2. Used 2 medically acceptable, highly effective forms of contraception for the duration of study, and at least 30 days after discontinuing TreT. Medically acceptable, highly effective forms of contraception included approved hormonal contraceptives (oral, injectable, and implantable), intrauterine devices or systems, and barrier methods (such as a condom or diaphragm) when used with a spermicide. 4. Males with a partner of childbearing potential must have used a condom for the duration of treatment and for at least 48 hours after discontinuing TreT. 5. Subject was diagnosed with PAH as defined by the following World Health Organization (WHO) Group 1 categories: 1. Idiopathic/familial 2. Associated with unrepaired or repaired congenital systemic-to-pulmonary shunts (repaired ≥5 years prior to Screening) 3. Associated with collagen vascular disease 4. Associated with human immunodeficiency virus 5. Associated with appetite suppressant/other drug or toxin use 6. Subject must have started Tyvaso ≥3 months prior to the Baseline Visit and was currently on a stable regimen (no change in dose within 30 days of Baseline Visit) of Tyvaso (6 to 12 breaths QID). 7. Baseline 6MWD ≥150 m. 8. If the subject was currently receiving other approved background therapy (eg, endothelin receptor antagonist or phosphodiesterase type 5 inhibitor or both), the subject must have been on a stable dose with no additions or discontinuations for a minimum of 30 days prior to Screening. 9. The subject had evidence of forced expiratory volume in 1 second (FEV1) ≥60% and FEV1/forced vital capacity ratio ≥60% during the 6 months prior to enrollment. 10. In the opinion of the Investigator, the subject was able to communicate effectively with study personnel, and was considered reliable, willing, and likely to be cooperative with protocol requirements, including all study visits.
Exclusion criteria
1. Subject was pregnant or lactating. 2. Subject was diagnosed with pulmonary hypertension for reasons other than WHO Group 1 as outlined in Inclusion Criterion 5 (including but not limited to portal hypertension, chronic thromboembolic disease, pulmonary veno-occlusive disease, hemolytic anemia, sarcoidosis). 3. Subject had a history of uncontrolled sleep apnea, parenchymal lung disease, or hemodynamically significant left-sided heart disease (including but not limited to aortic or mitral valve disease, pericardial constriction, restrictive or congestive cardiomyopathy, or coronary artery disease). 4. Subject was currently taking any other prostacyclin analogue or agonist, including but not limited to selexipag, epoprostenol, iloprost, or beraprost; except for acute vasoreactivity testing. 5. Subject experienced an acute exacerbation of disease or hospitalization for any reason within 30 days of the Screening Visit or between Screening and Baseline. 6. Subject was WHO Functional Class IV at Screening. 7. Subject had used any investigational drug/device or participated in any other investigational study with therapeutic intent within 30 days prior to the Screening Visit. 8. Subject had a history of anaphylaxis, a documented hypersensitivity reaction, or a clinically significant idiosyncratic reaction to treprostinil or excipients in the investigational product. 9. Subject had conditions that, in the opinion of the Investigator, would make the subject ineligible. 10. Subject was not able to perform inhalation maneuvers that met inspiratory training criteria. 11. Subject had a musculoskeletal disorder (eg, arthritis affecting the lower limbs, recent hip or knee joint replacement) or any disease that would likely be the primary limit to ambulation, or was connected to a machine that was not portable enough to allow for a 6MWT. 12. Subject had a new type of chronic therapy (including but not limited to oxygen, a different class of vasodilator, diuretic, and digoxin) for pulmonary hypertension added within 30 days of the Screening Phase. 13. Initiation of pulmonary rehabilitation within 12 weeks prior to the Baseline Visit.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in 6-Minute Walk Distance (6MWD) From Baseline to Week 3 | From Baseline to 3 weeks of treatment with TreT | 6MWD was evaluated at study entry and after 3 weeks of treatment with TreT. |
| Subject Satisfaction With and Preference for Inhaled Treprostinil Devices | After 3 weeks of treatment with TreT (after switching from the Tyvaso Inhalation System) | Subject satisfaction with and preference for the inhaled treprostinil device was evaluated with the Preference Questionnaire for Inhaled Treprostinil Devices (PQ-ITD). The PQ-ITD is a questionnaire given to evaluate subject satisfaction with and preference for inhaled treprostinil devices. The questionnaire provides 12 different statements around inhaled device satisfaction and allows for 5 response options: strongly disagree, disagree, neutral, agree, and strongly agree. |
| Change in Patient-reported PAH Symptoms and Impact From Baseline to Week 3 | From Baseline to 3 weeks of treatment with TreT | Patient-reported PAH symptoms and impact were evaluated with the PAH Symptoms and Impact (PAH-SYMPACT) Questionnaire. The PAH-SYMPACT is a 23-item patient-reported outcome questionnaire that consists of 11 symptom items, 11 impact items, and 1 item on oxygen use. The symptom items are divided into cardiopulmonary and cardiovascular domains, and the impact items are divided into physical and emotional/cognitive domains. Symptom and impact domain scores (range 0 to 4) are calculated as the sum of the scores for the items included in the domain divided by the number of items in the domain. For all domains, a higher score indicates more severe symptoms/impacts. |
| Change in Patient-reported PAH Symptoms and Impact From Baseline to Week 11 (for Subjects Participating in the OEP) | From Baseline to 11 weeks of treatment with TreT | Patient-reported PAH symptoms and impact were evaluated with the PAH Symptoms and Impact (PAH-SYMPACT) Questionnaire. The PAH-SYMPACT is a 23-item patient-reported outcome questionnaire that consists of 11 symptom items, 11 impact items, and 1 item on oxygen use. The symptom items are divided into cardiopulmonary and cardiovascular domains, and the impact items are divided into physical and emotional/cognitive domains. Symptom and impact domain scores (range 0 to 4) are calculated as the sum of the scores for the items included in the domain divided by the number of items in the domain. For all domains, a higher score indicates more severe symptoms/impacts. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tyvaso to TreT Each subject received a corresponding dose of TreT for 3 weeks during the Treatment Phase based on the subject's current stable Tyvaso dose.
Treprostinil Inhalation Powder: Treprostinil inhalation powder single-use cartridges containing either 32 or 48 micrograms of treprostinil per cartridge (QID) | 51 |
| Total | 51 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Optional Extension Phase | Adverse Event | 7 |
| Optional Extension Phase | Death | 1 |
| Optional Extension Phase | Lost to Follow-up | 2 |
| Optional Extension Phase | Pregnancy | 1 |
| Optional Extension Phase | Progressive Disease | 5 |
| Optional Extension Phase | Site Closure | 2 |
| Treatment Phase | Adverse Event | 2 |
Baseline characteristics
| Characteristic | Tyvaso to TreT |
|---|---|
| Age, Continuous | 57.0 years |
| Age, Customized <65 years | 38 Participants |
| Age, Customized ≥65 years | 13 Participants |
| Background PAH Medications Endothelin receptor antagonist | 43 participants |
| Background PAH Medications No background PAH medication | 1 participants |
| Background PAH Medications Phosphodiesterase type 5 inhibitor | 41 participants |
| Background PAH Medications Soluble guanylate cyclase | 7 participants |
| Current PAH Diagnosis Associated with Appetite Suppressant/Other Drug or Toxin Use | 3 Participants |
| Current PAH Diagnosis Associated with Collagen Vascular Disease | 14 Participants |
| Current PAH Diagnosis Associated with HIV | 1 Participants |
| Current PAH Diagnosis Associated with Unrepaired or Repaired Congenital Systemic-to-Pulmonary Shunts | 4 Participants |
| Current PAH Diagnosis Idiopathic/Familial | 29 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 47 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 40 Participants |
| Region of Enrollment United States | 51 participants |
| Sex: Female, Male Female | 43 Participants |
| Sex: Female, Male Male | 8 Participants |
| Time Since PAH Diagnosis | 7.820 years |
| WHO Functional Class at Screening I | 6 Participants |
| WHO Functional Class at Screening II | 31 Participants |
| WHO Functional Class at Screening III | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 27 | 0 / 22 | 0 / 2 | 0 / 26 | 1 / 21 |
| other Total, other adverse events | 0 / 2 | 17 / 27 | 14 / 22 | 2 / 2 | 25 / 26 | 20 / 21 |
| serious Total, serious adverse events | 0 / 2 | 1 / 27 | 1 / 22 | 1 / 2 | 12 / 26 | 12 / 21 |
Outcome results
Primary
Change in 6-Minute Walk Distance (6MWD) From Baseline to Week 3
6MWD was evaluated at study entry and after 3 weeks of treatment with TreT.
Time frame: From Baseline to 3 weeks of treatment with TreT
Population: Safety Population with 6MWD measurements at Week 3
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tyvaso to TreT | Change in 6-Minute Walk Distance (6MWD) From Baseline to Week 3 | 11.5 meters | Standard Deviation 32.9 |
Primary
Change in Patient-reported PAH Symptoms and Impact From Baseline to Week 11 (for Subjects Participating in the OEP)
Patient-reported PAH symptoms and impact were evaluated with the PAH Symptoms and Impact (PAH-SYMPACT) Questionnaire. The PAH-SYMPACT is a 23-item patient-reported outcome questionnaire that consists of 11 symptom items, 11 impact items, and 1 item on oxygen use. The symptom items are divided into cardiopulmonary and cardiovascular domains, and the impact items are divided into physical and emotional/cognitive domains. Symptom and impact domain scores (range 0 to 4) are calculated as the sum of the scores for the items included in the domain divided by the number of items in the domain. For all domains, a higher score indicates more severe symptoms/impacts.
Time frame: From Baseline to 11 weeks of treatment with TreT
Population: Safety Population with PAH-SYMPACT scores at Week 11
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tyvaso to TreT | Change in Patient-reported PAH Symptoms and Impact From Baseline to Week 11 (for Subjects Participating in the OEP) | Cardiopulmonary Symptoms Domain Score | -0.04 score on a scale | Standard Deviation 0.36 |
| Tyvaso to TreT | Change in Patient-reported PAH Symptoms and Impact From Baseline to Week 11 (for Subjects Participating in the OEP) | Cardiovascular Symptoms Domain Score | -0.05 score on a scale | Standard Deviation 0.4 |
| Tyvaso to TreT | Change in Patient-reported PAH Symptoms and Impact From Baseline to Week 11 (for Subjects Participating in the OEP) | Physical Impacts Domain Score | -0.20 score on a scale | Standard Deviation 0.59 |
| Tyvaso to TreT | Change in Patient-reported PAH Symptoms and Impact From Baseline to Week 11 (for Subjects Participating in the OEP) | Cognitive/Emotional Impacts Domain Score | -0.13 score on a scale | Standard Deviation 0.51 |
Primary
Change in Patient-reported PAH Symptoms and Impact From Baseline to Week 3
Patient-reported PAH symptoms and impact were evaluated with the PAH Symptoms and Impact (PAH-SYMPACT) Questionnaire. The PAH-SYMPACT is a 23-item patient-reported outcome questionnaire that consists of 11 symptom items, 11 impact items, and 1 item on oxygen use. The symptom items are divided into cardiopulmonary and cardiovascular domains, and the impact items are divided into physical and emotional/cognitive domains. Symptom and impact domain scores (range 0 to 4) are calculated as the sum of the scores for the items included in the domain divided by the number of items in the domain. For all domains, a higher score indicates more severe symptoms/impacts.
Time frame: From Baseline to 3 weeks of treatment with TreT
Population: Safety Population with PAH-SYMPACT scores at Week 3
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tyvaso to TreT | Change in Patient-reported PAH Symptoms and Impact From Baseline to Week 3 | Cardiopulmonary Symptoms Domain Score | -0.05 score on a scale | Standard Deviation 0.27 |
| Tyvaso to TreT | Change in Patient-reported PAH Symptoms and Impact From Baseline to Week 3 | Cardiovascular Symptoms Domain Score | -0.06 score on a scale | Standard Deviation 0.33 |
| Tyvaso to TreT | Change in Patient-reported PAH Symptoms and Impact From Baseline to Week 3 | Physical Impacts Domain Score | -0.14 score on a scale | Standard Deviation 0.46 |
| Tyvaso to TreT | Change in Patient-reported PAH Symptoms and Impact From Baseline to Week 3 | Cognitive/Emotional Impacts Domain Score | -0.17 score on a scale | Standard Deviation 0.4 |
Primary
Subject Satisfaction With and Preference for Inhaled Treprostinil Devices
Subject satisfaction with and preference for the inhaled treprostinil device was evaluated with the Preference Questionnaire for Inhaled Treprostinil Devices (PQ-ITD). The PQ-ITD is a questionnaire given to evaluate subject satisfaction with and preference for inhaled treprostinil devices. The questionnaire provides 12 different statements around inhaled device satisfaction and allows for 5 response options: strongly disagree, disagree, neutral, agree, and strongly agree.
Time frame: After 3 weeks of treatment with TreT (after switching from the Tyvaso Inhalation System)
Population: Safety Population with PQ-ITD responses at Week 3
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tyvaso to TreT | Subject Satisfaction With and Preference for Inhaled Treprostinil Devices | Strongly Disagree | 0 Participants |
| Tyvaso to TreT | Subject Satisfaction With and Preference for Inhaled Treprostinil Devices | Disagree | 0 Participants |
| Tyvaso to TreT | Subject Satisfaction With and Preference for Inhaled Treprostinil Devices | Neutral | 1 Participants |
| Tyvaso to TreT | Subject Satisfaction With and Preference for Inhaled Treprostinil Devices | Agree | 5 Participants |
| Tyvaso to TreT | Subject Satisfaction With and Preference for Inhaled Treprostinil Devices | Strongly Agree | 40 Participants |