Pulmonary Arterial Hypertension
Conditions
Brief summary
A sub-study to the TDE-PH-304 protocol to assess the pharmacokinetics of patients transitioning from a twice daily dosing regimen of oral treprostinil to a three times daily dosing regimen.
Detailed description
As noted above in Brief Summary.
Interventions
DRUGUT-15C SR
Open label study drug.
Sponsors
United Therapeutics
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1\) Only subjects who are eligible for and have entered into Protocol TDE-PH-304 may participate in this substudy.
Exclusion criteria
1. The subject must voluntarily give informed consent to participate in the substudy. 2. No dose changes to study drug are made within 5 days of the pharmacokinetic (PK)substudy visits. 3. No additions or deletions to concurrent medications are made within 7 days of the pharmacokinetic substudy visit. Note: changes to diuretics and/or anticoagulants are permitted. 4. The preceding evening dose of study drug should have been taken 9 to 13 hours prior to the BID dose and 6-10 hours prior to the TID morning dose of study drug to ensure a trough level of study drug for PK sampling. 5. Subject dosing of study drug on the day of PK sampling must be observed in the clinic by study personnel. 6. Subject has not experienced a significant loss of blood (\> 450 mL) within the last 6 weeks of the pharmacokinetic substudy visit. 7. The subject must not be receiving any CYP 2C8 inducers or inhibitors
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To Assess the Pharmacokinetics (Mean AM Dose) in Subjects During Twice Daily (BID) Dosing (up to 14 Days Prior to Transitioning to Three Times Daily [TID] Dosing Regimen at PK Visit 1) and up to 35 Days After Transitioning to TID Dosing (at PK Visit 2). | Up to 14 days prior to transitioning to TID dosing regimen (PK Visit 1) and up to 35 days after transitioning to TID dosing regiment (PK Visit 2) | The PK sampling occurred over a 12-hour period in subjects during BID dosing (PK Visit 1) and during TID dosing (PK Visit 2). Prior to each PK sampling day, subjects must have been receiving a stable dose for at least 5 days. |
| To Assess the Pharmacokinetics (Cmax, Cmin) in Subjects During BID Dosing (up to 14 Days Prior to Transitioning to TID Dosing Regimen at PK Visit 1) and up to 35 Days After Transitioning to TID Dosing Regiment (PK Visit 2) | Up to 14 days prior to transitioning to TID dosing regimen (PK Visit 1) and up to 35 days after transitioning to TID dosing regiment (PK Visit 2) | The PK sampling occurred over a 12-hour period in subjects during BID dosing (PK Visit 1) and during TID dosing (PK Visit 2). Prior to each PK sampling day, subjects must have been receiving a stable dose for at least 5 days. |
| To Assess the Pharmacokinetics (AUClast) in Subjects During Twice Daily (BID) Dosing (up to 14 Days Prior to Transitioning to Three Times Daily [TID] Dosing Regimen at PK Visit 1) and up to 35 Days After Transitioning to TID Dosing (at PK Visit 2). | 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose at up to 14 days prior to transitioning to TID dosing regimen (PK Visit 1) and at up to 35 days after transitioning to TID dosing regiment (PK Visit 2) | The PK sampling occurred over a 12-hour period in subjects during BID dosing (PK Visit 1) and during TID dosing (PK Visit 2). Prior to each PK sampling day, subjects must have been receiving a stable dose for at least 5 days. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To Assess 6-minute Walk Distance for Both Groups (BID and TID) 3 to 6 Hours Post-morning Dose. | The 6MWT was conducted during BID dosing PK collection (up to 14 days prior to transitioning to TID dosing regimen [PK Visit 1]) and during TID dosing PK collection (up to 35 days after transitioning to TID dosing regimen [PK Visit 2]). | The 6-minute walk test (6MWT) was conducted at PK Visits 1 and 2, and was performed between hours 3 to 6 post-morning dose to correlate with the predicted peak plasma concentration of oral treprostinil. |
| To Compare the Adverse Event (AE) Profile of BID Versus TID Dosing. | The AEs were recorded for up to 50 days. | AE diaries including 8 therapy-specific terms were collected during both BID and TID dosing to allow for comparison of events from both regimens. The therapy-specific events included: diarrhea, extremity pain, flushing, headache, hypotension, jaw pain, nausea, and vomiting. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Open-label Extension PK Population The PK population included all subjects enrolled in the PK substudy having met the study criteria, who had sufficient treprostinil concentration-time data to derive noncompartmental PK parameters for at least 1 treatment of open-label treprostinil diethanolamine. | 13 |
| Total | 13 |
Baseline characteristics
| Characteristic | Open-label Extension PK Population |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 6 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants |
| Age, Continuous | 60.6 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 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 | 12 Participants |
| Region of Enrollment United States | 13 participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 13 / 13 | 13 / 13 |
| serious Total, serious adverse events | 0 / 13 | 0 / 13 |
Outcome results
Primary
To Assess the Pharmacokinetics (AUClast) in Subjects During Twice Daily (BID) Dosing (up to 14 Days Prior to Transitioning to Three Times Daily [TID] Dosing Regimen at PK Visit 1) and up to 35 Days After Transitioning to TID Dosing (at PK Visit 2).
The PK sampling occurred over a 12-hour period in subjects during BID dosing (PK Visit 1) and during TID dosing (PK Visit 2). Prior to each PK sampling day, subjects must have been receiving a stable dose for at least 5 days.
Time frame: 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose at up to 14 days prior to transitioning to TID dosing regimen (PK Visit 1) and at up to 35 days after transitioning to TID dosing regiment (PK Visit 2)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| PK Visit 1 | To Assess the Pharmacokinetics (AUClast) in Subjects During Twice Daily (BID) Dosing (up to 14 Days Prior to Transitioning to Three Times Daily [TID] Dosing Regimen at PK Visit 1) and up to 35 Days After Transitioning to TID Dosing (at PK Visit 2). | 47.8 h*ng/mL |
| PK Visit 2 | To Assess the Pharmacokinetics (AUClast) in Subjects During Twice Daily (BID) Dosing (up to 14 Days Prior to Transitioning to Three Times Daily [TID] Dosing Regimen at PK Visit 1) and up to 35 Days After Transitioning to TID Dosing (at PK Visit 2). | 58.0 h*ng/mL |
Primary
To Assess the Pharmacokinetics (Cmax, Cmin) in Subjects During BID Dosing (up to 14 Days Prior to Transitioning to TID Dosing Regimen at PK Visit 1) and up to 35 Days After Transitioning to TID Dosing Regiment (PK Visit 2)
The PK sampling occurred over a 12-hour period in subjects during BID dosing (PK Visit 1) and during TID dosing (PK Visit 2). Prior to each PK sampling day, subjects must have been receiving a stable dose for at least 5 days.
Time frame: Up to 14 days prior to transitioning to TID dosing regimen (PK Visit 1) and up to 35 days after transitioning to TID dosing regiment (PK Visit 2)
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| PK Visit 1 | To Assess the Pharmacokinetics (Cmax, Cmin) in Subjects During BID Dosing (up to 14 Days Prior to Transitioning to TID Dosing Regimen at PK Visit 1) and up to 35 Days After Transitioning to TID Dosing Regiment (PK Visit 2) | Cmax | 8.60 ng/mL |
| PK Visit 1 | To Assess the Pharmacokinetics (Cmax, Cmin) in Subjects During BID Dosing (up to 14 Days Prior to Transitioning to TID Dosing Regimen at PK Visit 1) and up to 35 Days After Transitioning to TID Dosing Regiment (PK Visit 2) | Cmin | 1.19 ng/mL |
| PK Visit 2 | To Assess the Pharmacokinetics (Cmax, Cmin) in Subjects During BID Dosing (up to 14 Days Prior to Transitioning to TID Dosing Regimen at PK Visit 1) and up to 35 Days After Transitioning to TID Dosing Regiment (PK Visit 2) | Cmax | 8.94 ng/mL |
| PK Visit 2 | To Assess the Pharmacokinetics (Cmax, Cmin) in Subjects During BID Dosing (up to 14 Days Prior to Transitioning to TID Dosing Regimen at PK Visit 1) and up to 35 Days After Transitioning to TID Dosing Regiment (PK Visit 2) | Cmin | 2.14 ng/mL |
Primary
To Assess the Pharmacokinetics (Mean AM Dose) in Subjects During Twice Daily (BID) Dosing (up to 14 Days Prior to Transitioning to Three Times Daily [TID] Dosing Regimen at PK Visit 1) and up to 35 Days After Transitioning to TID Dosing (at PK Visit 2).
The PK sampling occurred over a 12-hour period in subjects during BID dosing (PK Visit 1) and during TID dosing (PK Visit 2). Prior to each PK sampling day, subjects must have been receiving a stable dose for at least 5 days.
Time frame: Up to 14 days prior to transitioning to TID dosing regimen (PK Visit 1) and up to 35 days after transitioning to TID dosing regiment (PK Visit 2)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| PK Visit 1 | To Assess the Pharmacokinetics (Mean AM Dose) in Subjects During Twice Daily (BID) Dosing (up to 14 Days Prior to Transitioning to Three Times Daily [TID] Dosing Regimen at PK Visit 1) and up to 35 Days After Transitioning to TID Dosing (at PK Visit 2). | 8.12 mg |
| PK Visit 2 | To Assess the Pharmacokinetics (Mean AM Dose) in Subjects During Twice Daily (BID) Dosing (up to 14 Days Prior to Transitioning to Three Times Daily [TID] Dosing Regimen at PK Visit 1) and up to 35 Days After Transitioning to TID Dosing (at PK Visit 2). | 6.75 mg |
Secondary
To Assess 6-minute Walk Distance for Both Groups (BID and TID) 3 to 6 Hours Post-morning Dose.
The 6-minute walk test (6MWT) was conducted at PK Visits 1 and 2, and was performed between hours 3 to 6 post-morning dose to correlate with the predicted peak plasma concentration of oral treprostinil.
Time frame: The 6MWT was conducted during BID dosing PK collection (up to 14 days prior to transitioning to TID dosing regimen [PK Visit 1]) and during TID dosing PK collection (up to 35 days after transitioning to TID dosing regimen [PK Visit 2]).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| PK Visit 1 | To Assess 6-minute Walk Distance for Both Groups (BID and TID) 3 to 6 Hours Post-morning Dose. | 332.5 Meters |
| PK Visit 2 | To Assess 6-minute Walk Distance for Both Groups (BID and TID) 3 to 6 Hours Post-morning Dose. | 347.9 Meters |
Secondary
To Compare the Adverse Event (AE) Profile of BID Versus TID Dosing.
AE diaries including 8 therapy-specific terms were collected during both BID and TID dosing to allow for comparison of events from both regimens. The therapy-specific events included: diarrhea, extremity pain, flushing, headache, hypotension, jaw pain, nausea, and vomiting.
Time frame: The AEs were recorded for up to 50 days.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PK Visit 1 | To Compare the Adverse Event (AE) Profile of BID Versus TID Dosing. | Diarrhea | 46 percentage of subjects |
| PK Visit 1 | To Compare the Adverse Event (AE) Profile of BID Versus TID Dosing. | Extremity pain | 54 percentage of subjects |
| PK Visit 1 | To Compare the Adverse Event (AE) Profile of BID Versus TID Dosing. | Flushing | 85 percentage of subjects |
| PK Visit 1 | To Compare the Adverse Event (AE) Profile of BID Versus TID Dosing. | Headache | 69 percentage of subjects |
| PK Visit 1 | To Compare the Adverse Event (AE) Profile of BID Versus TID Dosing. | Hypotension | 23 percentage of subjects |
| PK Visit 1 | To Compare the Adverse Event (AE) Profile of BID Versus TID Dosing. | Jaw Pain | 38 percentage of subjects |
| PK Visit 1 | To Compare the Adverse Event (AE) Profile of BID Versus TID Dosing. | Nausea | 38 percentage of subjects |
| PK Visit 1 | To Compare the Adverse Event (AE) Profile of BID Versus TID Dosing. | Vomiting | 0 percentage of subjects |
| PK Visit 2 | To Compare the Adverse Event (AE) Profile of BID Versus TID Dosing. | Vomiting | 0 percentage of subjects |
| PK Visit 2 | To Compare the Adverse Event (AE) Profile of BID Versus TID Dosing. | Diarrhea | 38 percentage of subjects |
| PK Visit 2 | To Compare the Adverse Event (AE) Profile of BID Versus TID Dosing. | Hypotension | 23 percentage of subjects |
| PK Visit 2 | To Compare the Adverse Event (AE) Profile of BID Versus TID Dosing. | Extremity pain | 38 percentage of subjects |
| PK Visit 2 | To Compare the Adverse Event (AE) Profile of BID Versus TID Dosing. | Nausea | 77 percentage of subjects |
| PK Visit 2 | To Compare the Adverse Event (AE) Profile of BID Versus TID Dosing. | Flushing | 54 percentage of subjects |
| PK Visit 2 | To Compare the Adverse Event (AE) Profile of BID Versus TID Dosing. | Jaw Pain | 46 percentage of subjects |
| PK Visit 2 | To Compare the Adverse Event (AE) Profile of BID Versus TID Dosing. | Headache | 85 percentage of subjects |