Pulmonary Hypertension
Conditions
Keywords
Sarcoidosis Associated Pulmonary Hypertension
Brief summary
This study is designed to assess safety and efficacy of tadalafil in patients with Sarcoidosis Associated Pulmonary Hypertension. Hypothesis: Tadalafil is safe and effective in treating pulmonary hypertension in patients with Sarcoidosis
Interventions
DRUGTadalafil
20mg/day for one month then 40mg/day for additional 4 months
Sponsors
Eli Lilly and Company
United Therapeutics
University of Cincinnati
University of North Carolina, Chapel Hill
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Biopsy proven sarcoidosis * Mean pulmonary artery pressure \> 25 mmHg at rest or greater than 30 mmHg with exercise by right heart catheterization within 1 year prior to entry into study * Pulmonary capillary wedge pressure ≤ 15 mmHg * PVR values ≥ 3.0 Woods units * Forced vital capacity (FVC) \> 40% predicted * Forced expiratory volume in 1 second (FEV1) \> 40% predicted * WHO functional class II or III * Stable sarcoidosis treatment regimen for three months prior to entry into study * 6 minute walk distance between 150-450 meters * Stable dose of antihypertensive medications * On no other medication to treat PAH (sildenafil, vardenafil, treprostinil, epoprostenol, iloprost, bosentan, ambrisentan) within one month prior to enrollment and during duration of the study * Non-pregnant females
Exclusion criteria
* Exercise limitation related to a non-cardiopulmonary reason (e.g. arthritis) * Severe systemic hypertension \> 170/95 * Severe systemic hypotension \< 90/50 * History of priapism * Patients with congestive heart failure (left ventricular dysfunction) LVEF \< 45% by echocardiogram * Anticipation by the investigator for escalation in sarcoidosis treatment during the course of the study * Pulmonary hypertension related to etiology other than sarcoidosis (i.e. HIV, scleroderma, chronic thromboemboli) * Use within 1 month of an sildenafil or vardenafil * WHO functional class IV status * Patients with severe other organ disease felt by investigators to impact on survival during the course of the study * Subjects with liver function abnormalities (ALT or AST \> 3 times the upper limit of normal at screening or at baseline) or chronic liver disease * Advanced kidney failure (GFR \< 30 ml/min at screening or at baseline) * History of hypersensitivity reaction or adverse effect related to tadalafil * Pregnant or lactating women * Concomitant use of nitrates (any form) either regularly or intermittently * Concomitant use of potent CYP3A inhibitors (eg, ritonavir, ketoconazole, itraconazole) * Any additional contraindications and precautions specified in the package inserts for Tadalafil (Adcirca) not listed above
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 6 Minute Walk Distance | Baseline, Week 8, Week 16, Week 24 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Oxygen Desaturation During 6 Minute Walk Test | Baseline, Week 24 | Change (decrease) in oxygen saturation from start of 6 minute walk to nadir during the 6 minute walk test |
| Maximum Borg Dyspnea Score During 6 Minute Walk Test | Baseline, Week 8, Week 16, Week 24 | The modified Borg scale consists of a vertical scale labelled 0 to10 with corresponding verbal expressions of progressively increasing sensation (shortness of breath) intensity. 0 represents no dyspnea, and 10 is the highest level of perceived dyspnea. |
| Brain Natriuretic Peptide Level | Baseline, Week 8, Week 16, Week 24 | — |
| Resting Oxygen Saturation | Baseline, Week 24 | Percent oxygen saturation of hemoglobin as measured by pulse oximetry in the resting state. |
| St. George's Respiratory Questionnaire (SGRQ) Score | Baseline, Week 8, Week 16, Week 24 | The SGRQ ranges from 0 (no impairment of quality of life) to 100 (highest impairment of quality of life) |
| Number of Participants With Change in WHO Functional Class (WHO FC) | Baseline, Week 24 | The WHO functional classification ranges from I (patient's disease does not affect daily activities) to IV (patient's disease causes severe impairment). Higher scores indicate more severe impairment. |
| Short Form-36 Global Score | Baseline, Week 8, Week 16, Week 24 | SF- 36 investigates the standard of quality of life through a general health assessment and not specific to a particular disease, age or treatment group. It is a 36-item questionnaire measuring 8 domains (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health). Each domain score ranges from 0 (worst) to 100 (best), with higher scores reflecting better health-related functional status. The global score is determined by taking an average of the individual domain scores. The global score range is from 0 (worst) to 100 (best). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tadalafil 40 mg daily | 12 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Tadalafil |
|---|---|
| Age, Continuous | 54.5 years STANDARD_DEVIATION 9.48 |
| Cardiac Index | 2.4 L/min/m² STANDARD_DEVIATION 0.6 |
| DLCO | 60.3 percent predicted STANDARD_DEVIATION 25 |
| FEV1 | 58.0 percent predicted STANDARD_DEVIATION 14.7 |
| FVC | 65.9 percent predicted STANDARD_DEVIATION 13.4 |
| Mean Pulmonary Artery Pressure | 34.8 mm Hg STANDARD_DEVIATION 7.1 |
| Pulmonary Artery Wedge Pressure | 10.3 mm Hg STANDARD_DEVIATION 3.6 |
| Pulmonary Vascular Resistance | 6.2 Wood Units STANDARD_DEVIATION 3.6 |
| Race/Ethnicity, Customized Black or African American | 9 Participants |
| Race/Ethnicity, Customized White | 3 Participants |
| Region of Enrollment United States | 12 participants |
| Right Atrial Pressure | 6.2 mm Hg STANDARD_DEVIATION 4 |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 12 |
| other Total, other adverse events | 5 / 12 |
| serious Total, serious adverse events | 0 / 12 |
Outcome results
Primary
6 Minute Walk Distance
Time frame: Baseline, Week 8, Week 16, Week 24
Population: Only 6 of the 7 study completers performed 6 minute walk test through week 24
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tadalafil | 6 Minute Walk Distance | Baseline | 419.1 meters | Standard Deviation 170.1 |
| Tadalafil | 6 Minute Walk Distance | Week 8 | 418.1 meters | Standard Deviation 143.5 |
| Tadalafil | 6 Minute Walk Distance | Week 16 | 436.5 meters | Standard Deviation 178.1 |
| Tadalafil | 6 Minute Walk Distance | Week 24 | 377.1 meters | Standard Deviation 140.9 |
Comparison: Comparing baseline to week 24.p-value: 0.68t-test, 2 sided
Secondary
Brain Natriuretic Peptide Level
Time frame: Baseline, Week 8, Week 16, Week 24
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tadalafil | Brain Natriuretic Peptide Level | Baseline | 58.8 pg/mL | Standard Deviation 89.6 |
| Tadalafil | Brain Natriuretic Peptide Level | Week 8 | 32.3 pg/mL | Standard Deviation 46.6 |
| Tadalafil | Brain Natriuretic Peptide Level | Week 16 | 37.5 pg/mL | Standard Deviation 51.4 |
| Tadalafil | Brain Natriuretic Peptide Level | Week 24 | 42.6 pg/mL | Standard Deviation 49.7 |
Comparison: Comparing Baseline to week 24.p-value: 0.68t-test, 2 sided
Secondary
Maximum Borg Dyspnea Score During 6 Minute Walk Test
The modified Borg scale consists of a vertical scale labelled 0 to10 with corresponding verbal expressions of progressively increasing sensation (shortness of breath) intensity. 0 represents no dyspnea, and 10 is the highest level of perceived dyspnea.
Time frame: Baseline, Week 8, Week 16, Week 24
Population: Only 6 of the 7 study completers performed 6 minute walk test through the end of the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tadalafil | Maximum Borg Dyspnea Score During 6 Minute Walk Test | Baseline | 4.8 units on a scale | Standard Deviation 1.2 |
| Tadalafil | Maximum Borg Dyspnea Score During 6 Minute Walk Test | Week 8 | 5.0 units on a scale | Standard Deviation 2.4 |
| Tadalafil | Maximum Borg Dyspnea Score During 6 Minute Walk Test | Week 16 | 5.3 units on a scale | Standard Deviation 2.1 |
| Tadalafil | Maximum Borg Dyspnea Score During 6 Minute Walk Test | Week 24 | 6.3 units on a scale | Standard Deviation 2.3 |
Comparison: comparing baseline to week 24p-value: 0.19t-test, 2 sided
Secondary
Number of Participants With Change in WHO Functional Class (WHO FC)
The WHO functional classification ranges from I (patient's disease does not affect daily activities) to IV (patient's disease causes severe impairment). Higher scores indicate more severe impairment.
Time frame: Baseline, Week 24
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tadalafil | Number of Participants With Change in WHO Functional Class (WHO FC) | Number of participants that improved to WHO FC III | 0 participants |
| Tadalafil | Number of Participants With Change in WHO Functional Class (WHO FC) | Number of participants that improved to WHO FC I | 1 participants |
| Tadalafil | Number of Participants With Change in WHO Functional Class (WHO FC) | Number of participants that improved to WHO FC II | 0 participants |
Secondary
Oxygen Desaturation During 6 Minute Walk Test
Change (decrease) in oxygen saturation from start of 6 minute walk to nadir during the 6 minute walk test
Time frame: Baseline, Week 24
Population: Only 6 of the 7 study completers performed the 6 minute walk test through week 24
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tadalafil | Oxygen Desaturation During 6 Minute Walk Test | Baseline | 9 oxygen saturation percentage points | Standard Deviation 6 |
| Tadalafil | Oxygen Desaturation During 6 Minute Walk Test | Week 24 | 9 oxygen saturation percentage points | Standard Deviation 9 |
p-value: 0.99t-test, 2 sided
Secondary
Resting Oxygen Saturation
Percent oxygen saturation of hemoglobin as measured by pulse oximetry in the resting state.
Time frame: Baseline, Week 24
Population: only 6 of the 7 study completers performed the 6 minute walk test through week 24.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tadalafil | Resting Oxygen Saturation | Baseline | 96.5 percent | Standard Deviation 1.8 |
| Tadalafil | Resting Oxygen Saturation | Week 24 | 95.2 percent | Standard Deviation 2.6 |
p-value: 0.34t-test, 2 sided
Secondary
Short Form-36 Global Score
SF- 36 investigates the standard of quality of life through a general health assessment and not specific to a particular disease, age or treatment group. It is a 36-item questionnaire measuring 8 domains (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health). Each domain score ranges from 0 (worst) to 100 (best), with higher scores reflecting better health-related functional status. The global score is determined by taking an average of the individual domain scores. The global score range is from 0 (worst) to 100 (best).
Time frame: Baseline, Week 8, Week 16, Week 24
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tadalafil | Short Form-36 Global Score | Baseline | 38.5 units on a scale | Standard Deviation 5.3 |
| Tadalafil | Short Form-36 Global Score | Week 8 | 37.7 units on a scale | Standard Deviation 6.7 |
| Tadalafil | Short Form-36 Global Score | Week 16 | 39.2 units on a scale | Standard Deviation 6.5 |
| Tadalafil | Short Form-36 Global Score | Week 24 | 38.9 units on a scale | Standard Deviation 8.5 |
Comparison: comparing baseline to week 24p-value: 0.92t-test, 2 sided
Secondary
St. George's Respiratory Questionnaire (SGRQ) Score
The SGRQ ranges from 0 (no impairment of quality of life) to 100 (highest impairment of quality of life)
Time frame: Baseline, Week 8, Week 16, Week 24
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tadalafil | St. George's Respiratory Questionnaire (SGRQ) Score | Baseline | 64.5 units on a scale | Standard Deviation 15.5 |
| Tadalafil | St. George's Respiratory Questionnaire (SGRQ) Score | Week 8 | 65.1 units on a scale | Standard Deviation 18.9 |
| Tadalafil | St. George's Respiratory Questionnaire (SGRQ) Score | Week 16 | 64.3 units on a scale | Standard Deviation 15.2 |
| Tadalafil | St. George's Respiratory Questionnaire (SGRQ) Score | Week 24 | 71.1 units on a scale | Standard Deviation 15.2 |
Comparison: comparison of baseline to week 24p-value: 0.44t-test, 2 sided