Hypertension, Pulmonary
Conditions
Brief summary
Study to determine the long term safety of tadalafil in patients with increased blood pressure in the blood vessel that carries blood from the right heart to the lungs and to see if it will keep the disease from getting worse.
Interventions
DRUGtadalafil
20 milligram (mg) tablet, taken by mouth once a day for 52 weeks for the phase 1 portion. Open label phase includes 40 mg tablet taken by mouth once a day until the sponsor concludes the study or tadalafil becomes commercially available for the treatment of Pulmonary Arterial Hypertension (PAH).
Sponsors
ICOS Corporation
Eli Lilly and Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Must have participated and discontinued in the previous PAH placebo controlled study due to clinical worsening on placebo or tadalafil 2.5 mg, 10mg, or 20 mg * Must have completed Week 16 of the previous PAH study and had either no clinical worsening or became clinically worse at the Week 16 visit on placebo or tadalafil 2.5 mg, 10mg, or 20 mg * Females who have a negative urine pregnancy test and are willing to use 2 types of birth control * Be 12 years or older (country specific regulations apply) with parental approval
Exclusion criteria
* Participated in the placebo controlled study and had clinical worsening on 40 mg tadalafil * Have left-sided heart disease * Have a musculoskeletal disorder that limits being able to get around * Nitrate use * Certain current systemic treatments
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs) | Baseline (Double-Blind Period) up to Week 243 (End of Open-Label Period) | A summary of serious and all other non-serious AEs, which include adverse events reported for laboratory tests and vital signs, is located in the Reported Adverse Event module. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 6-Minute Walk Distance (6MWD) at Baseline and Weeks 16, 28, 40 and 52 | Baseline and Weeks 16, 28, 40 and 52 | 6MWD measured the distance a participant was able to walk unassisted in 6 minutes. |
| Borg Dyspnea Assessment at Baseline and Weeks 16, 28, 40 and 52 | Baseline and Weeks 16, 28, 40 and 52 | Borg dyspnea score is a participant rated measure of their greatest degree of shortness of breath during exertion (6-minute walk test). Score ranged from 0 (nothing at all) to 10 (very, very severe \[maximal\]). |
| Probability of No Pulmonary Arterial Hypertension (PAH) Deterioration at Weeks 16, 28, 40 and up to 52 | Baseline and Weeks 16, 28, 40 and 52 | World Health Organization Functional Classification Assessment (WHO FC) is a method of classifying disease severity in PAH. The classes are: Class I: pulmonary hypertension (PH) but without resulting limitation of physical activity, Class II: PH resulting in slight limitation of physical activity, Class III: PH resulting in marked limitation of physical activity, Class IV: PH with inability to carry out any physical activity without symptoms. Deterioration of WHO FC is defined as moving to a higher WHO FC within one visit. Results are presented as Kaplan-Meier estimates (% probability) of remaining free from WHO FC deterioration after a given time. |
Countries
Belgium, Canada, France, Germany, Ireland, Italy, Japan, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
Participants were previously enrolled in H6D-MC-LVGY (NCT00125918), a placebo-controlled double-blind study.
Participants by arm
| Arm | Count |
|---|---|
| Tadalafil 20 Milligrams (mg) Double-Blind Tadalafil, 20 milligram (mg) administered orally as 1 tadalafil tablet and 1 matched placebo tablet once daily from Day 1 up to 52 weeks of treatment. | 63 |
| Tadalafil 40 mg Double-Blind Tadalafil, 40 mg (two 20 mg tablets) administered orally once daily from Day 1 up to 52 weeks of treatment. | 294 |
| Total | 357 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Double-Blind | Adverse Event | 3 | 16 | 0 |
| Double-Blind | Death | 2 | 9 | 0 |
| Double-Blind | Investigator Decision | 1 | 5 | 0 |
| Double-Blind | Lost to Follow-up | 1 | 2 | 0 |
| Double-Blind | New condition or starts new therapy | 0 | 2 | 0 |
| Double-Blind | New Drug Pulmonary Atrial Hypertension | 1 | 10 | 0 |
| Double-Blind | Sponsor Decision | 0 | 1 | 0 |
| Double-Blind | Withdrawal by Subject | 3 | 8 | 0 |
| Open-Label | Adverse Event | 0 | 0 | 11 |
| Open-Label | Death | 0 | 0 | 40 |
| Open-Label | Investigator Decision | 0 | 0 | 5 |
| Open-Label | Lost to Follow-up | 0 | 0 | 2 |
| Open-Label | New drug pulmonary atrial hypertension | 0 | 0 | 2 |
| Open-Label | Other | 0 | 0 | 3 |
| Open-Label | Withdrawal by Subject | 0 | 0 | 6 |
Baseline characteristics
| Characteristic | Tadalafil 20 Milligrams (mg) Double-Blind | Tadalafil 40 mg Double-Blind | Total |
|---|---|---|---|
| Age Continuous | 53.04 years STANDARD_DEVIATION 15.58 | 53.94 years STANDARD_DEVIATION 15.36 | 53.78 years STANDARD_DEVIATION 15.38 |
| Current Bosentan Use No | 26 participants | 139 participants | 165 participants |
| Current Bosentan Use Yes | 37 participants | 155 participants | 192 participants |
| Ethnicity Hispanic or Latino | 4 participants | 36 participants | 40 participants |
| Ethnicity Not Hispanic or Latino | 59 participants | 258 participants | 317 participants |
| Etiology Associated with Atrial Septal Defect | 3 participants | 26 participants | 29 participants |
| Etiology Idiopathic | 37 participants | 186 participants | 223 participants |
| Etiology Related to Anorexigen Use | 4 participants | 11 participants | 15 participants |
| Etiology Related to Collagen Vascular Disease | 16 participants | 62 participants | 78 participants |
| Etiology Surgical Repair, of at least 1 Year Duration | 3 participants | 9 participants | 12 participants |
| Race American Indian or Alaska Native | 2 participants | 3 participants | 5 participants |
| Race American Indian or Alaska Native/White | 0 participants | 1 participants | 1 participants |
| Race Asian | 7 participants | 22 participants | 29 participants |
| Race Black or African American | 5 participants | 23 participants | 28 participants |
| Race Black or African American/Native Hawaiian or Other | 1 participants | 0 participants | 1 participants |
| Race Native Hawaiian or Other Pacific Islander | 0 participants | 2 participants | 2 participants |
| Race White | 48 participants | 243 participants | 291 participants |
| Region of Enrollment Belgium | 2 participants | 5 participants | 7 participants |
| Region of Enrollment Canada | 4 participants | 38 participants | 42 participants |
| Region of Enrollment France | 3 participants | 22 participants | 25 participants |
| Region of Enrollment Germany | 6 participants | 34 participants | 40 participants |
| Region of Enrollment Ireland | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Italy | 4 participants | 25 participants | 29 participants |
| Region of Enrollment Japan | 5 participants | 17 participants | 22 participants |
| Region of Enrollment Spain | 2 participants | 4 participants | 6 participants |
| Region of Enrollment United Kingdom | 4 participants | 9 participants | 13 participants |
| Region of Enrollment United States | 33 participants | 139 participants | 172 participants |
| Sex: Female, Male Female | 48 Participants | 230 Participants | 278 Participants |
| Sex: Female, Male Male | 15 Participants | 64 Participants | 79 Participants |
| Weight | 73.92 kilograms (kg) STANDARD_DEVIATION 18.9 | 75.26 kilograms (kg) STANDARD_DEVIATION 19.8 | 75.02 kilograms (kg) STANDARD_DEVIATION 19.63 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 334 / 357 |
| serious Total, serious adverse events | 184 / 357 |
Outcome results
Primary
Number of Participants With Adverse Events (AEs)
A summary of serious and all other non-serious AEs, which include adverse events reported for laboratory tests and vital signs, is located in the Reported Adverse Event module.
Time frame: Baseline (Double-Blind Period) up to Week 243 (End of Open-Label Period)
Population: Safety Population: all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tadalafil 20 mg or 40 mg Double-Blind and 40 mg Open-Label | Number of Participants With Adverse Events (AEs) | Serious AEs | 184 participants |
| Tadalafil 20 mg or 40 mg Double-Blind and 40 mg Open-Label | Number of Participants With Adverse Events (AEs) | Other Non-Serious AEs | 334 participants |
Secondary
6-Minute Walk Distance (6MWD) at Baseline and Weeks 16, 28, 40 and 52
6MWD measured the distance a participant was able to walk unassisted in 6 minutes.
Time frame: Baseline and Weeks 16, 28, 40 and 52
Population: All randomized participants who received at least 1 dose of study drug and who completed 6MWD test; Last Observation Carried Forward (LOCF)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tadalafil 20 mg or 40 mg Double-Blind and 40 mg Open-Label | 6-Minute Walk Distance (6MWD) at Baseline and Weeks 16, 28, 40 and 52 | Distance walked at Baseline (n=63, 287 | 397.74 meters (m) | Standard Deviation 71.74 |
| Tadalafil 20 mg or 40 mg Double-Blind and 40 mg Open-Label | 6-Minute Walk Distance (6MWD) at Baseline and Weeks 16, 28, 40 and 52 | Distance walked at Week 28 (n=55, 250) | 406.41 meters (m) | Standard Deviation 106.76 |
| Tadalafil 20 mg or 40 mg Double-Blind and 40 mg Open-Label | 6-Minute Walk Distance (6MWD) at Baseline and Weeks 16, 28, 40 and 52 | Endpoint-Week 52 or LOCF (n=60,281) | 401.52 meters (m) | Standard Deviation 90.29 |
| Tadalafil 20 mg or 40 mg Double-Blind and 40 mg Open-Label | 6-Minute Walk Distance (6MWD) at Baseline and Weeks 16, 28, 40 and 52 | Distance walked at Week 40 (n=51, 241) | 411.81 meters (m) | Standard Deviation 78.72 |
| Tadalafil 20 mg or 40 mg Double-Blind and 40 mg Open-Label | 6-Minute Walk Distance (6MWD) at Baseline and Weeks 16, 28, 40 and 52 | Distance walked at Week 16 (n=58, 272) | 396.37 meters (m) | Standard Deviation 77.01 |
| Tadalafil 20 mg or 40 mg Double-Blind and 40 mg Open-Label | 6-Minute Walk Distance (6MWD) at Baseline and Weeks 16, 28, 40 and 52 | Distance walked at Week 52 (n=51, 235) | 415.31 meters (m) | Standard Deviation 79.82 |
| Tadalafil 40 mg Double-Blind | 6-Minute Walk Distance (6MWD) at Baseline and Weeks 16, 28, 40 and 52 | Distance walked at Week 16 (n=58, 272) | 381.47 meters (m) | Standard Deviation 96.86 |
| Tadalafil 40 mg Double-Blind | 6-Minute Walk Distance (6MWD) at Baseline and Weeks 16, 28, 40 and 52 | Endpoint-Week 52 or LOCF (n=60,281) | 379.80 meters (m) | Standard Deviation 99.12 |
| Tadalafil 40 mg Double-Blind | 6-Minute Walk Distance (6MWD) at Baseline and Weeks 16, 28, 40 and 52 | Distance walked at Baseline (n=63, 287 | 375.38 meters (m) | Standard Deviation 93.41 |
| Tadalafil 40 mg Double-Blind | 6-Minute Walk Distance (6MWD) at Baseline and Weeks 16, 28, 40 and 52 | Distance walked at Week 52 (n=51, 235) | 394.00 meters (m) | Standard Deviation 91.56 |
| Tadalafil 40 mg Double-Blind | 6-Minute Walk Distance (6MWD) at Baseline and Weeks 16, 28, 40 and 52 | Distance walked at Week 28 (n=55, 250) | 384.97 meters (m) | Standard Deviation 95.03 |
| Tadalafil 40 mg Double-Blind | 6-Minute Walk Distance (6MWD) at Baseline and Weeks 16, 28, 40 and 52 | Distance walked at Week 40 (n=51, 241) | 386.57 meters (m) | Standard Deviation 94.04 |
Secondary
Borg Dyspnea Assessment at Baseline and Weeks 16, 28, 40 and 52
Borg dyspnea score is a participant rated measure of their greatest degree of shortness of breath during exertion (6-minute walk test). Score ranged from 0 (nothing at all) to 10 (very, very severe \[maximal\]).
Time frame: Baseline and Weeks 16, 28, 40 and 52
Population: All randomized participants who received at least 1 dose of study drug and who completed the Borg Dyspnea Assessment; LOCF
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tadalafil 20 mg or 40 mg Double-Blind and 40 mg Open-Label | Borg Dyspnea Assessment at Baseline and Weeks 16, 28, 40 and 52 | Score at Baseline (n=62, 287) | 3.41 units on a scale | Standard Deviation 2.38 |
| Tadalafil 20 mg or 40 mg Double-Blind and 40 mg Open-Label | Borg Dyspnea Assessment at Baseline and Weeks 16, 28, 40 and 52 | Score at Week 16 (n=58, 271) | 3.41 units on a scale | Standard Deviation 2.48 |
| Tadalafil 20 mg or 40 mg Double-Blind and 40 mg Open-Label | Borg Dyspnea Assessment at Baseline and Weeks 16, 28, 40 and 52 | Score at Week 28 (n=54,249) | 3.46 units on a scale | Standard Deviation 2.4 |
| Tadalafil 20 mg or 40 mg Double-Blind and 40 mg Open-Label | Borg Dyspnea Assessment at Baseline and Weeks 16, 28, 40 and 52 | Score at Week 40 (n=51, 240) | 3.21 units on a scale | Standard Deviation 2.43 |
| Tadalafil 20 mg or 40 mg Double-Blind and 40 mg Open-Label | Borg Dyspnea Assessment at Baseline and Weeks 16, 28, 40 and 52 | Score at Week 52 (n=51,235) | 3.68 units on a scale | Standard Deviation 2.43 |
| Tadalafil 20 mg or 40 mg Double-Blind and 40 mg Open-Label | Borg Dyspnea Assessment at Baseline and Weeks 16, 28, 40 and 52 | Endpoint-Week 52 or LOCF (n=60,281) | 3.75 units on a scale | Standard Deviation 2.34 |
| Tadalafil 40 mg Double-Blind | Borg Dyspnea Assessment at Baseline and Weeks 16, 28, 40 and 52 | Score at Week 52 (n=51,235) | 3.29 units on a scale | Standard Deviation 2.16 |
| Tadalafil 40 mg Double-Blind | Borg Dyspnea Assessment at Baseline and Weeks 16, 28, 40 and 52 | Score at Baseline (n=62, 287) | 3.65 units on a scale | Standard Deviation 2.43 |
| Tadalafil 40 mg Double-Blind | Borg Dyspnea Assessment at Baseline and Weeks 16, 28, 40 and 52 | Score at Week 40 (n=51, 240) | 3.38 units on a scale | Standard Deviation 2.27 |
| Tadalafil 40 mg Double-Blind | Borg Dyspnea Assessment at Baseline and Weeks 16, 28, 40 and 52 | Score at Week 16 (n=58, 271) | 3.51 units on a scale | Standard Deviation 2.35 |
| Tadalafil 40 mg Double-Blind | Borg Dyspnea Assessment at Baseline and Weeks 16, 28, 40 and 52 | Endpoint-Week 52 or LOCF (n=60,281) | 3.54 units on a scale | Standard Deviation 2.36 |
| Tadalafil 40 mg Double-Blind | Borg Dyspnea Assessment at Baseline and Weeks 16, 28, 40 and 52 | Score at Week 28 (n=54,249) | 3.44 units on a scale | Standard Deviation 2.21 |
Secondary
Probability of No Pulmonary Arterial Hypertension (PAH) Deterioration at Weeks 16, 28, 40 and up to 52
World Health Organization Functional Classification Assessment (WHO FC) is a method of classifying disease severity in PAH. The classes are: Class I: pulmonary hypertension (PH) but without resulting limitation of physical activity, Class II: PH resulting in slight limitation of physical activity, Class III: PH resulting in marked limitation of physical activity, Class IV: PH with inability to carry out any physical activity without symptoms. Deterioration of WHO FC is defined as moving to a higher WHO FC within one visit. Results are presented as Kaplan-Meier estimates (% probability) of remaining free from WHO FC deterioration after a given time.
Time frame: Baseline and Weeks 16, 28, 40 and 52
Population: Safety Population: all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tadalafil 20 mg or 40 mg Double-Blind and 40 mg Open-Label | Probability of No Pulmonary Arterial Hypertension (PAH) Deterioration at Weeks 16, 28, 40 and up to 52 | Week 16 (n=57, 262) | 95 probability (%) no PAH deterioration |
| Tadalafil 20 mg or 40 mg Double-Blind and 40 mg Open-Label | Probability of No Pulmonary Arterial Hypertension (PAH) Deterioration at Weeks 16, 28, 40 and up to 52 | Week 28 (n=50, 238) | 88 probability (%) no PAH deterioration |
| Tadalafil 20 mg or 40 mg Double-Blind and 40 mg Open-Label | Probability of No Pulmonary Arterial Hypertension (PAH) Deterioration at Weeks 16, 28, 40 and up to 52 | Week 40 (n=45, 222) | 81 probability (%) no PAH deterioration |
| Tadalafil 20 mg or 40 mg Double-Blind and 40 mg Open-Label | Probability of No Pulmonary Arterial Hypertension (PAH) Deterioration at Weeks 16, 28, 40 and up to 52 | Week 52 (n=33,136) | 81 probability (%) no PAH deterioration |
| Tadalafil 40 mg Double-Blind | Probability of No Pulmonary Arterial Hypertension (PAH) Deterioration at Weeks 16, 28, 40 and up to 52 | Week 52 (n=33,136) | 85 probability (%) no PAH deterioration |
| Tadalafil 40 mg Double-Blind | Probability of No Pulmonary Arterial Hypertension (PAH) Deterioration at Weeks 16, 28, 40 and up to 52 | Week 16 (n=57, 262) | 96 probability (%) no PAH deterioration |
| Tadalafil 40 mg Double-Blind | Probability of No Pulmonary Arterial Hypertension (PAH) Deterioration at Weeks 16, 28, 40 and up to 52 | Week 40 (n=45, 222) | 88 probability (%) no PAH deterioration |
| Tadalafil 40 mg Double-Blind | Probability of No Pulmonary Arterial Hypertension (PAH) Deterioration at Weeks 16, 28, 40 and up to 52 | Week 28 (n=50, 238) | 90 probability (%) no PAH deterioration |