Peripheral Arterial Diseases
Conditions
Keywords
Drug Therapy
Brief summary
The purpose of the study is to evaluate the efficacy and safety of actovegin in participants with peripheral arterial disease (PAD) Fontaine Stage IIB.
Detailed description
The study will enroll approximately 366 participants. Participants will be randomly assigned to one of the two treatment groups in 1:1 ratio: 1. Actovegin 2. Placebo (dummy inactive substance) - this is a tablet/intravenous infusion that looks like the study drug but has no active ingredient All participants will be asked to take intravenous infusion for 2 weeks followed by oral tablets for 10 weeks. This multi-center trial will be conducted Russia, Georgia, and Kazakhstan. The overall time to participate in this study is 25 to 26 weeks. Participants will make multiple visits to the clinic, and 12 weeks after last dose of study drug for a follow-up assessment.
Interventions
DRUGActovegin
Actovegin intravenous infusion and tablets.
DRUGPlacebo
Actovegin placebo-matching intravenous infusion and tablets.
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Has a history of stable intermittent claudication lasting more than 6 months before Screening. 2. Has a diagnosis of peripheral arterial disease (PAD) (Code I70.2 according to the international classification of diseases-10th revision) Fontaine Stage IIB confirmed by ultrasound color duplex imaging. 3. Has a resting Doppler ankle-brachial index of less than or equal to (\<=) 0.9. 4. Has intermittent claudication with initial claudication distance (ICD) less than (\<) 200 meters. 5. Is not newly diagnosed with PAD and has a history of stable PAD therapy for at least 2 weeks before Screening.
Exclusion criteria
1. Has PAD Fontaine Stage III or IV (pain at rest, non-healing ulceration, or gangrene). 2. Has evidence of nonatherosclerotic PAD. 3. Has greater than (\>) 25 percent (%) variability in absolute claudication distance (ACD) based on treadmill testing during the screening period. 4. Has lower extremity arterial reconstruction (surgical or endovascular) or sympathectomy within 3 months before Screening. 5. Is eligible for surgical/interventional reconstruction. 6. Had a myocardial infarction or major cardiac surgery within 3 months before Screening. 7. Has congestive heart failure (New York Heart Association Class III/IV). 8. Has uncontrolled diabetes mellitus (glycosylated hemoglobin \[HbA1c \>9%\]) or diabetic polyneuropathy. 9. Has any other illness that significantly limits exercise capacity or other medical condition, including any psychiatric disorder that limits participation (in the judgement of the investigator). 10. The subject has received any prohibited medication within 14 days before Randomization (Day 1) 11. The subject is undergoing the supervised exercise training program by the time of Screening and is going to continue this program due to its effectiveness.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Initial Claudication Distance (ICD) at Week 12 | Baseline up to Week 12 | ICD was the distance walked at the onset of claudication pain or pain-free walking distance. ICD was assessed using treadmill testing. A fixed load treadmill test was carried out at 3.0 kilometer per hour (km/h) with a 10 percent (%) grade. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in ICD at Weeks 2 and 24 | Baseline up to Weeks 2 and 24 | ICD was the distance walked at the onset of claudication pain or pain-free walking distance. ICD was assessed using treadmill testing. A fixed load treadmill test was carried out at 3.0 km/h with a 10% grade. |
| Absolute Change From Baseline in Absolute Claudication Distance (ACD) at Weeks 2, 12 and 24 | Baseline, Weeks 2, 12 and 24 | ACD was the distance at which claudication pain becomes so severe that the participant was forced to stop, also known as maximal walking distance. ACD was assessed using treadmill testing. A fixed load treadmill test was carried out at 3.0 km/h with a 10% grade. The investigator will record the distance from walking start to the point where the participant is unable to walk anymore. |
| Percentage of Participants With Rest Pain at Weeks 12 and 24 | Weeks 12 and 24 | Rest pain was defined as a continuous burning pain, that begins, or is aggravated, after reclining or elevating the limb and is relieved by sitting or standing. |
| Percentage of Participants With Revascularization Procedures at Week 24 | Week 24 | Revascularization was defined by a Thrombolysis in Myocardial Infarction (TIMI) score of 2 or 3 following use of the Penumbra System. TIMI scores were used to describe blood flow at the treated vessel with 0 designating no flow and 3 for normal flow. |
| Change From Baseline in 36-Item Short Form Survey (SF-36) at Weeks 12 and 24 | Baseline, Weeks 12 and 24 | The SF-36 was a questionnaire that evaluated a participant's health related quality of life. SF-36 included 36 questions related to 8 health dimensions: physical functioning, role-physical (role limitations due to physical health problems), bodily pain, general health, vitality (energy/fatigue), social functioning, role-emotional (role limitations due to emotional problems), and mental health. Based on these 4 scales (physical functioning, role-physical, bodily pain, general health), the physical health score was generated which ranges between 0 and 100, with higher scores indicating a better quality of life. Based on these 4 scales (vitality, social functioning, role-emotional, and mental health), the mental health score was generated which ranges between 0 and 100, with higher scores indicating a better quality of life. |
Countries
Georgia, Kazakhstan, Russia
Participant flow
Recruitment details
Participants took part in the study at 19 investigative sites in Russia, Kazakhstan and Georgia from 01 May 2018 to 28 August 2019.
Pre-assignment details
Participants with peripheral arterial occlusive disease (PAD) Fontaine stage IIB were enrolled in this study to receive either actovegin or placebo in a 1:1 ratio.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Actovegin placebo-matching infusion, intravenously, once daily for up to 2 weeks followed by actovegin placebo-matching tablets, orally, thrice daily for up to 10 weeks. | 182 |
| Actovegin 1200 mg Actovegin 1200 mg, infusion, intravenously, once daily for up to 2 weeks followed by actovegin 200 mg, tablets, orally, thrice daily (1200 mg/day) for up to 10 weeks. | 184 |
| Total | 366 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 4 |
| Overall Study | Lost to Follow-up | 2 | 2 |
| Overall Study | Progressive Disease | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 3 |
Baseline characteristics
| Characteristic | Placebo | Actovegin 1200 mg | Total |
|---|---|---|---|
| Age, Continuous | 62.9 years STANDARD_DEVIATION 6.56 | 63.7 years STANDARD_DEVIATION 6.76 | 63.3 years STANDARD_DEVIATION 6.66 |
| Ankle Brachial Index (ABI) at Bilateral (BL) | 0.580 ratio STANDARD_DEVIATION 0.1511 | 0.589 ratio STANDARD_DEVIATION 0.1564 | 0.584 ratio STANDARD_DEVIATION 0.1536 |
| Body Mass Index (BMI) | 27.42 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 3.733 | 27.44 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 4.131 | 27.43 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 3.933 |
| Diabetic Status Diabetic | 29 Participants | 40 Participants | 69 Participants |
| Diabetic Status Non-diabetic | 153 Participants | 144 Participants | 297 Participants |
| Height | 172.0 centimeter (cm) STANDARD_DEVIATION 7.66 | 172.1 centimeter (cm) STANDARD_DEVIATION 7.43 | 172.1 centimeter (cm) STANDARD_DEVIATION 7.53 |
| Location of the Lesion Aorto-iliac segment | 8 Participants | 6 Participants | 14 Participants |
| Location of the Lesion Both segments | 89 Participants | 90 Participants | 179 Participants |
| Location of the Lesion Femoro-popliteal segment | 85 Participants | 88 Participants | 173 Participants |
| PAD Stage II Duration | 5.482 years STANDARD_DEVIATION 4.2019 | 5.283 years STANDARD_DEVIATION 4.9374 | 5.382 years STANDARD_DEVIATION 4.5812 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 9 Participants | 5 Participants | 14 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 173 Participants | 179 Participants | 352 Participants |
| Region of Enrollment Georgia | 16 participants | 16 participants | 32 participants |
| Region of Enrollment Kazakhstan | 12 participants | 12 participants | 24 participants |
| Region of Enrollment Russia | 154 participants | 156 participants | 310 participants |
| Sex: Female, Male Female | 27 Participants | 24 Participants | 51 Participants |
| Sex: Female, Male Male | 155 Participants | 160 Participants | 315 Participants |
| Smoking Status Current smoker | 69 Participants | 69 Participants | 138 Participants |
| Smoking Status Former smoker | 82 Participants | 76 Participants | 158 Participants |
| Smoking Status Never-smoked. | 31 Participants | 39 Participants | 70 Participants |
| Weight | 81.17 kilogram (Kg) STANDARD_DEVIATION 12.483 | 81.30 kilogram (Kg) STANDARD_DEVIATION 13.351 | 81.24 kilogram (Kg) STANDARD_DEVIATION 12.909 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 182 | 0 / 184 |
| other Total, other adverse events | 20 / 182 | 23 / 184 |
| serious Total, serious adverse events | 3 / 182 | 9 / 184 |
Outcome results
Primary
Percent Change From Baseline in Initial Claudication Distance (ICD) at Week 12
ICD was the distance walked at the onset of claudication pain or pain-free walking distance. ICD was assessed using treadmill testing. A fixed load treadmill test was carried out at 3.0 kilometer per hour (km/h) with a 10 percent (%) grade.
Time frame: Baseline up to Week 12
Population: The full analysis set (FAS) included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 valid post-baseline value for assessment of primary endpoint. Here, overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Initial Claudication Distance (ICD) at Week 12 | 21.99 percent change | Standard Error 9.286 |
| Actovegin 1200 mg | Percent Change From Baseline in Initial Claudication Distance (ICD) at Week 12 | 51.17 percent change | Standard Error 9.187 |
Comparison: Least squares means, p-values were obtained using a mixed model for repeated measures (MMRM) analysis of covariance with treatment, center, sex, age group, smoking status, diabetic status, visit and treatment-by-visit interaction as fixed effects and baseline value as covariate.p-value: 0.004195% CI: [9.35, 49.02]MMRM
Secondary
Absolute Change From Baseline in Absolute Claudication Distance (ACD) at Weeks 2, 12 and 24
ACD was the distance at which claudication pain becomes so severe that the participant was forced to stop, also known as maximal walking distance. ACD was assessed using treadmill testing. A fixed load treadmill test was carried out at 3.0 km/h with a 10% grade. The investigator will record the distance from walking start to the point where the participant is unable to walk anymore.
Time frame: Baseline, Weeks 2, 12 and 24
Population: The FAS included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 valid post-baseline value for assessment of primary endpoint. Participants evaluable for this measure at given time point were included for the assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Absolute Change From Baseline in Absolute Claudication Distance (ACD) at Weeks 2, 12 and 24 | Baseline | 134.5 meter | Standard Deviation 58.84 |
| Placebo | Absolute Change From Baseline in Absolute Claudication Distance (ACD) at Weeks 2, 12 and 24 | Change at Week 2 | 17.61 meter | Standard Deviation 30.781 |
| Placebo | Absolute Change From Baseline in Absolute Claudication Distance (ACD) at Weeks 2, 12 and 24 | Change at Week 12 | 30.05 meter | Standard Deviation 50.53 |
| Placebo | Absolute Change From Baseline in Absolute Claudication Distance (ACD) at Weeks 2, 12 and 24 | Change at Week 24 | 36.37 meter | Standard Deviation 71.834 |
| Actovegin 1200 mg | Absolute Change From Baseline in Absolute Claudication Distance (ACD) at Weeks 2, 12 and 24 | Change at Week 24 | 86.47 meter | Standard Deviation 227.491 |
| Actovegin 1200 mg | Absolute Change From Baseline in Absolute Claudication Distance (ACD) at Weeks 2, 12 and 24 | Baseline | 137.1 meter | Standard Deviation 72.76 |
| Actovegin 1200 mg | Absolute Change From Baseline in Absolute Claudication Distance (ACD) at Weeks 2, 12 and 24 | Change at Week 12 | 75.51 meter | Standard Deviation 190.808 |
| Actovegin 1200 mg | Absolute Change From Baseline in Absolute Claudication Distance (ACD) at Weeks 2, 12 and 24 | Change at Week 2 | 46.28 meter | Standard Deviation 179.356 |
Comparison: Week 2: p-values were obtained using a MMRM analysis of covariance with treatment, center, sex, age group, smoking status, diabetic status, visit and treatment-by-visit interaction as fixed effects and baseline value as covariate.p-value: 0.0227MMRM
Comparison: Week 12: p-values were obtained using a MMRM analysis of covariance with treatment, center, sex, age group, smoking status, diabetic status, visit and treatment-by-visit interaction as fixed effects and baseline value as covariate.p-value: 0.0007MMRM
Comparison: Week 24: p-values were obtained using a MMRM analysis of covariance with treatment, center, sex, age group, smoking status, diabetic status, visit and treatment-by-visit interaction as fixed effects and baseline value as covariate.p-value: 0.0023MMRM
Secondary
Change From Baseline in 36-Item Short Form Survey (SF-36) at Weeks 12 and 24
The SF-36 was a questionnaire that evaluated a participant's health related quality of life. SF-36 included 36 questions related to 8 health dimensions: physical functioning, role-physical (role limitations due to physical health problems), bodily pain, general health, vitality (energy/fatigue), social functioning, role-emotional (role limitations due to emotional problems), and mental health. Based on these 4 scales (physical functioning, role-physical, bodily pain, general health), the physical health score was generated which ranges between 0 and 100, with higher scores indicating a better quality of life. Based on these 4 scales (vitality, social functioning, role-emotional, and mental health), the mental health score was generated which ranges between 0 and 100, with higher scores indicating a better quality of life.
Time frame: Baseline, Weeks 12 and 24
Population: The FAS included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 valid post-baseline value for assessment of primary endpoint. Participants evaluable for this measure at given time point were included for the assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in 36-Item Short Form Survey (SF-36) at Weeks 12 and 24 | Physical Health Score: Change at Week 12 | 2.029 points on a scale | Standard Deviation 5.1633 |
| Placebo | Change From Baseline in 36-Item Short Form Survey (SF-36) at Weeks 12 and 24 | Mental Health Score: Change at Week 24 | 0.571 points on a scale | Standard Deviation 8.6698 |
| Placebo | Change From Baseline in 36-Item Short Form Survey (SF-36) at Weeks 12 and 24 | Physical Health Score: Change at Week 24 | 1.752 points on a scale | Standard Deviation 6.1229 |
| Placebo | Change From Baseline in 36-Item Short Form Survey (SF-36) at Weeks 12 and 24 | Physical Health Score: Baseline | 39.533 points on a scale | Standard Deviation 6.3023 |
| Placebo | Change From Baseline in 36-Item Short Form Survey (SF-36) at Weeks 12 and 24 | Mental Health Score: Baseline | 47.961 points on a scale | Standard Deviation 9.4891 |
| Placebo | Change From Baseline in 36-Item Short Form Survey (SF-36) at Weeks 12 and 24 | Mental Health Score: Change at Week 12 | 1.134 points on a scale | Standard Deviation 7.2459 |
| Actovegin 1200 mg | Change From Baseline in 36-Item Short Form Survey (SF-36) at Weeks 12 and 24 | Mental Health Score: Change at Week 24 | 3.063 points on a scale | Standard Deviation 9.0286 |
| Actovegin 1200 mg | Change From Baseline in 36-Item Short Form Survey (SF-36) at Weeks 12 and 24 | Mental Health Score: Change at Week 12 | 2.434 points on a scale | Standard Deviation 8.2234 |
| Actovegin 1200 mg | Change From Baseline in 36-Item Short Form Survey (SF-36) at Weeks 12 and 24 | Physical Health Score: Baseline | 39.905 points on a scale | Standard Deviation 6.5138 |
| Actovegin 1200 mg | Change From Baseline in 36-Item Short Form Survey (SF-36) at Weeks 12 and 24 | Physical Health Score: Change at Week 12 | 2.368 points on a scale | Standard Deviation 5.3725 |
| Actovegin 1200 mg | Change From Baseline in 36-Item Short Form Survey (SF-36) at Weeks 12 and 24 | Physical Health Score: Change at Week 24 | 2.333 points on a scale | Standard Deviation 5.195 |
| Actovegin 1200 mg | Change From Baseline in 36-Item Short Form Survey (SF-36) at Weeks 12 and 24 | Mental Health Score: Baseline | 47.531 points on a scale | Standard Deviation 9.8667 |
Comparison: Physical Health Score: Week 12; Least squares means, p-values were obtained using a MMRM analysis of covariance with treatment, center, sex, age group, smoking status, diabetic status, visit and treatment-by-visit interaction as fixed effects and baseline value as covariate.p-value: 0.3758MMRM
Comparison: Physical Health Score: Week 24; Least squares means, p-values were obtained using a MMRM analysis of covariance with treatment, center, sex, age group, smoking status, diabetic status, visit and treatment-by-visit interaction as fixed effects and baseline value as covariate.p-value: 0.1412MMRM
Comparison: Mental Health Score: Week 12; Least squares means, p-values were obtained using a MMRM analysis of covariance with treatment, center, sex, age group, smoking status, diabetic status, visit and treatment-by-visit interaction as fixed effects and baseline value as covariate.p-value: 0.1009MMRM
Comparison: Mental Health Score: Week 24; Least squares means, p-values were obtained using a MMRM analysis of covariance with treatment, center, sex, age group, smoking status, diabetic status, visit and treatment-by-visit interaction as fixed effects and baseline value as covariate.p-value: 0.0015MMRM
Secondary
Percentage of Participants With Rest Pain at Weeks 12 and 24
Rest pain was defined as a continuous burning pain, that begins, or is aggravated, after reclining or elevating the limb and is relieved by sitting or standing.
Time frame: Weeks 12 and 24
Population: The FAS included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 valid post-baseline value for assessment of primary endpoint. Participants evaluable for this measure at given time point were included for the assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Participants With Rest Pain at Weeks 12 and 24 | Week 12 | 0 percentage of participants |
| Placebo | Percentage of Participants With Rest Pain at Weeks 12 and 24 | Week 24 | 1.1 percentage of participants |
| Actovegin 1200 mg | Percentage of Participants With Rest Pain at Weeks 12 and 24 | Week 12 | 0.6 percentage of participants |
| Actovegin 1200 mg | Percentage of Participants With Rest Pain at Weeks 12 and 24 | Week 24 | 0.6 percentage of participants |
Comparison: Week 12p-value: 0.9592Regression, Logistic
Comparison: Week 24p-value: 0.5823Regression, Logistic
Secondary
Percentage of Participants With Revascularization Procedures at Week 24
Revascularization was defined by a Thrombolysis in Myocardial Infarction (TIMI) score of 2 or 3 following use of the Penumbra System. TIMI scores were used to describe blood flow at the treated vessel with 0 designating no flow and 3 for normal flow.
Time frame: Week 24
Population: The FAS included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 valid post-baseline value for assessment of primary endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Revascularization Procedures at Week 24 | 0.0 percentage of participants |
| Actovegin 1200 mg | Percentage of Participants With Revascularization Procedures at Week 24 | 1.1 percentage of participants |
p-value: 0.9424Regression, Logistic
Secondary
Percent Change From Baseline in ICD at Weeks 2 and 24
ICD was the distance walked at the onset of claudication pain or pain-free walking distance. ICD was assessed using treadmill testing. A fixed load treadmill test was carried out at 3.0 km/h with a 10% grade.
Time frame: Baseline up to Weeks 2 and 24
Population: The FAS included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 valid post-baseline value for assessment of primary endpoint. Participants evaluable for this measure at given time point were included for the assessment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Percent Change From Baseline in ICD at Weeks 2 and 24 | Week 2 | 6.58 percent change | Standard Error 8.131 |
| Placebo | Percent Change From Baseline in ICD at Weeks 2 and 24 | Week 24 | 25.12 percent change | Standard Error 10.665 |
| Actovegin 1200 mg | Percent Change From Baseline in ICD at Weeks 2 and 24 | Week 2 | 22.45 percent change | Standard Error 7.981 |
| Actovegin 1200 mg | Percent Change From Baseline in ICD at Weeks 2 and 24 | Week 24 | 60.63 percent change | Standard Error 10.614 |
Comparison: Week 2: Least squares means, p-values were obtained using a MMRM analysis of covariance with treatment, center, sex, age group, smoking status, diabetic status, visit and treatment-by-visit interaction as fixed effects and baseline value as covariate.p-value: 0.043195% CI: [0.49, 31.24]MMRM
Comparison: Week 24: Least squares means, p-values were obtained using a MMRM analysis of covariance with treatment, center, sex, age group, smoking status, diabetic status, visit and treatment-by-visit interaction as fixed effects and baseline value as covariate.p-value: 0.004795% CI: [10.96, 60.05]MMRM