Trial Outcomes & Findings for Actovegin 12-Week Treatment Given First Intravenously and Subsequently Orally in Participants With Peripheral Arterial Occlusive Disease Fontaine Stage IIB (NCT NCT03469349)

Last Updated: 2020-10-28

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

366 participants

Primary outcome timeframe

Baseline up to Week 12

Results posted on

2020-10-28

Participant Flow

Participants took part in the study at 19 investigative sites in Russia, Kazakhstan and Georgia from 01 May 2018 to 28 August 2019.

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.

Participant milestones

Participant milestones
Measure	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.	Actovegin 1200 mg Actovegin 1200 milligram (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.
Overall Study STARTED	182	184
Overall Study COMPLETED	177	174
Overall Study NOT COMPLETED	5	10

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	Actovegin 1200 mg Actovegin 1200 milligram (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.
Overall Study Withdrawal by Subject	1	3
Overall Study Progressive Disease	0	1
Overall Study Lost to Follow-up	2	2
Overall Study Adverse Event	2	4

Baseline Characteristics

Actovegin 12-Week Treatment Given First Intravenously and Subsequently Orally in Participants With Peripheral Arterial Occlusive Disease Fontaine Stage IIB

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=182 Participants 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.	Actovegin 1200 mg n=184 Participants 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.	Total n=366 Participants Total of all reporting groups
Age, Continuous	62.9 years STANDARD_DEVIATION 6.56 • n=5 Participants	63.7 years STANDARD_DEVIATION 6.76 • n=7 Participants	63.3 years STANDARD_DEVIATION 6.66 • n=5 Participants
Sex: Female, Male Female	27 Participants n=5 Participants	24 Participants n=7 Participants	51 Participants n=5 Participants
Sex: Female, Male Male	155 Participants n=5 Participants	160 Participants n=7 Participants	315 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	9 Participants n=5 Participants	5 Participants n=7 Participants	14 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	173 Participants n=5 Participants	179 Participants n=7 Participants	352 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment Russia	154 participants n=5 Participants	156 participants n=7 Participants	310 participants n=5 Participants
Region of Enrollment Kazakhstan	12 participants n=5 Participants	12 participants n=7 Participants	24 participants n=5 Participants
Region of Enrollment Georgia	16 participants n=5 Participants	16 participants n=7 Participants	32 participants n=5 Participants
Height	172.0 centimeter (cm) STANDARD_DEVIATION 7.66 • n=5 Participants	172.1 centimeter (cm) STANDARD_DEVIATION 7.43 • n=7 Participants	172.1 centimeter (cm) STANDARD_DEVIATION 7.53 • n=5 Participants
Weight	81.17 kilogram (Kg) STANDARD_DEVIATION 12.483 • n=5 Participants	81.30 kilogram (Kg) STANDARD_DEVIATION 13.351 • n=7 Participants	81.24 kilogram (Kg) STANDARD_DEVIATION 12.909 • n=5 Participants
Body Mass Index (BMI)	27.42 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 3.733 • n=5 Participants	27.44 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 4.131 • n=7 Participants	27.43 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 3.933 • n=5 Participants
PAD Stage II Duration	5.482 years STANDARD_DEVIATION 4.2019 • n=5 Participants	5.283 years STANDARD_DEVIATION 4.9374 • n=7 Participants	5.382 years STANDARD_DEVIATION 4.5812 • n=5 Participants
Diabetic Status Diabetic	29 Participants n=5 Participants	40 Participants n=7 Participants	69 Participants n=5 Participants
Diabetic Status Non-diabetic	153 Participants n=5 Participants	144 Participants n=7 Participants	297 Participants n=5 Participants
Location of the Lesion Aorto-iliac segment	8 Participants n=5 Participants	6 Participants n=7 Participants	14 Participants n=5 Participants
Location of the Lesion Femoro-popliteal segment	85 Participants n=5 Participants	88 Participants n=7 Participants	173 Participants n=5 Participants
Location of the Lesion Both segments	89 Participants n=5 Participants	90 Participants n=7 Participants	179 Participants n=5 Participants
Ankle Brachial Index (ABI) at Bilateral (BL)	0.580 ratio STANDARD_DEVIATION 0.1511 • n=5 Participants	0.589 ratio STANDARD_DEVIATION 0.1564 • n=7 Participants	0.584 ratio STANDARD_DEVIATION 0.1536 • n=5 Participants
Smoking Status Current smoker	69 Participants n=5 Participants	69 Participants n=7 Participants	138 Participants n=5 Participants
Smoking Status Former smoker	82 Participants n=5 Participants	76 Participants n=7 Participants	158 Participants n=5 Participants
Smoking Status Never-smoked.	31 Participants n=5 Participants	39 Participants n=7 Participants	70 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=180 Participants 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.	Actovegin 1200 mg n=177 Participants 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.
Percent Change From Baseline in Initial Claudication Distance (ICD) at Week 12	21.99 percent change Standard Error 9.286	51.17 percent change Standard Error 9.187

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=182 Participants 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.	Actovegin 1200 mg n=180 Participants 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.
Percent Change From Baseline in ICD at Weeks 2 and 24 Week 2	6.58 percent change Standard Error 8.131	22.45 percent change Standard Error 7.981
Percent Change From Baseline in ICD at Weeks 2 and 24 Week 24	25.12 percent change Standard Error 10.665	60.63 percent change Standard Error 10.614

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=182 Participants 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.	Actovegin 1200 mg n=180 Participants 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.
Absolute Change From Baseline in Absolute Claudication Distance (ACD) at Weeks 2, 12 and 24 Baseline	134.5 meter Standard Deviation 58.84	137.1 meter Standard Deviation 72.76
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	46.28 meter Standard Deviation 179.356
Absolute Change From Baseline in Absolute Claudication Distance (ACD) at Weeks 2, 12 and 24 Change at Week 12	30.05 meter Standard Deviation 50.530	75.51 meter Standard Deviation 190.808
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	86.47 meter Standard Deviation 227.491

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=182 Participants 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.	Actovegin 1200 mg n=180 Participants 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.
Percentage of Participants With Rest Pain at Weeks 12 and 24 Week 12	0 percentage of participants	0.6 percentage of participants
Percentage of Participants With Rest Pain at Weeks 12 and 24 Week 24	1.1 percentage of participants	0.6 percentage of participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=182 Participants 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.	Actovegin 1200 mg n=180 Participants 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.
Percentage of Participants With Revascularization Procedures at Week 24	0.0 percentage of participants	1.1 percentage of participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=182 Participants 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.	Actovegin 1200 mg n=180 Participants 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.
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	2.434 points on a scale Standard Deviation 8.2234
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	39.905 points on a scale Standard Deviation 6.5138
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	2.368 points on a scale Standard Deviation 5.3725
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	2.333 points on a scale Standard Deviation 5.1950
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	47.531 points on a scale Standard Deviation 9.8667
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	3.063 points on a scale Standard Deviation 9.0286

Adverse Events

Placebo

Serious events: 3 serious events

Other events: 20 other events

Deaths: 0 deaths

Actovegin 1200 mg

Serious events: 9 serious events

Other events: 23 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=182 participants at risk 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.	Actovegin 1200 mg n=184 participants at risk 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.
Cardiac disorders Angina unstable	0.00% 0/182 • Treatment emergent adverse events (TEAEs) are adverse events that started after the first dose of study drug up to Day 168 At each visit the investigator had to assess any occurrence of adverse events. Participants may report adverse events occurring at any other time during the study. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.54% 1/184 • Treatment emergent adverse events (TEAEs) are adverse events that started after the first dose of study drug up to Day 168 At each visit the investigator had to assess any occurrence of adverse events. Participants may report adverse events occurring at any other time during the study. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Gangrene	0.55% 1/182 • Treatment emergent adverse events (TEAEs) are adverse events that started after the first dose of study drug up to Day 168 At each visit the investigator had to assess any occurrence of adverse events. Participants may report adverse events occurring at any other time during the study. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	1.1% 2/184 • Treatment emergent adverse events (TEAEs) are adverse events that started after the first dose of study drug up to Day 168 At each visit the investigator had to assess any occurrence of adverse events. Participants may report adverse events occurring at any other time during the study. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Pneumonia	0.00% 0/182 • Treatment emergent adverse events (TEAEs) are adverse events that started after the first dose of study drug up to Day 168 At each visit the investigator had to assess any occurrence of adverse events. Participants may report adverse events occurring at any other time during the study. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.54% 1/184 • Treatment emergent adverse events (TEAEs) are adverse events that started after the first dose of study drug up to Day 168 At each visit the investigator had to assess any occurrence of adverse events. Participants may report adverse events occurring at any other time during the study. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Injury, poisoning and procedural complications Arterial bypass thrombosis	0.00% 0/182 • Treatment emergent adverse events (TEAEs) are adverse events that started after the first dose of study drug up to Day 168 At each visit the investigator had to assess any occurrence of adverse events. Participants may report adverse events occurring at any other time during the study. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.54% 1/184 • Treatment emergent adverse events (TEAEs) are adverse events that started after the first dose of study drug up to Day 168 At each visit the investigator had to assess any occurrence of adverse events. Participants may report adverse events occurring at any other time during the study. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Injury, poisoning and procedural complications Hip fracture	0.00% 0/182 • Treatment emergent adverse events (TEAEs) are adverse events that started after the first dose of study drug up to Day 168 At each visit the investigator had to assess any occurrence of adverse events. Participants may report adverse events occurring at any other time during the study. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.54% 1/184 • Treatment emergent adverse events (TEAEs) are adverse events that started after the first dose of study drug up to Day 168 At each visit the investigator had to assess any occurrence of adverse events. Participants may report adverse events occurring at any other time during the study. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Haemorrhagic stroke	0.00% 0/182 • Treatment emergent adverse events (TEAEs) are adverse events that started after the first dose of study drug up to Day 168 At each visit the investigator had to assess any occurrence of adverse events. Participants may report adverse events occurring at any other time during the study. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.54% 1/184 • Treatment emergent adverse events (TEAEs) are adverse events that started after the first dose of study drug up to Day 168 At each visit the investigator had to assess any occurrence of adverse events. Participants may report adverse events occurring at any other time during the study. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/182 • Treatment emergent adverse events (TEAEs) are adverse events that started after the first dose of study drug up to Day 168 At each visit the investigator had to assess any occurrence of adverse events. Participants may report adverse events occurring at any other time during the study. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.54% 1/184 • Treatment emergent adverse events (TEAEs) are adverse events that started after the first dose of study drug up to Day 168 At each visit the investigator had to assess any occurrence of adverse events. Participants may report adverse events occurring at any other time during the study. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Vascular disorders Peripheral artery occlusion	0.00% 0/182 • Treatment emergent adverse events (TEAEs) are adverse events that started after the first dose of study drug up to Day 168 At each visit the investigator had to assess any occurrence of adverse events. Participants may report adverse events occurring at any other time during the study. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.54% 1/184 • Treatment emergent adverse events (TEAEs) are adverse events that started after the first dose of study drug up to Day 168 At each visit the investigator had to assess any occurrence of adverse events. Participants may report adverse events occurring at any other time during the study. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Vascular disorders Thrombophlebitis	0.00% 0/182 • Treatment emergent adverse events (TEAEs) are adverse events that started after the first dose of study drug up to Day 168 At each visit the investigator had to assess any occurrence of adverse events. Participants may report adverse events occurring at any other time during the study. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.54% 1/184 • Treatment emergent adverse events (TEAEs) are adverse events that started after the first dose of study drug up to Day 168 At each visit the investigator had to assess any occurrence of adverse events. Participants may report adverse events occurring at any other time during the study. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Vascular disorders Extremity necrosis	0.55% 1/182 • Treatment emergent adverse events (TEAEs) are adverse events that started after the first dose of study drug up to Day 168 At each visit the investigator had to assess any occurrence of adverse events. Participants may report adverse events occurring at any other time during the study. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/184 • Treatment emergent adverse events (TEAEs) are adverse events that started after the first dose of study drug up to Day 168 At each visit the investigator had to assess any occurrence of adverse events. Participants may report adverse events occurring at any other time during the study. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Vascular disorders Thrombophlebitis superficial	0.55% 1/182 • Treatment emergent adverse events (TEAEs) are adverse events that started after the first dose of study drug up to Day 168 At each visit the investigator had to assess any occurrence of adverse events. Participants may report adverse events occurring at any other time during the study. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/184 • Treatment emergent adverse events (TEAEs) are adverse events that started after the first dose of study drug up to Day 168 At each visit the investigator had to assess any occurrence of adverse events. Participants may report adverse events occurring at any other time during the study. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

Other adverse events

Additional Information

Medical Director

Takeda

Phone: +1-877-825-3327

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.
Publication restrictions are in place

Restriction type: OTHER