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

A Randomized, International, Multicenter, Parallel Group, Double-Blind, Placebo Controlled Study to Evaluate the Efficacy and Safety of Actovegin 12-Week Treatment Given First Intravenously and Subsequently Orally in Subjects With Peripheral Arterial Occlusive Disease Fontaine Stage IIB

The purpose of the study is to evaluate the efficacy and safety of actovegin in participants with peripheral arterial disease (PAD) Fontaine Stage IIB.

Study Overview

• Status: Completed
• Conditions: Peripheral Arterial Diseases
• Intervention / Treatment: Drug: Actovegin; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 366
• Phase: Phase 3

Contacts and Locations

Study Locations

• Georgia
  • Tbilisi, Georgia, 0159
    • Center of Vascular and Heart Disease
  • Tbilisi, Georgia, 0160
    • Aversi Clinic
• Kazakhstan
  • Astana, Kazakhstan, Z05K4F3
    • "National scientific centre of oncology and transplantology"
  • Shymkent, Kazakhstan, X09E1G4
    • Regional Clinic Hospital
• Russian Federation
  • Chelyabinsk, Russian Federation, 454092
    • NSHI Road clinical hospital at Chelyabinsk station of OAO RZD
  • Kemerovo, Russian Federation, 650002
    • Federal state budgetary research institution Research Institute for Complex Issues of Cardiovascular Diseases
  • Kursk, Russian Federation, 305007
    • BMH Kursk regional clinical hospital of Healthcare department of Kursk region
  • Moscow, Russian Federation, 111020
    • SBHI of Moscow city "City clinical hospital #29 n.a. N.E. Bauman of Moscow Healthcare department
  • Moscow, Russian Federation, 111539
    • SBHI of Moscow healthcare department City clinical hospital #15 n.a. O.M Filatov of Moscow healthcare department
  • Moscow, Russian Federation, 129090
    • SBHI of Moscow Research Institute of Emergency Medicine n.a. N.V. Sklifosofsky of Moscow Healthcare department
  • Novosibirsk, Russian Federation, 630117
    • Scientific Research Institute of Clinical and Experimental Lymphology - a branch of the Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences
  • Omsk, Russian Federation, 644111
    • BHI of Omsk region Regional clinical hospital, vessel surgery department
  • Rostov-on-Don, Russian Federation, 344022
    • FSBEI HE Rostov State Medical University of MoH of Russia
  • Ryazan, Russian Federation, 390026
    • SBHI of Ryazan region Regional clinical cardiological dispensary, vessel surgery department/ FSBI of Ryazan Region "Ryazan State Medical Univesity n.a. I.P. Pavlov" of MoH of Russia
  • Saint Petersburg, Russian Federation, 197022
    • Pavlov First Saint Petersburg State Medical University, Faculty surgery chair, cardio-vessel surgery department
  • Saint Petersburg, Russian Federation, 198260
    • SPb SBHI Consulting and diagnostic center #85
  • Saint-Petersburg, Russian Federation, 191015
    • North-Western state Medical University named after I.I. Mechnikov
  • Saint-Petersburg, Russian Federation, 194354
    • SPb SBHI City multipurpose hospital #2
  • Saratov, Russian Federation, 410053
    • State Healthcare Institution of Saratov region "Region clinical hospitai"
  • Sochi, Russian Federation, 354057
    • Municipal State Budgetary Healthcare Institution of Sochi "City hospital 4"

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Actovegin 1200 mg; Actovegin 1200 milligram (mg), intravenously, once daily for up to 2 weeks followed by actovegin 200 mg, tablets, orally, thrice daily (TID) (1200 mg/day) for up to 10 weeks.	Drug: Actovegin; Actovegin intravenous infusion and tablets.
Placebo Comparator: Placebo; Actovegin placebo-matching, intravenously, once daily for up to 2 weeks and actovegin placebo-matching tablets, orally, TID for up to 10 weeks.	Drug: Placebo; Actovegin placebo-matching intravenous infusion and tablets.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline up to Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline up to Weeks 2 and 24
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.	Baseline, Weeks 2, 12 and 24
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.	Weeks 12 and 24
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.	Week 24
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.	Baseline, Weeks 12 and 24

Collaborators and Investigators

• Sponsor: Takeda

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2018
• Primary Completion (Actual): May 28, 2019
• Study Completion (Actual): August 28, 2019

Study Registration Dates

• First Submitted: March 13, 2018
• First Submitted That Met QC Criteria: March 13, 2018
• First Posted (Actual): March 19, 2018

Study Record Updates

• Last Update Posted (Actual): October 28, 2020
• Last Update Submitted That Met QC Criteria: October 2, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: Drug Therapy
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Atherosclerosis; Peripheral Arterial Disease; Peripheral Vascular Diseases; Arterial Occlusive Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Gastrointestinal Agents; Protective Agents; Anti-Ulcer Agents; Antioxidants; Central Nervous System Stimulants; Radiation-Protective Agents; Actovegin
• Other Study ID Numbers: Actovegin-3001; 2017-004741-24 (EudraCT Number); U1111-1201-7990 (Other Identifier: WHO)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Takeda makes patient-level, de-identified data sets and associated documents available for all interventional studies after applicable marketing approvals and commercial availability have been received (or program is completely terminated), an opportunity for the primary publication of the research and final report development has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No