Efficacy of γ-linolenic Acid and Thioctic Acid in Patients With Diabetic Neuropathy

A 12-week, Multi-center, Randomized, Double-blind, Double Dummy, Parallel Clinical Trial to Compare the Efficacy of γ-linolenic Acid and Thioctic Acid in Patients With Diabetic Neuropathy

This study was a 12-week, multi-center, randomized, double-blind, double dummy, parallel clinical trial to compare the efficacy of γ-linolenic acid and Thioctic acid in patients with diabetic neuropathy.

Study Overview

• Status: Completed
• Conditions: Diabetic Neuropathy
• Intervention / Treatment: Drug: γ-linoleic acid and placebo(Thioctic Acid); Drug: Thioctic Acid and placebo(γ-linoleic acid)

Detailed Description

This study evaluated non-inferiority about the efficacy and safety of γ-linolenic acid (Evoprim soft capsule) through patients with diabetic neuropathy were compared γ-linolenic acid (Evoprim soft capsule) and Thioctic acid(LipoA HR Tab. 600mg) using double-blind, double dummy clinical trials. First outcome measures are Visual Analog Scale(VAS) and Total Symptom Score(TSS), secondary outcome measures are Michigan Neuropathy Screening Instrument(MNSI), Current perception Threshold(CPT), Modified Brief Pain Inventory-diabetic polyneuropathy(Modified BPI-DPN) and EuroQol-5 Dimensions(EQ 5D).

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 4

Contacts and Locations

Study Locations

• Korea, Republic of
  • Daegu, Korea, Republic of, 42472
    • Daegu Catholic University Medical Center
  • Incheon, Korea, Republic of, 2156
    • Gachon University Gil Medical Center
  • Pusan, Korea, Republic of, 49241
    • Pusan National University Hospital
  • Seoul, Korea, Republic of, 06591
    • The Catholic University of Korea Seoul St. Mary's Hospital
  • Seoul, Korea, Republic of, 01757
    • Inje University Sanggye Paik Hospital
  • Seoul, Korea, Republic of, 03722
    • Yonsei univesity severance hospital
  • Seoul, Korea, Republic of, 07345
    • The Catholic University of Korea Yeouido St. Mary's Hospital
  • Gyeonggi
    • Bucheon, Gyeonggi, Korea, Republic of, 14754
      • Sejong Hospital
  • Jeollabuk-do
    • Jeonju, Jeollabuk-do, Korea, Republic of, 54907
      • Obesity Research Center of Chonbuk National University
  • North Gyeongsang-do
    • Gyeongju, North Gyeongsang-do, Korea, Republic of, 38067
      • Dongguk university gyeongju hospital
  • South Chungcheong Province
    • Cheonan, South Chungcheong Province, Korea, Republic of, 31151
      • Soon Chun Hyang University Hospital Cheonan

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients who were between 20 years and 75 years at screening
• Patients who were diagnosed with type 2 diabetes and whose HbA1c levels were less than 11% at screening
• Patients with a score of 4 or more on the Visual Analogue Score(VAS)

• One or more of the following items

  • If the physical examination score of the Michigan Neuropathy Screening Instrument Score (MNSI) is more than 2 points at the initial screening
  • type 2 diabetic patient who complained one or more of pain, burning sensation, numbness, and sensory loss and measured the current perception threshold (CPT) of the peroneal nerve at three frequencies (2000Hz, 250Hz, 5Hz) Anyone whose diabetes mellitus has been diagnosed as diabetic neuropathy
• Patients who decided to voluntarily participate in clinical trials and agreed in writing

Exclusion Criteria:

• Peripheral neuropathy caused by other causes other than diabetes
• Those are suffering from other painful conditions that are so severe that diabetic neuropathy can not be assessed
• If you have a progressive or degenerative neurological disorder
• Patients with a systolic blood pressure(SBP)≥ 160 mmHg or ≤ 100 mmHg or a diastolic blood pressure(DBP) ≥ 95 mmHg or ≤ 60 mmHg
• Patients who were positive for human immunodeficiency virus (HIV), hepatitis B (HBV), or hepatitis C (HCV) test
• patients with liver dysfunction (ALT / AST> 3 times the upper limit of normal)
• Patients with renal dysfunction (Serum creatine> 2.0 mg / dl)
• Patients with thyroid dysfunction (Thyroid and anti-thyroid medications may be included in this study if they are maintained in normal state.)
• Patients with amputation (including toes) or infections of the lower extremities

• The following diseases are clinically significant patients

  • Unstable coronary artery disease or peripheral vascular disease
  • Liver, kidney, lung, hematologic disease
  • Cancer (within 5 years if possible)
• Patients who have suicide attempts or suicidal tendencies and who have a psychiatric history within 6 months before starting the trial
• Patients with substance abuse or chronic alcohol abuse within 2 years prior to taking the test
• Patients who received intravenous steroid injection or topical anesthetic injection within 2 months before participating in the study
• Patients who participated in other studies within 4 weeks before participating in the trial, or who are currently taking medication for other research
• Screening After randomization for 2 weeks (pause period) before screening, antipsychotics, antipsychotics, sleep depressants, antidepressants, antiepileptics, muscle relaxants, analgesics (narcotic analgesics, NSAIDs, tramadol etc.) Patients who received capsaicin or who received percutaneous electrical nerve stimulation therapy (TENS) or acupuncture
• Patients with a history of hypersensitivity or clinically significant hypersensitivity reactions to this drug substance and soybean oil, soy or peanut
• Patients with clinically significant skin disease or severe skin irritability
• Pregnant or lactating women
• patients suffering from schizophrenia or those who are treated with chloropromazine, mesoridazine, thioridazine, fluphenazine, perphenazine, trifluoperazine, haloperidol (haloperidol), loxapine (loxapine) and other drugs known to cause epileptic seizures
• In addition to the above items, patients who are deemed inappropriate by clinical trial researchers

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Test group; γ-linoleic acid (Evoprim soft capsule) twice a day and 4 capsules at a time.; Thioctic Acid(LipoA HR Tab. 600mg) placebo once a day and 1 tablet at a time.	Drug: γ-linoleic acid and placebo(Thioctic Acid); γ-linoleic acid (Evoprim soft capsule) twice a day and 4 capsules at a time.; Thioctic Acid(LipoA HR Tab. 600mg) placebo once a day and 1 tablet at a time.
Experimental: Control Group; Thioctic Acid(LipoA HR Tab. 600mg) once a day and 1 tablet at a time.; γ-linoleic acid (Evoprim soft capsule) placebo twice a day and 4 capsules at a time.	Drug: Thioctic Acid and placebo(γ-linoleic acid); Thioctic Acid(LipoA HR Tab. 600mg) once a day and 1 tablet at a time.; γ-linoleic acid (Evoprim soft capsule) placebo twice a day and 4 capsules at a time.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes of Visual Analog Scale(VAS)	The Visual Analog Scale(VAS) score is 0 point for no symptom, 10 points for the most severe symptom, and the patient is asked to mark the degree of subjective pain symptoms as an integer.	12 weeks
Changes of Total Symptom Score(TSS)	Total Symptom Score(TSS) classifies diabetic neuropathy symptoms into four categories (pain, burning pain, paresthesia, numbness). The frequency (Occasional, Frequent, Continuous) and symptom intensity (Absent, Slight, Moderate, Severe) are calculated through each question and the score is obtained according to the visual analog scale. It is calculated from 0 point up to 14.64 points.	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes of Michigan Neuropathy Screening Instrument(MNSIQ)	A 15-item questionnaire (MNSIQ) is used to assess deformation, infection, skin thickening of the skin's stratum corneum, and ulcers. MNSIQ was designed to screen for diabetic neuropathy through questionnaires on 15 questions that are related to neuropathic symptoms (pain, temperature, and sensation). Two of 15 (number 4 and 10) are vascular symptoms and are excluded from the total score regardless of the results. If you answered 'No' to questions 7 and 13, you will get 1 point. In the end, scores ranging from 0 to 13 indicate that the higher the score, the more severe the neuropathic symptoms.	12 weeks
Changes of Michigan Neuropathy Screening Instrument(MNSIE)	A foot test (MNSIE) is used to assess deformation, infection, skin thickening of the skin's stratum corneum, and ulcers. MNSIE evaluates foot shape, foot ulceration, ankle reflex, sense of vibration of big toe, monofilament right and left. The score ranges from point 0 to 10, and when the score is above 2, it is diagnosed as neuropathy.	12 weeks
Changes of Current perception Threshold(CPT)	Sensory nerve conduction threshold (SNCT) is a unique method for evaluating all three sensory neurons (small unmyelinated fibers, small myelinated fibers, and large myelinated fibers) that make up more than 90% of sensory nerves. It seems to be possible to objectively evaluate sensory nerve of small fiber which recovered early in diabetic neuropathy(Using neurometer).	12 weeks
Changes of Modified Brief Pain Inventory-diabetic polyneuropathy(Modified BPI-DPN)	Modified Brief Pain Inventory-diabetic polyneuropathy(Modified BPI-DPN) displays the pain area on the human figure, the number of pain sites, treatment of pain, and pain medication. Pain severity refers to the pain sensation- identification aspect (pain threshold). The worst pain, the least pain, the pain average, and the pain now for the last 24 hours are displayed on the 10-point scale (0 points: none, ~ 10 Point: too big to imagine). Pain interference is the emotional-synchronous aspect of pain (pain tolerance). It classifies general activity, mood, walking, working, relationship, sleep and enjoyment of life, and use the 10-point scale (0 points: none to 10 points: completely disturbed).	12 weeks
Changes of EuroQol-5 Dimensions(EQ 5D)	EQ-5D index = 1 - (0.050 + 0.096 M2 + 0.418 x M3 + 0.046 x SC2 + 0.13 x SC3 + 0.051 x UA2 + 0.028 x UA3 + 0.037 x PD2 + 0.151 x PD3 + 0.043 x AD2 + 0.158 x AD3 + 0.050 × N3) - 1 if the variable is applicable, 0 if not (M: mobility, SC: self-care, UA: usual activity,, PD: pain / discomfort, AD: anxiety / depression) * Variable definition; M2: 1 if mobility is 'level 2', 0 if not; M3: 1 if mobility is 'level 3', 0 if not; SC2: 1 if self-care is 'level 2', 0 if not; SC3: 1 if self-care is 'level 3', 0 if not; UA2: 1 if usual activity is 'level 2', 0 if not; UA3: 1 if usual activity is 'level 3', 0 if not; PD2: 1 if pain / discomfort is 'level 2', 0 if not; PD3: 1 if pain / discomfort is 'level 3', 0 if not; AD2: 1 if anxiety / depression is 'level 2', 0 if not; AD3: 1 if anxiety / depression is 'level 3', 0 if not; N3: 1 if there is at least one level 3, others are 0	12 weeks

Collaborators and Investigators

• Sponsor: Chonbuk National University Hospital
• Investigators: Principal Investigator: Bong-Yeon Cha, MD,PhD, The Catholic University of Korea; Principal Investigator: Jong hwa Kim, MD, Sejong Hospital; Principal Investigator: Lee-byeong Park, MD,PhD, Gachon University Gil Medical Center; Principal Investigator: Hyuk Sang Kwon, MD,PhD, The Catholic University of Korea Yeouido St. Mary's Hospital; Principal Investigator: In Joo Kim, MD,PhD, Pusan National University Hospital; Principal Investigator: Ji hyun Lee, MD,PhD, Daegu Catholic University Medical Center; Principal Investigator: sung soo Moon, MD,PhD, DongGuk University; Principal Investigator: Sung wan Chun, MD,PhD, Soon Chun Hyang University; Principal Investigator: Byung-Wan Lee, MD,PhD, Yonsei univesity severance hospital; Principal Investigator: Jong chul Won, MD,PhD, Inje University; Principal Investigator: Tae-Sun Park, MD,PhD, Chonbuk National University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): January 26, 2016
• Primary Completion (Actual): March 30, 2016
• Study Completion (Actual): July 25, 2018

Study Registration Dates

• First Submitted: April 10, 2019
• First Submitted That Met QC Criteria: April 11, 2019
• First Posted (Actual): April 16, 2019

Study Record Updates

• Last Update Posted (Actual): April 16, 2019
• Last Update Submitted That Met QC Criteria: April 11, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Endocrine System Diseases; Diabetes Complications; Diabetes Mellitus; Neuromuscular Diseases; Peripheral Nervous System Diseases; Diabetic Neuropathies; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Protective Agents; Micronutrients; Vitamins; Antioxidants; Vitamin B Complex; Thioctic Acid
• Other Study ID Numbers: DLB-DN-EVOP

Drug and device information, study documents

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