Clinical Study Evaluating the Safety and Efficacy of Roflumilast in Type 2 Diabetic Patients With Diabetic Neuropathy

Study Overview
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Brief Summary
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Evaluation of the side effects and efficacy of roflumilast on glycemic parameters, insulin resistance, oxidative and inflammatory markers in Type 2 diabetic patients with diabetic neuropathy.

Official Title
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Clinical Study Evaluating the Safety and Efficacy of Roflumilast in Type 2 Diabetic Patients With Diabetic Neuropathy

Conditions
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Type 2 Diabetes (Adult Onset), Diabetic Neuropathies

Intervention / Treatment
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* Drug: Alpha lipoic acid
* Drug: Roflumilast


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with a diagnosis of type 2 diabetes mellitus (T2DM). HbA1c at baseline: ≥7.5 % to 8.5 %. BMI between ≥26 and ≤35 kg/ m2. Established Diabetic neuropathy diagnosed by nerve conduction study (NCS). Exclusion Criteria: Patients diagnosed with type 1 diabetes mellitus or diabetes secondary to pancreatitis or resection of the pancreas. Patients diagnosed with hemoglobinopathies, hemolytic anemia, or other diseases which interfere with HbA1c measurement. Thyroid disease, cardiovascular disease, peripheral vascular disease, coagulopathy, moderate to severe liver disease (bilirubin>1.5mg), or renal excretion ≤90ml/min. Patients on medications which can result in a change of weight (orlistat, metformin, clozapine, gabapentin) and patients on medications that can interfere with glucose or lipid metabolism (corticosteroids, non-selective β-blockers, thiazides, etc.) Treatment with any diabetes medications other than glimepiride prior to intervention. Clinically significant cardiac abnormalities (diagnosed clinically, history, or by X-ray/ECG) that were not related to type 2 diabetes mellitus and that required further evaluation. Patients with morbid obesity (BMI ≥ 40 kg/ m2). History or current diagnosis of major depressive disorders or other psychiatric disorders. Pregnant and breastfeeding women. Patients with any inflammatory diseases. Patients on cytochrome P450 inducers (e.g., rifampicin, phenobarbital, carbamazepine, phenytoin, etc.). Patients with Low vitamin B12 levels according to suggested normal values for T2DM patients over 60 years old (<400 pmol/L).

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Alpha-lipoic acid arm<br>Administration of alpha-lipoic acid 600 mg orally once daily for 3 months. | Drug: Alpha lipoic acid<br>* Administration of alpha-lipoic acid 600mg plus vildagliptin/metformin combination (50/1000mg) orally once daily for 3 months.<br>|
| Experimental: Roflumilast arm<br>Administration of roflumilast 500 mcg orally once daily for 3 months. | Drug: Roflumilast<br>* Administration of 500 mcg plus vildagliptin/metformin combination(50/1000mg) orally once daily for 3 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in fasting blood glucose | Using glucose oxidase method for assessment of blood glucose and subtracting pre-treatment from post-treatment values | baseline and 3 months later | 
| Change in plasma insulin level | Subtracting pre-treatment from post-treatment values of plasma insulin | baseline and 3 months later | 
| Change in HOMA-IR index | HOMA-IR will be calculated for all patients at baseline and 3 months later. | baseline and 3 months later | 
| Change in HOMA-B index | HOMA-B will be calculated for all patients at baseline and 3 months later. | baseline and 3 months later. | 
| Change in HbA1c | Subtracting pre-treatment from post-treatment values of HbA1C | baseline and 3 months later | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in TNF-alfa serum level | Subtracting pre-treatment from post-treatment values of TNF-alfa. | baseline and 3 months later | 
| Changes in malondialdehyde serum level (MDA) | Subtracting pre-treatment from post-treatment values of MDA. | baseline and 3 months later | 
| Changes in neurotensin serum levels | Subtracting pre-treatment from post-treatment values of neurotensin serum levels. | baseline and 3 months later | 
| Ewing score | Subtracting pre-treatment from post-treatment changes in summation of the cardiac autonomic reflex tests (CARTs) including heart response to a deep breathing test, changes in immediate heart rate response to standing, and changes in blood pressure response to sustained handgrip testing. | baseline and 3 months later | 
| Changes of Michigan Neuropathy Screening Instrument | 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. | baseline and 3 months later | 
| 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. | baseline and 3 months later | 
| Changes of Douleur Neuropathique-4 (DN4) questionnaire (DN4) | DN4 Neuropathic Pain Diagnostic Questionnaire which reflect positive symptoms for pain ( burning, painful cold, electric shocks, ) | baseline and 3 months later | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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diabetes mellitus, diabetic neuropathy, hyperglycemia