Effects on Insulin Resistance With Tadalafil in Type 2 Diabetes - a Double-blind, Placebo-controlled Crossover Study

NCT02601989 | Completed Phase 2

• 2 other identifiers: 2015-09-142015-000573-12
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 1

Brief Summary

The aim is to continue our program on PDE5 inhibition by evaluating effects on insulin resistance, including glucose metabolism and subclinical inflammation, after a 6-week administration of tadalafil in T2D patients. The primary objective is to study the effect of tadalafil compared with placebo on insulin sensitivity during a euglycemic hyperinsulinemic clamp. This is a double-blind, placebo-controlled crossover study with one study site. Twenty-five T2D patients will be recruited and randomized to per oral intake of tadalafil 20 mg o.d. for six weeks and after a wash-out period of eight weeks intake of placebo for another six weeks, or vice versa. At the end of each 6 week treatment period a glucose clamp, subcutaneous needle biopsies as well as muscle and subcutaneous microdialysis will be performed. Endothelial function tests and arginin stimulation of insulin secretion tests will be performed after 3 weeks in each treatment arm.

Conditions

Diabetes Mellitus, Type 2

Outcome Measures

Primary Outcomes (1)

• insulin sensitivity

  To evaluate the effect (difference in glucose disposal rate (mg/kg/min)) of daily administration of 20 mg tadalafil for 6 weeks ("chronic" treatment) on insulin sensitivity in muscle by assessing glucose disposal rate during a 3-hour euglycemic hyperinsulinemic glucose clamp (120 mU/m2/min) in T2D patients

  6 week treatment with drug or placebo

Secondary Outcomes (7)

• Mean glucose (HbA1c, mmol/mol) in blood

  Up to 6 weeks after start of treatment.

• Fasting plasma glucose levels (mmol/l)

  Up to 6 weeks after start of treatment.

• Arginine-induced insulin secretion (area under curve, AUC, mU/l/min) in blood

  3 weeks after start of treatment.

• Levels interstitial insulin

  Up to 6 weeks after start of treatment.

• Lactate concentrations in insulin sensitive tissues

  Up to 6 weeks after start of treatment.

Study Arms (2)

Tadalafil

EXPERIMENTAL

Per oral intake of tadalafil 20 mg o.d. for six weeks

Drug: Tadalafil

Placebo

PLACEBO COMPARATOR

Per oral intake of placebo

Drug: Placebo

Interventions

Tadalafil DRUG

Tadalafil

Placebo DRUG

Per oral intake of placebo for six weeks

Placebo

Eligibility Criteria

• Age: 40 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• T2D patient, previously diagnosed by fasting or 2-hr OGTT plasma glucose levels
• Age females: 55-70 yrs (post-menopausal state defined as natural amenorrhea for at least 12 months); Age males: 40-70 yrs
• BMI: 27-40 kg/m2
• HbA1c \< 60 mmol/mol
• Type 2 diabetes duration \> 3 months and \< 10 yrs
• Understand and speak Swedish

You may not qualify if:

• Diabetes treatment with glitazones, GLP-1 analogues or DPP-IV inhibitors
• Anti-hypertensive therapy with beta-blockers, ACE-inhibitors and/or angiotensin-II receptor blockers
• Significant microvascular complications e.g. nephropathy (GFR\<60), proliferative retinopathy and symptomatic neuropathy e.g. postural hypotension
• Previous significant vascular disease including angina pectoris and myocardial infarction, cerebral artery disease e.g. history of transient ischemic attacks and peripheral artery disease with no palpable pulses
• Smoking \> 10 cig/day and/or smokeless tobacco \> one can per 2 days
• Concurrent use of nitrates or NO donors, or an apparent risk that there may be a need of such medication
• Cardiac failure (stages NYHA II-IV)
• Uncontrolled hypertension \> 170/105 mm Hg
• Apparent ECG-pathology indicating current or previous myocardial ischemia;
• Males with erectile dysfunction
• Hemophilia or a history of bruises or hepatic failure (\> 2-fold increase upper limit normal values of ASAT/ALAT)
• Hypotension
• Treatment with doxazosin
• Anything in the contact with the patient that makes the doctor to believe that he/she will be uncompliant to the protocol.

Sponsors & Collaborators

• Göteborg University: lead
• Vastra Gotaland Region: collaborator

Study Sites (1)

Sahlgrenska University Hospital

Gothenburg, 41345, Sweden

Location

Related Publications (1)

• Fryk E, Rodrigues Silva VR, Bauza-Thorbrugge M, Schmelz M, Gan LM, Strindberg L, Jansson PA. Feasibility of high-dose tadalafil and effects on insulin resistance in well-controlled patients with type 2 diabetes (MAKROTAD): a single-centre, double-blind, randomised, placebo-controlled, cross-over phase 2 trial. EClinicalMedicine. 2023 May 4;59:101985. doi: 10.1016/j.eclinm.2023.101985. eCollection 2023 May.

  PMID: 37256099 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

Tadalafil

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Carbolines; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Indole Alkaloids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds, 3-Ring

Study Officials

• Per-Anders Jansson, MD

  Göteborg University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: SUPPORTIVE CARE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 26, 2015
• First Posted: November 11, 2015
• Study Start: November 1, 2015
• Primary Completion: January 1, 2019
• Study Completion: January 1, 2019
• Last Updated: February 11, 2020

Record last verified: 2020-02

Locations

SE (1)