Diabetes Mellitus, Type 2Phase 2MAKROTADNCT02601989
Effects on Insulin Resistance With Tadalafil in Type 2 Diabetes - a Double-blind, Placebo-controlled Crossover Study
A Phase 2 study testing Tadalafil in people with Diabetes Mellitus, Type 2, run by Göteborg University at 1 site in Sweden.
Trial 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. Read more about this study
- Who is it for?
- Ages 40 to 70 years
- Conditions the study is for
- Diabetes Mellitus, Type 2
- What is being tested?
- Tadalafil
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 23 participants
- Where
- 1 siteSweden
- Study dates
- Nov 2015to Jan 2019
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 14Show fewer
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Effects on Insulin Resistance With the Phosphodiesterase-5 Inhibitor Tadalafil in Type 2 Diabetes - a Double-blind, Placebo-controlled Crossover Study
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
- Being tested
- Tadalafil, Placebo
- Medical subject headings
- Diabetes Mellitus, Type 2
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TadalafilDrug
PlaceboDrug
Per oral intake of placebo for six weeks
| Study group | Role | What they receive |
|---|---|---|
| Tadalafil | Experimental | Per oral intake of tadalafil 20 mg o.d. for six weeks Receives: Drug: Tadalafil |
| Placebo | Placebo comparator | Per oral intake of placebo Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 6 week treatment with drug or placebo
Secondary outcomes (7)
Mean glucose (HbA1c, mmol/mol) in blood
Evaluation the effect of chronic tadalafil treatment on glucose metabolism and beta-cell function as measured by mean blood glucose (HbA1c)
Measured: Up to 6 weeks after start of treatment.
Fasting plasma glucose levels (mmol/l)
Evaluation the effect of chronic tadalafil treatment on glucose metabolism and beta-cell function as measured by circulating glucose levels
Measured: Up to 6 weeks after start of treatment.
Arginine-induced insulin secretion (area under curve, AUC, mU/l/min) in blood
Glucose metabolism and beta-cell function as measured by arginine-induced insulin secretion (difference in AUC, mU/l/min).
Measured: 3 weeks after start of treatment.
Levels interstitial insulin
levels interstitial insulin (mU/l)
Measured: Up to 6 weeks after start of treatment.
Lactate concentrations in insulin sensitive tissues
Lactate concentrations (micromoles/l) in insulin sensitive tissues
Measured: Up to 6 weeks after start of treatment.
Levels of inflammatory markers in blood
Difference in endothelin-1 levels (pg/ml)
Measured: Up to 6 weeks after start of treatment.
Endothelial function in peripheral arteries measured with EndoPAT, measured as difference in reactive hyperemia
Measured: 3 weeks after start of treatment.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Nov 2015 (estimated)
- Study startNov 2015
- Primary completionJan 2019
- Study completionJan 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Diabetes Mellitus, Type 2Studies of the same condition, open and under way.
- More trials run by Göteborg UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Supportive care
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 23 participants (actual)
Sponsor and investigators
- Lead sponsor
- Göteborg University
- Sponsor type
- University, hospital or other
- Collaborators
- Vastra Gotaland Region
- Responsible party
- Sponsor
- Investigators
- Per-Anders Jansson, MD, Principal investigator, Göteborg University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02601989
- Sponsor's protocol ID
- 2015-09-14
- Other IDs
- 2015-000573-12, 2015
- Acronym
- MAKROTAD
- Status last verified
- Feb 2020
- First submitted
- 26 Oct 2015
- Last updated
- 11 Feb 2020
- Results posted
- No
- Data monitoring committee
- No
Publications
Fryk E, Rodrigues Silva VR, Strindberg L, Gisslen M, Zetterberg H, Blennow K, Jansson PA. Effect of 6-week tadalafil treatment on blood-based biomarkers of neurodegeneration: A post-hoc analysis of a randomized controlled trial. J Alzheimers Dis. 2026 Apr;110(3):1072-1078. doi: 10.1177/13872877261421227. Epub 2026 Mar 13.
PubMed 41823692Fryk 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.
PubMed 37256099
Study at a glance
From the registry record, last updated by the sponsor on 11 Feb 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effects on Insulin Resistance With the Phosphodiesterase-5 Inhibitor Tadalafil in Type 2 Diabetes - a Double-blind, Placebo-controlled Crossover Study
- ClinicalTrials.gov ID
- NCT02601989
- Acronym / sponsor ID
- MAKROTAD / 2015-09-14
- Conditions
- Diabetes Mellitus, Type 2
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 23 participants (actual)
- Lead sponsor
- Göteborg UniversityUniversity, hospital or other
- Collaborators
- Vastra Gotaland Region
- Study start
- Nov 2015 (actual)
- Primary completion
- Jan 2019 (actual)
- Study completion
- Jan 2019 (actual)
- First posted
- 11 Nov 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Supportive care
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Tadalafil | Experimental | Drug: TadalafilPer oral intake of tadalafil 20 mg o.d. for six weeks |
| Placebo | Placebo comparator | Drug: PlaceboPer oral intake of placebo |
Who may qualify
- Ages
- 40 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (14 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Tadalafil | Drug | Tadalafil |
| PlaceboPer oral intake of placebo for six weeks | Drug | Placebo |
Primary outcome
insulin sensitivity
Time frame: 6 week treatment with drug or placebo
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
7 secondary outcomes
Mean glucose (HbA1c, mmol/mol) in blood
Time frame: Up to 6 weeks after start of treatment.
Fasting plasma glucose levels (mmol/l)
Time frame: Up to 6 weeks after start of treatment.
Arginine-induced insulin secretion (area under curve, AUC, mU/l/min) in blood
Time frame: 3 weeks after start of treatment.
Levels interstitial insulin
Time frame: Up to 6 weeks after start of treatment.
Lactate concentrations in insulin sensitive tissues
Time frame: Up to 6 weeks after start of treatment.
Levels of inflammatory markers in blood
Time frame: Up to 6 weeks after start of treatment.
Endothelial function in peripheral arteries measured with EndoPAT, measured as difference in reactive hyperemia
Time frame: 3 weeks after start of treatment.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Feb 2020.
- Derived from this study: PubMed 41823692Fryk E, Rodrigues Silva VR, Strindberg L, Gisslen M, Zetterberg H, Blennow K, Jansson PA. Effect of 6-week tadalafil treatment on blood-based biomarkers of neurodegeneration: A post-hoc analysis of a randomized controlled trial. J Alzheimers Dis. 2026 Apr;110(3):1072-1078. doi: 10.1177/13872877261421227. Epub 2026 Mar 13.
- Derived from this study: PubMed 37256099Fryk 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Per-Anders Jansson, MD principal investigator
Göteborg University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Tadalafil in people with Diabetes Mellitus, Type 2, run by Göteborg University at 1 site in Sweden.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 11 Feb 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Sweden. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
insulin sensitivity (time frame: 6 week treatment with drug or placebo). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02601989, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Feb 2020.