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Heart FailurePhase 2Insulin-HFNCT03665350

Insulin Treatment in Diabetic Older People With Heart Failure.

A Phase 2 study testing Insulin in people with Heart Failure and Diabetes Mellitus, Type 2, run by Mario Negri Institute for Pharmacological Research at 3 sites in Italy.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

Cardiac failure (HF) and type 2 diabetes mellitus (T2DM) are two clinical conditions with a significant impact on public health worldwide. In the elderly population the prevalence of T2DM is constantly increasing as well as its incidence in all Western countries including Italy. Read more about this study

Who is it for?
Ages 70 to 100 years
Conditions the study is for
Heart Failure, Diabetes Mellitus, Type 2
What is being tested?
Insulin
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
10 participants
Where
3 sitesItaly
Study dates
8 Nov 2018to 18 Sep 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 70 to 100 years
  • All sexes
  • No healthy volunteers
  • Older adult

Who may be able to join

  • men and women aged ≥70 years;
  • at discharge after admission to hospital for worsening of HF or ambulatory patients with chronic HF;
  • New York Heart Association (NYHA) class II or III
  • with any level of left ventricular ejection fraction;
  • plasma natriuretic peptide (BNP) ≥200 pg/mL or N-terminal pro-BNP ≥900 pg/mL (NT pro-BNP)
  • prior history or newly diagnosed T2DM;
  • candidate by the responsible physician to insulin therapy;
  • signed informed consent.

Who cannot join

  • significant renal insufficiency (GFR <30 mL/min/1.73 m2) or severe liver disease (liver function test abnormalities (alanine or aspartate aminotransferase ≥ 3 × upper limit of normal [ULN]);
  • levels of hemoglobin <10 g/dl;
  • HbA1c ≤5% or ≥11%;
  • unstable diabetes: type of diabetes presentation in patients with an anamnesis of frequent episodes of hypoglycemia, hyperglycemic hyperosmolar state, ketoacidosis or lactic acidosis;
  • planned CV surgery or angioplasty in 3 months;
  • any non-cardiac disease that shortens life expectancy to<1 year (e.g.most cancers);
  • inability to comply with study protocol;
  • participation to another interventional clinical study.

Trial locations and contacts

3 sites in 1 country.

Italy3 sites

  • Ospedale di Passirana

    Passirana, MI, 20017

  • Ospedale Bolognini di Seriate

    Seriate, BG, 24068

  • Ospedale Treviglio

    Treviglio, BG, 24047

Other trials in Italy

About this study

Official title: Management of the Patient With Heart Failure and Diabetes: May Insulin be a Problem? A Pilot Randomized Clinical Study (Insulin-HF)

Cardiac failure (HF) and type 2 diabetes mellitus (T2DM) are two clinical conditions with a significant impact on public health worldwide. In the elderly population the prevalence of T2DM is constantly increasing as well as its incidence in all Western countries including Italy. The combination of HF and T2DM is frequent and leads to an increased risk of death and of non-fatal adverse cardiovascular (CV) events which justifies the frailty of this population. Although diabetic patients (pts) with HF respond to recommended treatments for HF, the effective and safe control of blood glucose levels is still an outstanding clinical problem, since glucose lowering drugs may increase the risk of CV adverse events. Insulin, used in about 30% of diabetic patients with HF, causes adverse effects such as fluid and sodium retention and unwanted effects of hypoglycemia. Even if insulin remains a milestone in glucose lowering therapy of T2DM, its risk/benefit ratio is still controversial, more so when given to old patients with HF. The issue has gained relevance since new antidiabetic agents, as the sodium glucose co-transporter 2 (SGLT- 2) inhibitors and glucagon-like peptide (GLP-1) analogues, with a safer CV profile have been made available. While the transferability of the CV benefits attributed to the new drugs needs to be assessed in clinical practice, the present study explore the benefit/risk profile of insulin in HF.

Objectives: to assess comparatively in patients with heart failure and T2DM the benefit/risk profile over 1-year follow-up of two antidiabetic strategies, standard care with vs without insulin in terms of humoral and clinical endpoints including body weight change, all-cause mortality and burden of care components (hospitalizations for CV events and episodes of severe hypoglycemia).

Read the detailed description

The project will consist in a controlled, randomized, open-label (PROBE design) multicenter, pilot study. Central randomization stratified by center, performed online, will allow a comparison of two groups of patients one receiving standard care including insulin, the other standard care without insulin. Patients considered not eligible for randomization will be included in a registry.

The first objective of this exploratory randomized study is to assess in patients with heart failure and T2DM if a standard anti-diabetic strategy which includes insulin has a different safety and efficacy profile than one without insulin. The number of patients to be included in this exploratory pilot study will be insufficient to prove or disprove a statistically significant beneficial effect of the two antidiabetic strategies on clinical events. Special care will be paid to the biologic consistency of the different endpoints, primary and secondary, even if none of them will individually yield statistically significant differences.

Being tested
Insulin
Keywords
Heart Failure, Type 2 diabetes mellitus, Insulin, Older adults
Medical subject headings
Heart Failure, Diabetes Mellitus, Type 2, Insulin Resistance

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • InsulinDrug

    Insulin as well as oral anti-diabetic drugs will be prescribed by the responsible physician and/or the diabetologist from each participating site, in conformity with the current guidelines, and the therapeutic target chosen according to patient characteristics.

    The choice of anti-diabetic medications should be guided by medical needs of each patient and taking into consideration their general safety profile.

Study groups in NCT03665350
Study groupRoleWhat they receive
non insulinNo interventionstandard care + antidiabetic therapy non insulin
InsulinExperimentalstandard care including insulin
Receives: Drug: Insulin

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change in blood glucose variability

    Mean change from baseline to 12 months in glucose variability. Glucose variability is estimated as standard deviation (SD) of serial glycemic values, and is based on 3 daily glucose profiles (each with at least 5 self-measurements of blood glucose).

    Measured: baseline to 12 months.

Secondary outcomes (13)

  1. Number of patients with episodes of hypoglycemia.

    Hypoglycemic episodes: an event accompanied or not accompanied by typical symptoms but with a measured plasma glucose concentration ≤70 mg/dl (3.9 mmol/l).

    Measured: baseline, 1, 6, 12 months.

  2. Change in body weight.

    Weight will be measured in Kg. An increase in body weight ≥2 kg gain in one week will be considered a marker of fluid congestion.

    Measured: baseline, 1, 6, 12 months.

  3. Change in plasma concentration of a natriuretic peptide

    BNP or NT-proBNP concentrations will be measured as ng/L of plasma.

    Measured: baseline, 1, 6, 12 months.

  4. Changes in urinary albumin excretion

    Urinary albumin concentration will be expressed as the urinary albumin-to-creatinine ratio (UACR), measured in milligrams per grams of creatinine, with a limit of detection of 1.5 mg/g.

    Measured: baseline, 1, 6, 12 months.

  5. Change in New York Heart Association (NYHA) class

    Any change in NYHA class. The New York Heart Association (NYHA) Functional Classification places patients in one of four categories (I through IV) based on heart failure symptoms and functional limitations. Higher NYHA classes indicate a greater heart failure severity and poorer outcome."

    Measured: baseline, 1, 6, 12 months.

  6. All-cause hospitalizations

    Number of patients admitted to hospital for any cause.

    Measured: baseline to 12 months

  7. Hospitalizations for worsening of HF.

    Number of patients admitted to hospital for worsening of HF.

    Measured: baseline to 12 months

  8. All-cause mortality

    Number of patients who died for cardiovascular and non-cardiovascular causes.

    Measured: baseline to 12 months

  9. Number of patients with episodes of ketoacidosis as evaluation of safety.

    Ketoacidosis is defined as the presence of at least two of the following factors: a) elevated plasma glucose (>250 mg/dL), b) ketones in serum or urine and c) acidosis (serum bicarbonate <18 mEq/L and/or pH <7.30).

    Measured: baseline to 12 months

  10. Number of patients with episodes of lactic acidosis as evaluation of safety.

    Lactic acidosis is characterized by persistently increased blood lactate levels (usually >5 mmol/L) in association with metabolic acidosis.

    Measured: baseline to 12 months

  11. Changes in left ventricular ejection fraction (LVEF).

    LVEF will be calculated from left ventricular volume in diastole and systole estimated by echocardiography. LVEF will be measured as percentage. A decrease in LVEF will be taken as a marker of worsening of cardiac function.

    Measured: baseline, 1, 6, 12 months.

  12. Changes in E/e'.

    E/e' ratio will be calculated from echo-Doppler recordings. As a ratio it will not have a unit of measure.

    Measured: baseline, 1, 6, 12 months.

  13. Changes in Hemoglobin A1c (HbA1c).

    HbA1c will be measured as percentage of total hemoglobin concentration.

    Measured: baseline, 1, 6, 12 months.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted11 Sep 2018
  2. Study start8 Nov 2018
  3. Primary completion18 Sep 2019
  4. Study completion18 Sep 2019

Why it stopped: Insulin-HF study was prematurely ended due principally to low recruitment rate.

Resources

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
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
The primary endpoint, glucose variability, will be computed from 3 daily glucose profiles performed before the baseline, 1, 6, 12 mo follow-up and at end study visit and calculated as the average of the three daily standard deviations. Blood glucose values will be reported by the patient in an ad hoc form and the responsible physician will input this data in the e-CRF. An intensive ambulatory self-monitoring of weekly body weight and possible changes in diuretic treatment is required. At 1, 6, 12 mo of follow up and/or at end of study visit: 1. patients will be examined, 2. the information about clinical events will be collected. 3. natriuretic peptide plasma concentration, HbA1c and urinary albumin excretion will be measured Echocardiographic evaluation will be done at baseline, 1 and 12 mo after randomization. Central randomization in a 1:1 ratio will be performed by a web-based system.
Masking
Single blind
Who is masked
Outcomes assessor
Enrolment
10 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03665350
Sponsor's protocol ID
IRFMN-7468
Other IDs
2018-001057-26, 2018
Acronym
Insulin-HF
Status last verified
Nov 2019
First submitted
26 Jul 2018
Last updated
18 Nov 2019
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Undecided

Publications

  • American Diabetes Association. 11. Older Adults: Standards of Medical Care in Diabetes-2018. Diabetes Care. 2018 Jan;41(Suppl 1):S119-S125. doi: 10.2337/dc18-S011.

    PubMed 29222382

  • Aspromonte N, Gulizia MM, Di Lenarda A, Mortara A, Battistoni I, De Maria R, Gabriele M, Iacoviello M, Navazio A, Pini D, Di Tano G, Marini M, Ricci RP, Alunni G, Radini D, Metra M, Romeo F. ANMCO/SIC Consensus Document: cardiology networks for outpatient heart failure care. Eur Heart J Suppl. 2017 May;19(Suppl D):D89-D101. doi: 10.1093/eurheartj/sux009. Epub 2017 May 2.

    PubMed 28751837

  • Bozkurt B, Aguilar D, Deswal A, Dunbar SB, Francis GS, Horwich T, Jessup M, Kosiborod M, Pritchett AM, Ramasubbu K, Rosendorff C, Yancy C; American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular and Stroke Nursing; Council on Hypertension; and Council on Quality and Outcomes Research. Contributory Risk and Management of Comorbidities of Hypertension, Obesity, Diabetes Mellitus, Hyperlipidemia, and Metabolic Syndrome in Chronic Heart Failure: A Scientific Statement From the American Heart Association. Circulation. 2016 Dec 6;134(23):e535-e578. doi: 10.1161/CIR.0000000000000450. Epub 2016 Oct 31. No abstract available.

    PubMed 27799274

  • Cosmi F, Shen L, Magnoli M, Abraham WT, Anand IS, Cleland JG, Cohn JN, Cosmi D, De Berardis G, Dickstein K, Franzosi MG, Gullestad L, Jhund PS, Kjekshus J, Kober L, Lepore V, Lucisano G, Maggioni AP, Masson S, McMurray JJV, Nicolucci A, Petrarolo V, Robusto F, Staszewsky L, Tavazzi L, Teli R, Tognoni G, Wikstrand J, Latini R. Treatment with insulin is associated with worse outcome in patients with chronic heart failure and diabetes. Eur J Heart Fail. 2018 May;20(5):888-895. doi: 10.1002/ejhf.1146. Epub 2018 Feb 28.

    PubMed 29488676

  • DeVries JH. Glucose variability: where it is important and how to measure it. Diabetes. 2013 May;62(5):1405-8. doi: 10.2337/db12-1610.

    PubMed 23613566

  • DeFronzo RA, Cooke CR, Andres R, Faloona GR, Davis PJ. The effect of insulin on renal handling of sodium, potassium, calcium, and phosphate in man. J Clin Invest. 1975 Apr;55(4):845-55. doi: 10.1172/JCI107996.

    PubMed 1120786

  • Giorda CB, Rossi MC, Ozzello O, Gentile S, Aglialoro A, Chiambretti A, Baccetti F, Gentile FM, Romeo F, Lucisano G, Nicolucci A; HYPOS-1 Study Group of AMD. Healthcare resource use, direct and indirect costs of hypoglycemia in type 1 and type 2 diabetes, and nationwide projections. Results of the HYPOS-1 study. Nutr Metab Cardiovasc Dis. 2017 Mar;27(3):209-216. doi: 10.1016/j.numecd.2016.10.005. Epub 2016 Nov 18.

    PubMed 28017523

  • Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Colvin MM, Drazner MH, Filippatos GS, Fonarow GC, Givertz MM, Hollenberg SM, Lindenfeld J, Masoudi FA, McBride PE, Peterson PN, Stevenson LW, Westlake C. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017 Aug 8;136(6):e137-e161. doi: 10.1161/CIR.0000000000000509. Epub 2017 Apr 28. No abstract available.

    PubMed 28455343

  • ORIGIN Trial Investigators; Gerstein HC, Bosch J, Dagenais GR, Diaz R, Jung H, Maggioni AP, Pogue J, Probstfield J, Ramachandran A, Riddle MC, Ryden LE, Yusuf S. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012 Jul 26;367(4):319-28. doi: 10.1056/NEJMoa1203858. Epub 2012 Jun 11.

    PubMed 22686416

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Insulin in people with Heart Failure and Diabetes Mellitus, Type 2, run by Mario Negri Institute for Pharmacological Research at 3 sites in Italy.

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 8 inclusion and 8 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: stopped early, as of the sponsor's last update on 18 Nov 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in Italy. 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. 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 was stopped early (reason given: Insulin-HF study was prematurely ended due principally to low recruitment rate.). Results are not available in the source record.

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?

Change in blood glucose variability (time frame: baseline to 12 months.). 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 NCT03665350, which also lists 9 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 18 Nov 2019.

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