xml: <clinical_study>
    <!-- This xml conforms to an XML Schema at:
      https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
    <required_header>
      <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
      <link_text>Link to the current ClinicalTrials.gov record.</link_text>
      <url>https://clinicaltrials.gov/ct2/show/NCT05989503</url>
    </required_header>
    <id_info>
      <org_study_id>INITIATE-HFrEF</org_study_id>
      <secondary_id>2022-502409-14-00</secondary_id>
      <nct_id>NCT05989503</nct_id>
    </id_info>
    <brief_title>Initiation of ARNi and SGLT2i in Patients With HFrEF</brief_title>
    <acronym>INITIATE</acronym>
    <official_title>Initiation of Angiotensin Receptor-neprilysin Inhibitor (ARNi) and Sodium-glucose Cotransporter-2 Inhibitors (SGLT2i) in Patients With Heart Failure With Reduced Ejection Fraction (HFrEF): the INITIATE-HFrEF Randomized Open-label Trial</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Universidade do Porto</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>Universidade do Porto</source>
    <oversight_info>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        Heart failure (HF) is a condition in which the heart does not contract (&quot;pump&quot;) or relax&#xD;
        well, leading to insufficient perfusion of vital organs. Ankle swelling, fatigue, and&#xD;
        breathlessness are some of the features of this syndrome. There are different causes for HF&#xD;
        (e.g., infarct and hypertension) and two distinct types: HFpEF - HF with preserved ejection&#xD;
        fraction - the heart &quot;pumps&quot; but does not relax well and HFrEF - HF with reduced ejection&#xD;
        fraction - where the heart does not &quot;pump&quot; properly.&#xD;
  &#xD;
        Patients with HFrEF experience substantially shorter life expectancies compared with people&#xD;
        in the general population of similar age. Compared to the different available therapeutics&#xD;
        for HFrEF patients, angiotensin receptor-neprilysin inhibitor (ARNi), sacubitril/valsartan,&#xD;
        has shown superiority for improving clinical outcomes. Furthermore, the new recently drug&#xD;
        sodium-glucose cotransporter 2 inhibitor (SGLT2i) was proven to reduce mortality and&#xD;
        morbidity on top of well-adapted background therapy.&#xD;
  &#xD;
        This work aims to test the safety of ARNi and SGLT2i initiation by comparing a strategy of&#xD;
        simultaneous initiation of ARNi and SGLT2i versus sequential initiation of an ARNi first&#xD;
        followed by a SGLT2i.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Sacubitril/valsartan and SGLT2i reduced HF hospitalizations and mortality in patients with&#xD;
        heart failure and a reduced ejection fraction with a rapid onset of action, but the timing of&#xD;
        initiation of each drug is uncertain. Clinicians may be reluctant to initiate both therapies&#xD;
        simultaneously due to fear of adverse events (e.g., hypotension and worsening renal function)&#xD;
        which may delay the initiation of (at least one) of these life-saving therapies.&#xD;
  &#xD;
        This study aims to fill this gap in knowledge by studying the initiation of&#xD;
        sacubitril/valsartan and a SGLT2i simultaneously or in sequence. This study will better&#xD;
        inform clinicians on their daily decisions.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Recruiting</overall_status>
    <start_date type="Actual">August 4, 2023</start_date>
    <completion_date type="Anticipated">February 2025</completion_date>
    <primary_completion_date type="Anticipated">November 2024</primary_completion_date>
    <phase>Phase 4</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Randomized</allocation>
      <intervention_model>Parallel Assignment</intervention_model>
      <intervention_model_description>Pragmatic study to be conducted in real-life routine practice conditions with a two-arm open randomization, to evaluate the efficacy (on surrogate markers) and safety of ARNi and SGLT2i combination in patients with HFrEF and the doses of ARNi.&#xD;
  initiation of ARNi and SGLT2i simultaneously (same day);&#xD;
  initial ARNi up-titration followed by SGLT2i initiation at week 12 (+ maximum 7 days)</intervention_model_description>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Composite outcome (time-to-first event' occurrence during the 6 months of follow-up):</measure>
      <time_frame>visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Symptomatic hypotension (systolic blood pressure &lt;100 mmHg with signs or symptoms compatible with hypoperfusion);&#xD;
  Hyperkalaemia (serum potassium &gt;6.0 mmol/L);&#xD;
  Hypokalemia (serum potassium &lt;3.0 mmol/L);&#xD;
  eGFR drop ≥50% from baseline or eGFR &lt;15 ml/min/1.73m2 or renal transplant or dialysis;&#xD;
  Increase in diuretic dose due to worsening heart failure;&#xD;
  Use of intravenous diuretics for worsening heart failure;&#xD;
  Heart failure hospitalization;&#xD;
  Death from cardiovascular causes.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Symptomatic hypotension (systolic blood pressure &lt;100 mmHg with signs or symptoms compatible with hypoperfusion)</measure>
      <time_frame>visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Time to event' occurrence during the 6 months of follow-up</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Hyperkalaemia (serum potassium &gt;6.0 mmol/L)</measure>
      <time_frame>visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Time to event' occurrence during the 6 months of follow-up</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Hypokalemia (serum potassium &lt;3.0 mmol/L)</measure>
      <time_frame>visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Time to event' occurrence during the 6 months of follow-up</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>eGFR drop ≥50% from baseline or eGFR &lt;15 ml/min/1.73m2 or renal transplant or dialysis</measure>
      <time_frame>visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Time to event' occurrence during the 6 months of follow-up</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Increase in diuretic dose due to worsening heart failure</measure>
      <time_frame>visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Time to event' occurrence during the 6 months of follow-up</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Use of intravenous diuretics for worsening heart failure</measure>
      <time_frame>visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Time to event' occurrence during the 6 months of follow-up</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Heart failure hospitalization</measure>
      <time_frame>visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Time to event' occurrence during the 6 months of follow-up</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Death from cardiovascular causes</measure>
      <time_frame>visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Time to event' occurrence during the 6 months of follow-up</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>NT-pro BNP or BNP (log)</measure>
      <time_frame>visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Concentration measured in blood samples</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>High sensitivity C-reactive protein</measure>
      <time_frame>visit 1 (day 0); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Concentration measured in blood samples</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Atrial fibrillation/flutter</measure>
      <time_frame>visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Electrocardiogram (yes/no)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Systolic and diastolic blood pressure</measure>
      <time_frame>visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Measure in the clinical appointments</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>High sensitivity Troponin</measure>
      <time_frame>visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Concentration measured in blood samples</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Left atrial volume</measure>
      <time_frame>visit 1 (day 0); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Transthoracic echocardiogram</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Left ventricular systolic volume</measure>
      <time_frame>visit 1 (day 0); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Transthoracic echocardiogram</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Left ventricular diastolic volume</measure>
      <time_frame>visit 1 (day 0); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Transthoracic echocardiogram</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>LV mass</measure>
      <time_frame>visit 1 (day 0); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Transthoracic echocardiogram</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>LV ejection fraction</measure>
      <time_frame>visit 1 (day 0); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Transthoracic echocardiogram</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Pulmonary artery systolic pressure</measure>
      <time_frame>visit 1 (day 0); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Transthoracic echocardiogram</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Serum sodium</measure>
      <time_frame>visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Concentration measured in blood samples</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Serum potassium</measure>
      <time_frame>visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Concentration measured in blood samples</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Serum creatinine</measure>
      <time_frame>visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Concentration measured in blood samples</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Glomerular filtration rate (eGFR)</measure>
      <time_frame>visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Calculated from the serum creatinine using the 2021 CKD-EPI creatinine-based formula</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Urinary sodium</measure>
      <time_frame>visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Spot urine sample</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Urinary potassium</measure>
      <time_frame>visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Spot urine sample</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Microalbuminuria</measure>
      <time_frame>visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Spot urine sample</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Total Cholesterol</measure>
      <time_frame>visit 1 (day 0); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Concentration measured in blood samples</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>LDL Cholesterol</measure>
      <time_frame>visit 1 (day 0); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Concentration measured in blood samples</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>HDL Cholesterol</measure>
      <time_frame>visit 1 (day 0); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Concentration measured in blood samples</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Triglycerides</measure>
      <time_frame>visit 1 (day 0); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Concentration measured in blood samples</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Glucose</measure>
      <time_frame>visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Measured in blood samples</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Glycated hemoglobin (HbA1C)</measure>
      <time_frame>visit 1 (day 0); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Concentration measured in blood samples</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Uric acid</measure>
      <time_frame>visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Concentration measured in blood samples</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>TSH</measure>
      <time_frame>visit 1 (day 0); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Concentration measured in blood samples</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Free thyroxin</measure>
      <time_frame>visit 1 (day 0); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Concentration measured in blood samples</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>ALAT</measure>
      <time_frame>visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Concentration measured in blood samples</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>ASAT</measure>
      <time_frame>visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Concentration measured in blood samples</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Gamma-GT</measure>
      <time_frame>visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Concentration measured in blood samples</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Alkaline Phosphatase</measure>
      <time_frame>visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Concentration measured in blood samples</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Total bilirubin</measure>
      <time_frame>visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Concentration measured in blood samples</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Serum iron</measure>
      <time_frame>visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Concentration measured in blood samples</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Ferritin</measure>
      <time_frame>visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Concentration measured in blood samples</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Transferrin saturation</measure>
      <time_frame>visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Concentration measured in blood samples</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Functional class (NYHA, New York Heart Association)</measure>
      <time_frame>visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>Assessed by the medical doctors in the clinical appointments (I / II / III / IV)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Quality of life (KCCQ, Kansas City Cardiomyopathy Questionnaire)</measure>
      <time_frame>visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)</time_frame>
      <description>HR-QoL assessed by the Kansas City Cardiomyopathy Questionnaire a 12-item instrument. All items are measured on a Likert scale with 5-7 response options. KCCQ scores are scaled from 0 to 100 and summarized in 25-point ranges, where scores represent health status as follows: 0 to 24: very poor to poor; 25 to 49: poor to fair; 50 to 74: fair to good; and 75 to 100: good to excellent</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Dosage titration of sacubitril/valsartan up to the dose 97/103 mg (b.i.d.) at 3 months</measure>
      <time_frame>visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days)</time_frame>
      <description>Assessed by the medical doctors in the clinical appointments</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">172</enrollment>
    <condition>Heart Failure With Reduced Ejection Fraction</condition>
    <arm_group>
      <arm_group_label>Simultaneous initiation</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>ARNi (initial dose 24/26mg b.i.d. or 49/51mg b.i.d. titrated to 97/103mg b.i.d. preferably in the first 3-6 weeks, up to 3 months of follow-up) and SGLT2i (10mg q.d.) on the same day.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Sequential initiation</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>Initial ARNi prescription (initial dose 24/26mg b.i.d. or 49/51mg b.i.d. titrated to 97/103mg b.i.d. preferably in the first 3-6 weeks, up to 3 months of follow-up) and addition of SGLT2i (10mg q.d.) after 3 months of follow-up.</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Sacubitril-valsartan</intervention_name>
      <description>Sacubitril-valsartan titration at the discretion of the treating physician</description>
      <arm_group_label>Sequential initiation</arm_group_label>
      <arm_group_label>Simultaneous initiation</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>SGLT2 inhibitor</intervention_name>
      <description>Either empagliflozin or dapagliflozin 10 mg/day</description>
      <arm_group_label>Sequential initiation</arm_group_label>
      <arm_group_label>Simultaneous initiation</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            1. Age ≥ 18 years&#xD;
  &#xD;
            2. Heart failure symptoms (NYHA II, III or IV)&#xD;
  &#xD;
            3. Left ventricle ejection fraction ≤ 49% (assessed by transthoracic echocardiogram)&#xD;
  &#xD;
            4. Glomerular filtration rate ≥ 25 ml/min/1.73m2 (CKD-EPI formula)&#xD;
  &#xD;
            5. Serum potassium (K+) ≤ 5.4 mmol/L&#xD;
  &#xD;
            6. Systolic blood pressure ≥ 100 mmHg&#xD;
  &#xD;
            7. Not treated with ARNi nor with SGLT2i within the previous month (30 days before&#xD;
               inclusion)&#xD;
  &#xD;
            8. If female, she must not be a woman of childbearing potential. That is, she must be:&#xD;
  &#xD;
                 1. Surgically sterilized (e.g., underwent hysterectomy, bilateral salpingectomy or&#xD;
                    bilateral oophorectomy)&#xD;
  &#xD;
                 2. Clinically diagnosed infertile&#xD;
  &#xD;
                 3. In a post-menopausal state, defined as no menses for 12 months without an&#xD;
                    alternative medical cause&#xD;
  &#xD;
            9. If female patient of childbearing potential, she must have a negative serum pregnancy&#xD;
               test at Visit 1 (Day 0) and must agree to consistently and correctly use (from 28 days&#xD;
               prior to first study treatment administration until at least 7 days after last study&#xD;
               treatment administration) one of the following highly effective methods of&#xD;
               contraception:&#xD;
  &#xD;
                 1. Abstinence of heterosexual intercourse (when this is in line with preferred and&#xD;
                    usual lifestyle of the subject)&#xD;
  &#xD;
                 2. Progestogen-only hormonal contraception associated with inhibition of ovulation&#xD;
                    (oral, injectable, implantable)&#xD;
  &#xD;
                 3. Combined (estrogen and progestogen containing) hormonal contraception associated&#xD;
                    with inhibition of ovulation (oral, intravaginal, transdermal)&#xD;
  &#xD;
                 4. Intrauterine device&#xD;
  &#xD;
                 5. Intrauterine hormone-releasing system&#xD;
  &#xD;
                 6. Bilateral tubal occlusion&#xD;
  &#xD;
                 7. Vasectomized partner, who has received medical assessment of the surgical&#xD;
                    success, or clinically diagnosed infertile partner&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            1. Involvement in the planning and/or conduct of the study (applies to both Investigator&#xD;
               staff and/or staff at the study site)&#xD;
  &#xD;
            2. Participation in another clinical study with an investigational product during the&#xD;
               last month&#xD;
  &#xD;
            3. Unwilling to sign inform consent&#xD;
  &#xD;
            4. Patients with a known hypersensitivity or intolerance to ARNi or SGLT2i or any of the&#xD;
               excipients of the products&#xD;
  &#xD;
            5. Hospitalization due to non-cardiovascular causes, surgical procedure, coronary,&#xD;
               cerebral or peripheral vascular events or sepsis in the prior month&#xD;
  &#xD;
            6. Cancer (life limiting with an estimated life expectancy of less than 2 years based on&#xD;
               investigator's judgement)&#xD;
  &#xD;
            7. Previously confirmed cardiac amyloidosis&#xD;
  &#xD;
            8. History of angioedema&#xD;
  &#xD;
            9. Implantable cardioverter-defibrillators or cardiac resynchronization therapy within 3&#xD;
               months prior to screening or if there is an intent to implant either device in the 3&#xD;
               months following screening&#xD;
  &#xD;
           10. Female patients currently pregnant (confirmed by a positive pregnancy test) or intent&#xD;
               to become pregnant or breast feeding&#xD;
  &#xD;
           11. Severe valvulopathy according to the echocardiogram report&#xD;
  &#xD;
           12. Previous history of ketoacidosis due to SGLT2i&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>João P. Ferreira, MD, PhD</last_name>
      <role>Principal Investigator</role>
      <affiliation>Universidade do Porto</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>João P. Ferreira, PhD</last_name>
      <phone>(+351) 220426820</phone>
      <email>jpferreira@med.up.pt</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Janete Santos, PhD</last_name>
      <phone>(+351) 961239890</phone>
      <email>investigaclinica@med.up.pt</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Centro Hospitalar Universitário de Santo António</name>
        <address>
          <city>Porto</city>
          <zip>4099-001</zip>
          <country>Portugal</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Mário Santos, MD, PhD</last_name>
        <phone>+351 22 207 7500</phone>
        <email>mariosantos.cardiologia@chporto.min-saude.pt</email>
      </contact>
      <investigator>
        <last_name>Mário Santos, MD, PhD</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location>
      <facility>
        <name>Centro Hospitalar Universitário São João</name>
        <address>
          <city>Porto</city>
          <zip>4200-319</zip>
          <country>Portugal</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Francisco Vasques-Nóvoa, MD, PhD</last_name>
        <phone>(+351) 225512100</phone>
        <email>francisco.faria@chsj.min-saude.pt</email>
      </contact>
      <contact_backup>
        <last_name>Francisca Saraiva, PhD</last_name>
        <phone>(+351) 225512100</phone>
        <email>f.saraiva@med.up.pt</email>
      </contact_backup>
      <investigator>
        <last_name>Francisco Vasques-Nóvoa</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location>
      <facility>
        <name>Centro Hospitalar Vila Nova de Gaia/Espinho</name>
        <address>
          <city>Porto</city>
          <zip>4434-502</zip>
          <country>Portugal</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Joana Pimenta, MD, PhD</last_name>
        <phone>(+351) 227865100</phone>
        <email>joana.pimenta@chvng.min-saude.pt</email>
      </contact>
      <contact_backup>
        <last_name>Ana C. Oliveira, MSc</last_name>
        <email>crisoliveira@med.up.pt</email>
      </contact_backup>
      <investigator>
        <last_name>Joana Pimenta, MD, PhD</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location>
      <facility>
        <name>Unidade Local de Saúde de Matosinhos - Hospital Pedro Hispano</name>
        <address>
          <city>Porto</city>
          <country>Portugal</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Cristina Gavina, MD, PhD</last_name>
        <email>cristina.gavina@ulsm.min-saude.pt</email>
      </contact>
      <investigator>
        <last_name>Cristina Gavina, MD, PhD</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location_countries>
      <country>Portugal</country>
    </location_countries>
    <verification_date>June 2023</verification_date>
    <study_first_submitted>July 14, 2023</study_first_submitted>
    <study_first_submitted_qc>August 9, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 14, 2023</study_first_posted>
    <last_update_submitted>August 18, 2023</last_update_submitted>
    <last_update_submitted_qc>August 18, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 21, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Heart Failure</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Sodium-Glucose Transporter 2 Inhibitors</mesh_term>
      <mesh_term>Valsartan</mesh_term>
      <mesh_term>Sacubitril and valsartan sodium hydrate drug combination</mesh_term>
    </intervention_browse>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: download date: ClinicalTrials.gov processed this data on September 20, 2023
  link text: Link to the current ClinicalTrials.gov record.
  url: https://clinicaltrials.gov/ct2/show/NCT05989503
  org study id: INITIATE-HFrEF
  secondary id: 2022-502409-14-00
  nct id: NCT05989503
  lead sponsor: 
  is fda regulated drug: No
  is fda regulated device: No
  Heart failure (HF) is a condition in which the heart does not contract ("pump") or relax
        well, leading to insufficient perfusion of vital organs. Ankle swelling, fatigue, and
        breathlessness are some of the features of this syndrome. There are different causes for HF
        (e.g., infarct and hypertension) and two distinct types: HFpEF - HF with preserved ejection
        fraction - the heart "pumps" but does not relax well and HFrEF - HF with reduced ejection
        fraction - where the heart does not "pump" properly.
  
        Patients with HFrEF experience substantially shorter life expectancies compared with people
        in the general population of similar age. Compared to the different available therapeutics
        for HFrEF patients, angiotensin receptor-neprilysin inhibitor (ARNi), sacubitril/valsartan,
        has shown superiority for improving clinical outcomes. Furthermore, the new recently drug
        sodium-glucose cotransporter 2 inhibitor (SGLT2i) was proven to reduce mortality and
        morbidity on top of well-adapted background therapy.
  
        This work aims to test the safety of ARNi and SGLT2i initiation by comparing a strategy of
        simultaneous initiation of ARNi and SGLT2i versus sequential initiation of an ARNi first
        followed by a SGLT2i.
  Sacubitril/valsartan and SGLT2i reduced HF hospitalizations and mortality in patients with
        heart failure and a reduced ejection fraction with a rapid onset of action, but the timing of
        initiation of each drug is uncertain. Clinicians may be reluctant to initiate both therapies
        simultaneously due to fear of adverse events (e.g., hypotension and worsening renal function)
        which may delay the initiation of (at least one) of these life-saving therapies.
  
        This study aims to fill this gap in knowledge by studying the initiation of
        sacubitril/valsartan and a SGLT2i simultaneously or in sequence. This study will better
        inform clinicians on their daily decisions.
  allocation: Randomized
  intervention model: Parallel Assignment
  intervention model description: Pragmatic study to be conducted in real-life routine practice conditions with a two-arm open randomization, to evaluate the efficacy (on surrogate markers) and safety of ARNi and SGLT2i combination in patients with HFrEF and the doses of ARNi.
  initiation of ARNi and SGLT2i simultaneously (same day);
  initial ARNi up-titration followed by SGLT2i initiation at week 12 (+ maximum 7 days)
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Composite outcome (time-to-first event' occurrence during the 6 months of follow-up):
  time frame: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
  description: Symptomatic hypotension (systolic blood pressure <100 mmHg with signs or symptoms compatible with hypoperfusion);
  Hyperkalaemia (serum potassium >6.0 mmol/L);
  Hypokalemia (serum potassium <3.0 mmol/L);
  eGFR drop ≥50% from baseline or eGFR <15 ml/min/1.73m2 or renal transplant or dialysis;
  Increase in diuretic dose due to worsening heart failure;
  Use of intravenous diuretics for worsening heart failure;
  Heart failure hospitalization;
  Death from cardiovascular causes.
  measure: Symptomatic hypotension (systolic blood pressure <100 mmHg with signs or symptoms compatible with hypoperfusion)
  time frame: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
  description: Time to event' occurrence during the 6 months of follow-up
  measure: Hyperkalaemia (serum potassium >6.0 mmol/L)
  time frame: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
  description: Time to event' occurrence during the 6 months of follow-up
  measure: Hypokalemia (serum potassium <3.0 mmol/L)
  time frame: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
  description: Time to event' occurrence during the 6 months of follow-up
  measure: eGFR drop ≥50% from baseline or eGFR <15 ml/min/1.73m2 or renal transplant or dialysis
  time frame: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
  description: Time to event' occurrence during the 6 months of follow-up
  measure: Increase in diuretic dose due to worsening heart failure
  time frame: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
  description: Time to event' occurrence during the 6 months of follow-up
  measure: Use of intravenous diuretics for worsening heart failure
  time frame: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
  description: Time to event' occurrence during the 6 months of follow-up
  measure: Heart failure hospitalization
  time frame: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
  description: Time to event' occurrence during the 6 months of follow-up
  measure: Death from cardiovascular causes
  time frame: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
  description: Time to event' occurrence during the 6 months of follow-up
  measure: NT-pro BNP or BNP (log)
  time frame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
  description: Concentration measured in blood samples
  measure: High sensitivity C-reactive protein
  time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
  description: Concentration measured in blood samples
  measure: Atrial fibrillation/flutter
  time frame: visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
  description: Electrocardiogram (yes/no)
  measure: Systolic and diastolic blood pressure
  time frame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
  description: Measure in the clinical appointments
  measure: High sensitivity Troponin
  time frame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
  description: Concentration measured in blood samples
  measure: Left atrial volume
  time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
  description: Transthoracic echocardiogram
  measure: Left ventricular systolic volume
  time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
  description: Transthoracic echocardiogram
  measure: Left ventricular diastolic volume
  time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
  description: Transthoracic echocardiogram
  measure: LV mass
  time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
  description: Transthoracic echocardiogram
  measure: LV ejection fraction
  time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
  description: Transthoracic echocardiogram
  measure: Pulmonary artery systolic pressure
  time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
  description: Transthoracic echocardiogram
  measure: Serum sodium
  time frame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
  description: Concentration measured in blood samples
  measure: Serum potassium
  time frame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
  description: Concentration measured in blood samples
  measure: Serum creatinine
  time frame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
  description: Concentration measured in blood samples
  measure: Glomerular filtration rate (eGFR)
  time frame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
  description: Calculated from the serum creatinine using the 2021 CKD-EPI creatinine-based formula
  measure: Urinary sodium
  time frame: visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
  description: Spot urine sample
  measure: Urinary potassium
  time frame: visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
  description: Spot urine sample
  measure: Microalbuminuria
  time frame: visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
  description: Spot urine sample
  measure: Total Cholesterol
  time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
  description: Concentration measured in blood samples
  measure: LDL Cholesterol
  time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
  description: Concentration measured in blood samples
  measure: HDL Cholesterol
  time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
  description: Concentration measured in blood samples
  measure: Triglycerides
  time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
  description: Concentration measured in blood samples
  measure: Glucose
  time frame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
  description: Measured in blood samples
  measure: Glycated hemoglobin (HbA1C)
  time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
  description: Concentration measured in blood samples
  measure: Uric acid
  time frame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
  description: Concentration measured in blood samples
  measure: TSH
  time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
  description: Concentration measured in blood samples
  measure: Free thyroxin
  time frame: visit 1 (day 0); visit 4 (visit 3 + 90±15 days)
  description: Concentration measured in blood samples
  measure: ALAT
  time frame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
  description: Concentration measured in blood samples
  measure: ASAT
  time frame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
  description: Concentration measured in blood samples
  measure: Gamma-GT
  time frame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
  description: Concentration measured in blood samples
  measure: Alkaline Phosphatase
  time frame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
  description: Concentration measured in blood samples
  measure: Total bilirubin
  time frame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
  description: Concentration measured in blood samples
  measure: Serum iron
  time frame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
  description: Concentration measured in blood samples
  measure: Ferritin
  time frame: visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
  description: Concentration measured in blood samples
  measure: Transferrin saturation
  time frame: visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
  description: Concentration measured in blood samples
  measure: Functional class (NYHA, New York Heart Association)
  time frame: visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
  description: Assessed by the medical doctors in the clinical appointments (I / II / III / IV)
  measure: Quality of life (KCCQ, Kansas City Cardiomyopathy Questionnaire)
  time frame: visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days)
  description: HR-QoL assessed by the Kansas City Cardiomyopathy Questionnaire a 12-item instrument. All items are measured on a Likert scale with 5-7 response options. KCCQ scores are scaled from 0 to 100 and summarized in 25-point ranges, where scores represent health status as follows: 0 to 24: very poor to poor; 25 to 49: poor to fair; 50 to 74: fair to good; and 75 to 100: good to excellent
  measure: Dosage titration of sacubitril/valsartan up to the dose 97/103 mg (b.i.d.) at 3 months
  time frame: visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days)
  description: Assessed by the medical doctors in the clinical appointments
  arm group label: Simultaneous initiation
  arm group type: Active Comparator
  description: ARNi (initial dose 24/26mg b.i.d. or 49/51mg b.i.d. titrated to 97/103mg b.i.d. preferably in the first 3-6 weeks, up to 3 months of follow-up) and SGLT2i (10mg q.d.) on the same day.
  arm group label: Sequential initiation
  arm group type: Active Comparator
  description: Initial ARNi prescription (initial dose 24/26mg b.i.d. or 49/51mg b.i.d. titrated to 97/103mg b.i.d. preferably in the first 3-6 weeks, up to 3 months of follow-up) and addition of SGLT2i (10mg q.d.) after 3 months of follow-up.
  intervention type: Drug
  intervention name: Sacubitril-valsartan
  description: Sacubitril-valsartan titration at the discretion of the treating physician
  arm group label: Sequential initiation
  arm group label: Simultaneous initiation
  intervention type: Drug
  intervention name: SGLT2 inhibitor
  description: Either empagliflozin or dapagliflozin 10 mg/day
  arm group label: Sequential initiation
  arm group label: Simultaneous initiation
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  last name: João P. Ferreira, MD, PhD
  role: Principal Investigator
  affiliation: Universidade do Porto
  last name: João P. Ferreira, PhD
  phone: (+351) 220426820
  email: jpferreira@med.up.pt
  last name: Janete Santos, PhD
  phone: (+351) 961239890
  email: investigaclinica@med.up.pt
  facility: 
  status: Recruiting
  contact: 
  investigator: 
  facility: 
  status: Recruiting
  contact: 
  contact backup: 
  investigator: 
  facility: 
  status: Recruiting
  contact: 
  contact backup: 
  investigator: 
  facility: 
  status: Recruiting
  contact: 
  investigator: 
  country: Portugal
  responsible party type: Sponsor
  mesh term: Heart Failure
  mesh term: Sodium-Glucose Transporter 2 Inhibitors
  mesh term: Valsartan
  mesh term: Sacubitril and valsartan sodium hydrate drug combination