E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
High level of sugar (glucose) in the blood |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10067584 |
E.1.2 | Term | Type 1 diabetes mellitus |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to demonstrate superiority of either LX4211 400 mg or 200 mg versus placebo on glycosylated hemoglobin A1C (A1C) reduction at Week 24 when used as an adjunct in adult patients with type 1 diabetes mellitus (T1D) who have inadequate glycemic control with insulin therapy. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives of this study are to evaluate the change from Baseline of LX4211 versus placebo in hierarchical order on the following:
-Proportion of patients with A1C <7.0% and no episode of severe hypoglycemia and no episode of diabetic ketoacidosis (DKA)
-Body weight
-Bolus insulin dose
-Fasting plasma glucose (FPG)
-Diabetes Treatment Satisfaction Questionnaire status (DTSQs) score, and 2-item Diabetes Distress Screening Scale (DDS2) questionnaire score |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Patient has given written informed consent to participate in the study in accordance with local regulations
2) Adult patients 18 years and older with a diagnosis of T1D made at least 1 year prior to informed consent
3) Patients are being treated with insulin or insulin analog delivered via CSII or MDI where the method of insulin delivery has not changed from CSII to MDI or vice-versa in the 3 months prior to the Screening Visit
4) At the Screening Visit, A1C must be 7.0% to 11.0%, inclusive
5) Must be willing and able to perform SMBG and complete the study diary as required per protocol
6) Females of childbearing potential must use an adequate method of contraception to avoid pregnancy throughout the duration of the study and for 30 days after the last dose of study drug. Females of childbearing potential include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal. Postmenopause is defined as no menses for ≥12 months without another cause. For females with questionable menopausal history (eg, irregular menstrual periods and age >40 years) a documented serum follicle-stimulating hormone (FSH) level must be ≥30 mIU/mL.
7) Females of childbearing potential must have a negative serum or urine pregnancy test prior to the start of study drug. In the case of positive urine pregnancy testing, a negative serum sample for pregnancy testing, to confirm that the patient is not pregnant, must be obtained prior to start of study. |
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E.4 | Principal exclusion criteria |
1) Therapies and/or medications
a) Use of antidiabetic agent other than insulin or insulin analog at the time of screening
b) Any prior exposure to LX4211
c) Use of SGLT inhibitors within 8 weeks prior to Screening
d) Chronic systemic corticosteroid use, defined as any dose of systemic corticosteroid taken for more than 4 consecutive weeks within the 6 months prior to the Screening Visit.
2) Diabetes-related conditions:
a) Type 2 diabetes mellitus, or severely uncontrolled diabetes mellitus as determined by the Investigator
b) History of severe hypoglycemic event within 1 month prior to the Screening Visit.
c) History of DKA within 1 month prior to Screening visit, or more than 2 episodes within 6 months prior to the Screening visit
d) History of nonketotic hyperosmolar state within 6 months prior to the Screening Visit
3) Laboratory Results
a) Estimated glomerular filtration rate <45 mL/min/1.73 m2 at Screening, as determined by the 4 variable Modification of Diet in Renal Disease (MDRD) equation
b) Fasting triglycerides >600 mg/dL.
c) Abnormal liver function at Screening defined as any of the following: aspartate aminotransferase (AST) >2X upper limit of the normal reference range (ULN), alanine aminotransferase (ALT) >2X ULN, serum total bilirubin (TB) >1.5X ULN.
d) Screening beta-hydroxy butyrate (BHB) >0.6 mmol/L.
4) Reproductive status:
a) Females who are pregnant or breastfeeding or intend to be during the course of the study
5) Gastrointestinal/hepatic:
a) By known history, serologic evidence of current infectious liver disease (hepatitis A, B, or C), including antihepatitis A virus (immunoglobulin M), hepatitis B surface antigen, or antihepatitis C virus.
b) Difficulty swallowing such that the patient cannot take the study drug
c) History of pancreatitis within 12 months of screening
6) Renal:
a) Initiation of chronic dialysis within 30 days prior to the Screening Visit or expected to occur within 180 days after the Screening Visit
b) Renal disease that required treatment with immunosuppressive therapy, or a history of dialysis or renal transplant
c) History of hereditary glucose-galactose malabsorption or primary renal glucosuria
7) Cardiovascular:
a) New York Heart Association Class III or IV heart failure within 3 months prior to Screening Visit
b) Hypertensive urgency or emergency within 30 days prior to randomization.
c) Patients with unstable/symptomatic or life-threatening arrhythmia or heart block.
d) Patient has had any of the following within 3 months prior to the Screening Visit:
i. Hospitalization due to unstable angina
ii. MI
iii. Coronary artery bypass graft or percutaneous transluminal coronary angioplasty
iv. Transient ischemic attack or significant cerebrovascular disease
8) Hematologic:
a) History of hemoglobinopathies (sickle cell anemia, thalassemia major, sideroblastic anemia) or other disorder that may interfere with A1C determination
b) Donation or loss of >400 mL of blood or blood product(s) within 8 weeks prior to Screening
9) Immune system: Known severe immunocompromised status, including, but not limited to, patients who have undergone organ transplantation.
10) Malignancy or active treatment for malignancy within 5 years prior to the Screening Visit.
11) Current eating disorder or increase or decrease of weight within the 12 weeks prior to Screening by more than 10%
12) Known allergies, hypersensitivity, or intolerance to LX4211 or any inactive component of LX4211 or placebo
13) Administration of any other investigational drug or participation in an interventional clinical research study within 30 days or 5 half-lives (whichever is longer) of planned Screening Visit
14) History of alcohol or illicit drug abuse within 12 months prior to the Screening Visit
15) Patient is a study coordinator, employee of an Investigator or Investigator’s site, or immediate family member of any of the aforementioned
16) Any condition that, in the opinion of the Investigator, may render the patient unable to complete the study
17) The presence of a clinically significant medical history, physical examination, or laboratory finding that, in the opinion of the Investigator or the Sponsor, may interfere with any aspect of study conduct or interpretation of results. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the change from Baseline to Week 24 in A1C of either dose of LX4211 (400 mg or 200 mg) treatment group compared to placebo. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints are to be measured as change from Baseline in either LX4211 dose compared to placebo for each of the following listed below.
-Proportion of patients with A1C <7.0% (at Week 24) and no episode of severe hypoglycemia, and no episode of DKA (severe hypoglycemia and DKA occurrence over the cumulative randomized double-blind 24-week Core Treatment Period)
-Body weight at Week 24 (absolute and percent change)
-Mean change from Baseline in mean daily bolus insulin dose at Week 24
-FPG at Week 24
-Diabetes Treatment Satisfaction as measured by DTSQs scores at Week 24
-Diabetes Distress as measured by 2-item DDS2 scores at Week 24 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 102 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Belgium |
Bulgaria |
France |
Germany |
Hungary |
Israel |
Italy |
Lithuania |
Netherlands |
Poland |
Romania |
Slovakia |
Spain |
Sweden |
Switzerland |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 6 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 6 |