| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 18.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10067585 |
| E.1.2 | Term | Type 2 diabetes mellitus |
| E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
|
| 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 |
| To test whether Mylan’s insulin glargine once daily is non-inferior to Lantus® once daily (both administered in combination with other anti-diabetic drugs) based on the change in HbA1c from baseline to 24 weeks |
|
| E.2.2 | Secondary objectives of the trial |
To compare Mylan’s insulin glargine to Lantus® when both are used in combination with other oral anti-diabetic drugs at 24 weeks (unless specified) with respect to:
- Rate of hypoglycemic events per 30 days and hypoglycemia occurrence
- Occurrence of local reactions, systemic reactions and other adverse events over time
- Comparison of change in immunogenicity (change in titer, incidence of ADA, anti-HCP and neutralizing antibodies) from baseline over time
- Device-related safety assessment
- Change in HbA1c from baseline to 12 weeks
- Change in fasting plasma glucose from baseline over time
- Change in basal insulin dose per unit body weight (U/Kg) from baseline over time
- Change in 7-point SMBG profile from baseline over time
- Percentage of participants with HbA1c <7% at end of study |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patients must give written and signed informed consent before starting any protocol-specific procedures;
2. Male and female patients between the ages of 18 to 65 years, both ages inclusive.
3. a. Patients with an established diagnosis of T2DM per ADA 2014 criteria who also fulfill the following:
- Diagnosis established 1 year prior to screening
- C-peptide testing (can be done if investigator suspects latent autoimmune diabetes)
- On stable dose of other anti-diabetic drugs for 3 months prior to screening
b. Patients must also be insulin-naïve (“insulin-naïve” means the patient was never prescribed an insulin/insulin analogue on a regular basis. Occasional use for up to 2 weeks while admitted in a hospital will not be considered as insulin use, and the patient will still be considered naïve)
OR
- If not insulin-naïve, on Lantus® once daily at stable dose (±15% variation in dose) for at least 3 months prior to screening
4. Body mass index (BMI) of 18.50 to 40.00 kg/m2 at screening (both values inclusive).
5. Stable weight, with no more than 5 kg gain or loss, in the 3 months prior to screening;
6. Hemoglobin ≥9.0 g/dL at screening.
7. Glycosylated hemoglobin (HbA1c) of <10.5% at screening or >7.5 to </= 10.5% for insulin naïve patients.
8. The patient has the capability of communicating appropriately with the investigator.
9. The patient is able and willing to comply with the requirements of the trial protocol including the 7-point self-monitored blood glucose (SMBG), completion of daily patient diary records and following a recommended diet and exercise plan for the entire duration of the trial.
10. Female patients complying with the following:
- Female patients of childbearing potential must be using oral contraception or two acceptable methods of contraception, (e.g., intra-uterine device plus condom, spermicidal gel plus condom, diaphragm plus condom, etc.), from the time of screening and for the duration of the trial, through trial completion.
- Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
- Postmenopausal females must have had no menstrual bleeding for at least 1 year prior to screening.
- Female patients who report surgical sterilization must have had the procedure at least 6 months prior to screening.
- All female patients of childbearing potential must have negative pregnancy test results at screening and at each clinic visit.
- If female patients have male partners who have undergone vasectomy, the vasectomy must have occurred more than 6 months prior to screening. |
|
| E.4 | Principal exclusion criteria |
1. History or presence of a medical condition/disease that in the investigator's opinion would place the patient at an unacceptable risk.
2. hypersensitivity to any of the active/inactive ingredients of the insulin/insulin analog preparations used in the trial, OR history of significant allergic drug reactions.
3. use of animal insulin within the last 3 years, any insulin other than Lantus® within the last 3 months prior to screening, or use of biosimilar insulin glargine at any time prior to screening.
4. Patients requiring basal-bolus insulin therapy or mealtime insulin in order to achieve glycemic control.
5. Regular use of immune-modulator therapy in the 1 year prior to screening.
6. autoimmune disorders other than sufficiently treated autoimmune thyroid disorders, judged clinically relevant by the investigator
7. ≥2 episodes of severe hypoglycemia within the 6 months before screening or history of hypoglycemia unawareness as judged by theinvestigator.
8. ≥1 episode of hyperglycemic hyperosmolar coma or emergency room visits for uncontrolled diabetes leading to hospitalization within the 6 months prior to screening.
9. clinically significant (i.e., significant enough to alter the insulin dose requirement, as per the investigator) acute bacterial, viral or fungal systemic infections in the 4 weeks prior to screening
10. Any clinically significant abnormality in electrocardiogram or safety laboratory tests (liver function test, renal function test, hematology or any other laboratory result) conducted at screening and making the patient ineligible for the study (as per investigator).
11. Serological evidence of human immunodeficiency virus, hepatitis B or hepatitis C antibodies at screening.
12. drug/alcohol dependence or abuse during the 1 year prior to screening.
13. Receipt of another investigational drug (IMP) in the 3 months prior to screening (or as per local regulations), or if the screening visit is within 5 half-lives of another IMP (whichever is longer), or scheduled to receive another IMP during the current trial period.
14. Following secondary complications of diabetes:
- Active proliferative retinopathy as confirmed by a dilated ophthalmoscopy/retinal photography examination performed within 6 months prior to screening (performed by a person legally authorized to do so).
- Clinical nephrotic syndrome or diabetic nephropathy having serum creatinine level >1.5 times of upper limit of reference range at screening.
- History of severe form of neuropathy or cardiac autonomic neuropathy (Patients with mild/moderate forms of neuropathy will be allowed)
- Patients with limb amputation as a complication of diabetes (at any time) or any vascular procedure during the 1 year prior to screening.
- diabetic foot or non-healing diabetic ulcers in the 1 year prior to screening.
15. Any major elective surgery requiring hospitalization planned during the trial period.
16. Clinically significant major organ disease at the time of screening including:
Uncontrolled hypertension; defined as stage 2 hypertension by Joint National Committee VII; Uncontrolled hyperlipidemia, hyperthyroidism or hypothyroidism; Impaired hepatic function. Patients with evidence of Gilberts disease may be included in the trial if they have total bilirubin of <3 mg/dL with indirect bilirubin contributing to >80% of the total
bilirubin.
17. Significant medical condition such as:
- Clinically significant cardiac disease like unstable angina, myocardial infarction, Grade 3 or 4 congestive heart failure according to the New York Heart Association criteria, valvular heart disease, cardiac arrhythmia requiring treatment, pulmonary hypertension within an year prior to screening.
- History of stroke or transient ischemic attack in the 6 months prior to screening.
18. Patients with major depressive illness in the last 3 years (patients with well-controlled depression for 3 months and are on a stable dose of antidepressants, with no major depressive episodes in the last 3 years, can be included), patients with history of other severe psychiatric diseases (e.g., manic depressive psychosis, schizophrenia), which in the
opinion of the investigator precludes the patient from participating in the trial
19. Hematological disorders that can affect the reliability of HbA1c estimation (hemoglobinopathies, hemolytic anemia, sickle cell anemia).
20. Patients who are on complementary or alternative medicines(homeopathy, ayurvedic etc.) intended to control diabetes, in the 3 months prior to screening should discontinue before randomization.
21. Moderate insulin resistance, defined as requiring insulin of ≥1.5 U/IU/kg/day.
22. Patients who have received ≥14 consecutive days of glucocorticoid
therapy (any route producing systemic effects) within the past 1 year, or have received steroids by any route (except intra-nasal, intra-ocular, and topical) within the 4 weeks immediately preceding screening. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change in HbA1c from baseline to 24 weeks |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Rate of hypoglycemic events per 30 days and hypoglycemia occurrence
2. Occurrence of local reactions, systemic reactions and other adverse events over time
3. Comparison of change in immunogenicity (change in titer, incidence of ADA, anti-HCP and neutralizing antibodies) from baseline over time
4. Device-related safety assessment
5. Change in HbA1c from baseline to 12 weeks
6. Change in fasting plasma glucose from baseline over time
7. Change in basal insulin dose per unit body weight (U/Kg) from baseline over time
8. Change in 7-point self-monitored blood glucose (SMBG) profile from baseline over time
9. Percentage of participants with HbA1c <7% at end of study |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Every 30 days
2. At each study visit
3. At screening and at study weeks 0, 2, 4, 12 and 24
4. At each study visit
5. At study week 12
6. At screening and at study weeks 0, 2, 4, 8, 12, 16, 20, 24
7. At each study visit
8. At study weeks 1, 2, 3, 4, 6, 8, 10, 12, 16, 20 and 24
9. At study week 24 |
|
| 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 | No |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 15 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 |
| Korea, Republic of |
| Slovakia |
| South Africa |
| Taiwan |
| United States |
| Jordan |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 22 |
| 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 | 8 |
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