| 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 |
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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 | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045228 |
| E.1.2 | Term | Type I 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 |
| To evaluate the safety and immunogenicity of Insugen R plus Insugen N compared to European Union (EU) sourced Actrapid plus Insulatard in patients with Type 1 diabetes mellitus (T1DM) |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate the efficacy of Insugen R plus Insugen N compared to EU-sourced Actrapid plus Insulatard in patients with T1DM |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provide written informed consent
2. Male and female patients between the ages of 18 to 80 years, inclusive
3. Patient must have been diagnosed with T1DM before 40 years of age and must have been on treatment with
insulin for at least one year (confirmed by interview with the patient). Patients should have a fasting plasma
C-peptide </= 0.2 pmol/mL (</=200 pmol/L or 0.6 ng/mL or </= 0.2 nmol/L) and/or a history of initiation of
insulin treatment within 6 months after diagnosis (confirmed by interview with patient)
4. At least 3 months on basal-bolus insulin therapy before enrolment requiring 3 or more daily injections
5. Body mass index of 18.5 to 34.99 kg/m2, inclusive
6. Stable weight with no more than 5 kg gain or loss within 3 months of Screening (obtained by patient history)
7. Glycosylated haemoglobin (HbA1c) ≤ 11.0% at Screening. One (1) re-test is permitted within the Screening
timeline, if required.
8. Ability and willingness to perform blood glucose profiles using blood glucose meter at home during the study
|
|
| E.4 | Principal exclusion criteria |
1. History of hypersensitivity to any of the active or inactive ingredients of the test and/or reference products
2. A clinically significant abnormality (including laboratory values) at Screening, on the basis of which the
Investigator advises against study inclusion
3. An electrocardiogram (ECG) abnormality at Screening considered clinically significant by the Investigator
4. Use of insulin pump therapy in the past 2 months before Screening
5. Moderate insulin resistance defined as requiring insulin of >/=1.4 IU/kg/day
6. Significant history of atopy or allergic drug reactions
7. Clinically significant major organ disease before Screening, except for well-controlled and stable conditions
such as essential hypertension (blood pressure >130/80 mmHg), well controlled hyperlipidaemia, and thyroid
disorders for at least 3 months before Screening.
8. Knowledge of secondary complications of diabetes:
a. Retinopathy: moderate to severe non-proliferative diabetic retinopathy or proliferative diabetic retinopathy of
any severity or history of treatment with laser surgery/vitrectomy within 6 months of the Screening visit
b. Nephropathy: Proteinuria ≥1+ by urine dipstick in the absence of infection or vaginal contamination and/or
serum creatinine ≥1.5 times of upper limit of reference range, one (1) re-test is permitted within the Screening
timeline, if required; history of renal transplant
c. Neuropathy: History or finding of severe form of sensorimotor, cardiac, gastrointestinal, or genitourinary
autonomic neuropathy
d. Peripheral vascular disease (PVD): Severe PVD that has resulted in amputation, chronic foot ulcer,
claudication on walking <200 metres, or absent pulses
9. Unstable coronary artery disease (unstable angina, myocardial infarction within the preceding 6 months), heart
failure (New York Heart Association Grade 2 or higher), history of stroke, or transient ischemic attack within the
preceding 6 months
10. History of drug or alcohol dependence or abuse within 6 months before Screening
11. Current use of systemic or inhaled glucocorticoids or other drugs which may affect glycaemic control
12. Treatment with blood-glucose lowering drugs other than insulin or insulin analogues in the last 4 weeks
before Screening or during the study
13. The use of prohibited concomitant medications, including oral hypoglycaemic agents; monoamine
oxidase (MAO) inhibitors; Beta blockers; salicylates >300 mg/day or chronic usage requiring uninterrupted
administration for >14 days during the study; anabolic steroids; diltiazem; niacin; isoniazid; epinephrine; thiazide
diuretics if >25 mg/day; and loop diuretics.
14. History of 2 or more episodes of hypoglycaemia requiring assistance by another person to administer glucose
or glucagon (severe hypoglycaemia) within 6 months before Screening
15. Any hospitalisation or emergency department visit due to poor diabetes control within 6 months before
Screening
16. Any electively planned surgery requiring hospitalisation
17. Pregnancy, breastfeeding, or planned pregnancy during the study duration. Women of childbearing potential
(any woman who is not surgically sterile or > 2 years post menopause) must agree to use a reliable method of
contraception (e.g., double-barrier, tubal ligation, or stable hormonal contraception) throughout the study period.
Women who become pregnant during the study must be discontinued from the study and followed for pregnancy
outcome
18. Impaired hepatic function (alanine transaminase [ALT] or aspartate aminotranferase [AST] value > 2 times
the upper limit of the reference range and/or serum bilirubin >1.5 times the upper limit of the reference range at
the Screening visit). One (1) re-test is permitted within the Screening timeline, if required.
19. Impaired renal function (serum creatinine ≥1.5 times of upper limit of the reference range at Screening) or
chronic kidney disease (estimated glomerular filtration rate < 60 mL/min/1.73m2)
20. Haemoglobinopathies, haemolytic anaemia, anaemia of chronic disease, or any factor affecting the
measurement of HbA1c
21. Receipt of another investigational drug within 6 weeks before Screening or within 5 half-lives of the drug,
whichever is longer, or scheduled treatment of another investigational drug during the current study period
22. Any patient who in the estimation of the Investigator does not show necessary compliance to participate in the
trial and comply with necessary trial requirements. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary endpoints phase 1:
Comparison of the change in mean anti-insulin antibody binding percentage from Baseline to Week 24 between
Insugen R plus Insugen N and Actrapid plus Insulatard groups.
Primary endpoints phase 2:
Change in mean anti-insulin antibody binding percentage from Baseline (Visit 3) to the end of Week 48.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At the end of the comparative phase (phase 1), at end of trial and as part of preparations for subsequent trials, exploratory analysis of subsets of data may be performed. |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints phase 1:
- Comparison of the change in mean anti-insulin antibody titres from Baseline to the end of Week 24
- Comparison of the change in incidence of anti-inslin antibodies from Baseline to Week 24
Secondary endpoints phase 2:
-Change in mean antibody titre from Baseline to Week 48
- Change in incidence of anti-insulin antibodies from Baseline to Week 48 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At the end of the comparative phase (phase 1), at end of trial and as part of preparations for subsequent trials, exploratory analysis of subsets of data may be performed. |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | Yes |
| 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 |
|
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Blinded endpoint analysis |
|
| 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| 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 |
| Germany |
| Hungary |
| India |
| Italy |
| Romania |
| Ukraine |
|
| 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
|
| The end of trial is the last patient last visit. |
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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