| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Type II Diabetes Mellitus with nephropathy and Albuminuria' |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061835 |
| E.1.2 | Term | Diabetic nephropathy |
| E.1.2 | System Organ Class | 10038359 - Renal and urinary 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 evaluate the safety and tolerability of multiple oral
doses of MT-3995 in subjects with Type II diabetic
nephropathy with albuminuria. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the effectes of multiple oral doses of MT 3995 on albuminuria as assessed by the urine albumin-to-creatinine ratio (UACR).
To determine plasma concentrations of MT-3995 and its
major metabolite (chlorinated metabolite: 1118174) after
multiple oral doses of MT-3995 in subjects with Type II
diabetic nephropathy with albuminuria.
-To determine the change from baseline in sitting Systolic
Blood Pressure (SBP) and Diastolic Blood Pressure
(DBP) in subjects with Type II diabetic nephropathy
with albuminuria. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
diagnosed with Type 2 diabetes mellitus according to the criteria of the
World Health Organisation (WHO) (WHO/NMH/CHP/CPM/11.1).
2. Subjects with a clinical diagnosis of diabetic nephropathy, who have
been treated with ACE-I or ARB for a minimum of 12 weeks prior to
screening and have been receiving a stable dose for at least 4 weeks
prior to screening and remain on a stable dose up to baseline (Day 1 predose).
3. Glycosylated haemoglobin (HbA1c) ≤10.5% at screening and Week -2.
4. An eGFR (MDRD formula20) ≥30 - <60 mL/min/1.73m2 at screening
and Week -2. Due to variability, subjects with an eGFR of 27-29 or 60-62
mL/min/1.73m2 may be enrolled in the study at the discretion of the
Investigator.
5. Albuminuria (UACR) ≥50 mg/g and ≤3500 mg/g (i.e., ≥5.66
mg/mmol and ≤395.85 mg/mmol) measured by median values of firstmorning
void urine samples on three consecutive days, both at screening
and Week -2.
6. Subjects with a DBP <100 mmHg and an SBP <160 mmHg at
screening.
7. Subjects with stable BP at Week -2 (compared with Week -4) and at
baseline, Day 1 pre-dose (compared with Week -2). Stable BP is defined
as a DBP within ± 10 mmHg from the previous BP measurement.
Subjects must also have a DBP <110 mmHg and an SBP <180 mmHg at
Week -4, Week -2 and baseline (Day 1 pre-dose).
8. Subjects who are on permitted medication must be on stable
treatment for at least 4 weeks prior to screening and remain on a stable
dose up to baseline as per Section 6.3.1 of Protocol.
9. Women may be enrolled if all of the following criteria (in addition to
the other criteria) are met:
• they are not pregnant.
• they are not breast-feeding.
• they do not plan on becoming pregnant during the study.
10. Women of childbearing potential must agree to use two forms of
effective contraception from the screening visit until at least 120 days
after the last dosing day. Examples of effective contraception are:
various types of hormonal contraception, barrier methods (male
condom/cap/diaphragm with spermicide), and intrauterine devices.
Women are considered to be of childbearing potential unless they meet
one of the following criteria as documented by the Investigator:
• they have had a hysterectomy or bilateral tubal ligation prior to
signing the Informed Consent Form (ICF); or
• they are post-menopausal, defined for women ≤50 years old as ≥2
years since their last menstrual period and for women >50 years old as
≥1 year since their last menstrual period.
If there are doubts as to the woman's menopausal status, the levels of
follicle stimulating hormone may be monitored. Women practicing
abstinence or where the partner is sterile should be considered to be of
childbearing potential.
11. Male participants in the study should use one of the following
methods of contraception while having sexual intercourse with WOCBP
from screening until at least 120 days after the last dosing day: total
abstinence, condom (male or female) with spermicide.
12. Subjects who are capable of giving informed consent, complying with
the restrictions and requirements of the protocol and, in the opinion of
the Investigator, will be able to complete the study. |
|
| E.4 | Principal exclusion criteria |
1. History of Type I diabetes, pancreas or β-cell transplantation, or
diabetes secondary to pancreatitis or pancreatectomy.
2. Central laboratory serum potassium level <3.5 or >5.2 mmol/L at
screening, Week -2 or baseline (Day 1 pre-dose).
3. Local laboratory serum potassium level <3.5 or >5.2 mmol/L at
baseline (Day 1 pre-dose).
4. Evidence of active urinary tract infection at screening.
5. Subjects who had acute kidney injury (AKI) within 3 months prior to
baseline (Day 1 pre dose) or have undergone renal dialysis at any time
prior to randomisation.
6. Subjects with a history of renal transplant.
7. Subjects diagnosed with non-diabetic kidney disease significantly
impacting on albuminuria.
8. Subjects who are on both ARB and ACE-I.
9. Subjects with a persistent DBP <50 mmHg or an SBP <110 mmHg or
symptomatic and clinically significant hypotension at screening, Week -
4, Week -2 (i.e., 2 consecutive visits) or at baseline (Day 1 pre-dose).
10. Orthostatic hypotension defined as a >20 mmHg decrease in SBP
and/or >10 mmHg decrease in DBP associated with clinical
manifestations at screening.
11. ≥3 × upper limit of normal (ULN) aspartate aminotransferase (AST)
or alanine aminotransferase (ALT) at screening or Week -2.
12. Clinically significant abnormalities of the thyroid (hypo- or
hyperthyroidism measured by TSH, FT3 and FT4) at screening or Week -
2, or subjects on thyroxine replacement therapy.
13. Subjects with evidence of acute ischaemia on 12-lead ECG at
screening or baseline (Day 1 pre-dose).
14. Presence, history or known family history of long QT syndrome or
Torsades de Pointes.
15. History of clinically significant multiple or severe drug allergies,
allergy to MT-3995 or to any excipients (mannitol, carmellose calcium,
light anhydrous silicic acid, talc and magnesium stearate) in the MT-
3995 and matching placebo capsule.
16. Excessive consumption of food or drink containing high levels of
potassium such as orange juice, melon and bananas, defined by local
practice.
17. History of hospitalisation for hyperkalemia or AKI induced by
previous RAAS blocker treatment.
18. Subjects who are taking any of the prohibited drugs, supplements or
herbal remedies at screening or baseline (Day 1 pre-dose) (see Section
6.3.2). Any other medications will be allowed to continue unless in the
opinion of the Sponsor and the Investigator, the medication will
interfere with the objective of the study or compromise the subject's
safety.
19. Subjects who had general laser eye surgery 3 months prior to
baseline (Day 1 pre-dose) or plan general laser eye surgery during the
time the subject is expected to participate in the study.
20. Stroke, acute limb ischaemia, coronary and peripheral
revascularisation procedure or myocardial infarction in the 6 months
prior to baseline (Day 1 pre-dose).
21. Subjects with heart failure New York Heart Association Class III-IV
at screening.
22. Body mass index (BMI) >45 kg/m2 at screening.
23. Subjects who are suffering from any disease which, in the opinion of
the Investigator, is sufficiently severe to render the subject unfit, or
affect the subject's ability to participate in the study. Subjects with
evidence of any malignancy within the last 5 years prior to screening,
with the exception of history of basal cell skin cancer.
24. Subjects who participated in a clinical study of any IMP (other than
placebo) within 12 weeks (from last administration) prior to baseline
(Day 1 pre-dose) or who are currently participating in another clinical
study.
25. Presence or history (in the last 2 years) of alcohol abuse or
alcoholism.
26. Presence or history of drug abuse. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy endpoint:
-Within-group comparison of percentage change in first-morning UACR from baseline (median of three values on consecutive days prior to Day 1) to Week 8. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Various timepoints throughout the study - please refer to the detailed Time and Events Schedule in the protocol for full details |
|
| E.5.2 | Secondary end point(s) |
-Percentage change in first-morning UACR from
baseline (median of three values on consecutive days
prior to Day 1) to Week 8 compared to placebo.
-Change from baseline (Day 1 pre-dose) in sitting
SBP/DBP to Weeks 1, 2, 4, 6 and 8 within group. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Various timepoints throughout the study - please refer to the detailed Time and Events Schedule in the protocol for full details |
|
| 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 | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | 14 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 150 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| 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 | 2 |
| 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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