Clinical Trial Results:
A Randomised, Double-blind, Placebo-controlled Study to Evaluate the Effect on Urine Albumin-to-Creatinine Ratio (UACR), Pharmacodynamics, Safety, Tolerability and Pharmacokinetics of Multiple Oral Doses of MT-3995 as Add-on Therapy to ACE-I or ARB in Type II Diabetic Nephropathy Subjects with Albuminuria and an eGFR =>30-<60 mL/min/1.73m2

Trial information Top of page
Trial identification
Sponsor protocol code	MT-3995-E07
Additional study identifiers
ISRCTN number	-
US NCT number	NCT01756716
WHO universal trial number (UTN)	-
Sponsors
Sponsor organisation name	Mitsubishi Tanabe Pharma Corporation
Sponsor organisation address	17-10, Nihonbashi-Koamicho, Chuo-ku, Tokyo, Japan, 103-8405
Public contact	General Information, Mitsubishi Tanabe Pharma Europe Ltd., regulatory@mt-pharma-eu.com
Scientific contact	General Information, Mitsubishi Tanabe Pharma Europe Ltd., regulatory@mt-pharma-eu.com
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP)	No
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Results analysis stage
Analysis stage	Final
Date of interim/final analysis	11 Nov 2014
Is this the analysis of the primary completion data?	Yes
Primary completion date	15 Sep 2014
Global end of trial reached?	Yes
Global end of trial date	15 Sep 2014
Was the trial ended prematurely?	No
General information about the trial
Main objective of the trial	To evaluate the safety and tolerability of multiple oral doses of MT-3995 in subjects with Type II diabetic kidney disease with protein in urine.
Protection of trial subjects	Serum potassium algorithm AST/ALT liver function withdrawal criteria Serum creatinine withdrawal criteria
Background therapy	- ACE-I or ARB treatment for at least 12 weeks prior to screening - Stable dose of ACE-I or ARB from at least 4 weeks prior to screening until baseline visit and throughout the study period
Evidence for comparator	-
Actual start date of recruitment	07 Dec 2012
Long term follow-up planned	No
Independent data monitoring committee (IDMC) involvement?	Yes
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	Poland: 4
Country: Number of subjects enrolled	Slovakia: 11
Country: Number of subjects enrolled	Bulgaria: 9
Country: Number of subjects enrolled	Czech Republic: 8
Country: Number of subjects enrolled	Hungary: 12
Country: Number of subjects enrolled	Romania: 5
Worldwide total number of subjects	49
EEA total number of subjects	49
Number of subjects enrolled per age group
In utero	0
Preterm newborn - gestational age < 37 wk	0
Newborns (0-27 days)	0
Infants and toddlers (28 days-23 months)	0
Children (2-11 years)	0
Adolescents (12-17 years)	0
Adults (18-64 years)	27
From 65 to 84 years	22
85 years and over	0

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	49 subjects were randomised from 64 enrolling sites in Bulgaria, Czech Republic, Hungary, Poland, Romania and Slovakia. FSS was 07/12/2012; LSS was 18/04/14. FSR was 14/02/2013; LSR was 20/06/2014. The study was conducted in university/public/private hospitals and specialised diabetes/renal impairment care practices.
Pre-assignment
Screening details	317 subjects were screened in order to randomise 49 subjects. The screening period for each subject was 2 weeks.
Period 1
Period 1 title	Overall Trial (overall period)
Is this the baseline period?	Yes
Allocation method	Randomised - controlled
Blinding used	Double blind
Roles blinded	Subject, Investigator, Monitor, Data analyst
Blinding implementation details	UACR and PK laboratory results were not distributed to the sites in order to prevent potential unblinding. MT-3995/placebo capsules appeared the same and same number of capsules were given.
Arms
Are arms mutually exclusive	Yes
Arm title	Placebo
Arm description	Group 1: Placebo oral capsules matching MT-3995 from Day 1 to the end of the treatment period (Week 8).
Arm type	Placebo
Investigational medicinal product name	Placebo
Investigational medicinal product code	Placebo
Other name
Pharmaceutical forms	Capsule
Routes of administration	Oral use
Dosage and administration details	Placebo was matching the MT-3995 capsules in number and appearance.
Arm title	MT-3995 - 2.5 mg
Arm description	Group 2: 40 mg loading dose on Day 1 and 2.5 mg od maintenance dose from Day 2 (Week 1) to the end of the treatment period (Week 8).
Arm type	Experimental
Investigational medicinal product name	MT-3995
Investigational medicinal product code	MT-3995
Other name
Pharmaceutical forms	Capsule
Routes of administration	Oral use
Dosage and administration details	40 mg loading dose respectively on day 1 followed by 2.5 mg maintenance dose od from Day 2 until end of treatment period (Week 8).
Arm title	MT-3995 - 5 mg
Arm description	Group 3: 80 mg loading dose on Day 1 and 5 mg od maintenance dose from Day 2 (Week 1) to the end of the treatment period (Week 8).
Arm type	Experimental
Investigational medicinal product name	MT-3995
Investigational medicinal product code	MT-3995
Other name
Pharmaceutical forms	Capsule
Routes of administration	Oral use
Dosage and administration details	80 mg loading dose respectively on day 1 followed by 5 mg maintenance dose od from Day 2 until end of treatment period (Week 8).
Number of subjects in period 1 Placebo MT-3995 - 2.5 mg MT-3995 - 5 mg Started 16 17 16 Completed 14 14 14 Not completed 2 3 2      Adverse event, not serious 1 - -      Protocol specific reason 1 1 -      ACE-I dose increase during run-in - 1 -      Central serum potassium was high at baseline - 1 2

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	Placebo
Reporting group description	Group 1: Placebo oral capsules matching MT-3995 from Day 1 to the end of the treatment period (Week 8).
Reporting group title	MT-3995 - 2.5 mg
Reporting group description	Group 2: 40 mg loading dose on Day 1 and 2.5 mg od maintenance dose from Day 2 (Week 1) to the end of the treatment period (Week 8).
Reporting group title	MT-3995 - 5 mg
Reporting group description	Group 3: 80 mg loading dose on Day 1 and 5 mg od maintenance dose from Day 2 (Week 1) to the end of the treatment period (Week 8).
Reporting group values Placebo MT-3995 - 2.5 mg MT-3995 - 5 mg Total Number of subjects 16 17 16 49 Age categorical Units: Subjects     In utero 0 0 0 0     Preterm newborn infants (gestational age < 37 wks) 0 0 0 0     Newborns (0-27 days) 0 0 0 0     Infants and toddlers (28 days-23 months) 0 0 0 0     Children (2-11 years) 0 0 0 0     Adolescents (12-17 years) 0 0 0 0     Adults (18-64 years) 6 11 10 27     From 65-84 years 10 6 6 22     85 years and over 0 0 0 0 Age continuous Units: years     arithmetic mean (standard deviation) 66.4 ± 4.5 62.1 ± 7.1 60.4 ± 9.1 - Gender categorical Units: Subjects     Female 5 5 6 16     Male 11 12 10 33

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	Placebo
Reporting group description	Group 1: Placebo oral capsules matching MT-3995 from Day 1 to the end of the treatment period (Week 8).
Reporting group title	MT-3995 - 2.5 mg
Reporting group description	Group 2: 40 mg loading dose on Day 1 and 2.5 mg od maintenance dose from Day 2 (Week 1) to the end of the treatment period (Week 8).
Reporting group title	MT-3995 - 5 mg
Reporting group description	Group 3: 80 mg loading dose on Day 1 and 5 mg od maintenance dose from Day 2 (Week 1) to the end of the treatment period (Week 8).

End points Top of page

Primary: Not Applicable - none reported as safety is primary endpoint Top of page
End point title	Not Applicable - none reported as safety is primary endpoint [1]
End point description	No primary endpoints were defined for efficacy or PD variables. Safety was the primary endpoint.
End point type	Primary
End point timeframe	Not applicable
Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The primary endpoint was safety and the data are provided in the AE section.
End point values Placebo MT-3995 - 2.5 mg MT-3995 - 5 mg Number of subjects analysed 0 [2] 0 [3] 0 [4] Units: Not applicable
Notes [2] - Not applicable as the primary endpoint was safety and the data are provided in the AE section. [3] - Not applicable as the primary endpoint was safety and the data are provided in the AE section. [4] - Not applicable as the primary endpoint was safety and the data are provided in the AE section.
No statistical analyses for this end point

Primary: Not Applicable - none reported as safety is primary endpoint Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	Start of double-blind treatment to end of 8 week follow-up period. Treatment-Emergent AEs were defined as those which started or worsened in severity after the first dose of double-blind study medication.
Adverse event reporting additional description	During the study visits regular questioning of each subject by study staff. No leading questions were asked. Data recorded under "Non Serious Adverse Events" also includes serious adverse events.
Assessment type	Systematic
Dictionary used for adverse event reporting
Dictionary name	MedDRA
Dictionary version	17
Reporting groups
Reporting group title	Placebo
Reporting group description	Group 1: Placebo oral capsules matching MT-3995 from Day 1 to the end of the treatment period (Week 8).
Reporting group title	MT-3995 - 2.5 mg
Reporting group description	Group 2: 40 mg loading dose on Day 1 and 2.5 mg od maintenance dose from Day 2 (Week 1) to the end of the treatment period (Week 8).
Reporting group title	MT-3995 - 5 mg
Reporting group description	Group 3: 80 mg loading dose on Day 1 and 5 mg od maintenance dose from Day 2 (Week 1) to the end of the treatment period (Week 8) and 8 week follow up.
Serious adverse events Placebo MT-3995 - 2.5 mg MT-3995 - 5 mg Total subjects affected by serious adverse events      subjects affected / exposed 1 / 16 (6.25%) 0 / 17 (0.00%) 1 / 16 (6.25%)      number of deaths (all causes) 0 0 0      number of deaths resulting from adverse events 0 0 0 Cardiac disorders Acute myocardial infarction      subjects affected / exposed 1 / 16 (6.25%) 0 / 17 (0.00%) 0 / 16 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Blood and lymphatic system disorders Anaemia      subjects affected / exposed 0 / 16 (0.00%) 0 / 17 (0.00%) 1 / 16 (6.25%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Skin and subcutaneous tissue disorders Eczema      subjects affected / exposed 0 / 16 (0.00%) 0 / 17 (0.00%) 1 / 16 (6.25%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0
Frequency threshold for reporting non-serious adverse events: 0%
Non-serious adverse events Placebo MT-3995 - 2.5 mg MT-3995 - 5 mg Total subjects affected by non serious adverse events      subjects affected / exposed 5 / 16 (31.25%) 5 / 17 (29.41%) 3 / 16 (18.75%) Investigations Amylase increased      subjects affected / exposed 1 / 16 (6.25%) 0 / 17 (0.00%) 0 / 16 (0.00%)      occurrences all number 1 0 0 Blood creatine phosphokinase increased      subjects affected / exposed 0 / 16 (0.00%) 1 / 17 (5.88%) 0 / 16 (0.00%)      occurrences all number 0 1 0 Blood creatinine increased      subjects affected / exposed 0 / 16 (0.00%) 1 / 17 (5.88%) 0 / 16 (0.00%)      occurrences all number 0 1 0 Glomerular filtration rate decreased      subjects affected / exposed 0 / 16 (0.00%) 1 / 17 (5.88%) 0 / 16 (0.00%)      occurrences all number 0 1 0 Cardiac disorders Acute myocardial infarction      subjects affected / exposed 1 / 16 (6.25%) 0 / 17 (0.00%) 0 / 16 (0.00%)      occurrences all number 1 0 0 Angina pectoris      subjects affected / exposed 0 / 16 (0.00%) 1 / 17 (5.88%) 0 / 16 (0.00%)      occurrences all number 0 1 0 Arteriospasm coronary      subjects affected / exposed 0 / 16 (0.00%) 1 / 17 (5.88%) 0 / 16 (0.00%)      occurrences all number 0 1 0 Left ventricular hypertrophy      subjects affected / exposed 0 / 16 (0.00%) 1 / 17 (5.88%) 0 / 16 (0.00%)      occurrences all number 0 1 0 Myocardial ischaemia      subjects affected / exposed 0 / 16 (0.00%) 0 / 17 (0.00%) 1 / 16 (6.25%)      occurrences all number 0 0 1 Nervous system disorders Headache      subjects affected / exposed 0 / 16 (0.00%) 0 / 17 (0.00%) 1 / 16 (6.25%)      occurrences all number 0 0 1 General disorders and administration site conditions Chest pain      subjects affected / exposed 0 / 16 (0.00%) 1 / 17 (5.88%) 0 / 16 (0.00%)      occurrences all number 0 1 0 Oedema peripheral      subjects affected / exposed 1 / 16 (6.25%) 0 / 17 (0.00%) 0 / 16 (0.00%)      occurrences all number 1 0 0 Blood and lymphatic system disorders Anaemia      subjects affected / exposed 0 / 16 (0.00%) 0 / 17 (0.00%) 1 / 16 (6.25%)      occurrences all number 0 0 1 Gastrointestinal disorders Abdominal pain upper      subjects affected / exposed 1 / 16 (6.25%) 0 / 17 (0.00%) 0 / 16 (0.00%)      occurrences all number 1 0 0 Gastrointestinal sounds abnormal      subjects affected / exposed 1 / 16 (6.25%) 0 / 17 (0.00%) 0 / 16 (0.00%)      occurrences all number 1 0 0 Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease      subjects affected / exposed 1 / 16 (6.25%) 0 / 17 (0.00%) 0 / 16 (0.00%)      occurrences all number 1 0 0 Skin and subcutaneous tissue disorders Eczema      subjects affected / exposed 0 / 16 (0.00%) 0 / 17 (0.00%) 1 / 16 (6.25%)      occurrences all number 0 0 1 Erythema      subjects affected / exposed 1 / 16 (6.25%) 0 / 17 (0.00%) 0 / 16 (0.00%)      occurrences all number 1 0 0 Musculoskeletal and connective tissue disorders Muscle spasms      subjects affected / exposed 0 / 16 (0.00%) 1 / 17 (5.88%) 0 / 16 (0.00%)      occurrences all number 0 1 0 Neck pain      subjects affected / exposed 0 / 16 (0.00%) 0 / 17 (0.00%) 1 / 16 (6.25%)      occurrences all number 0 0 1 Tendon pain      subjects affected / exposed 0 / 16 (0.00%) 0 / 17 (0.00%) 1 / 16 (6.25%)      occurrences all number 0 0 1 Infections and infestations Nasopharyngitis      subjects affected / exposed 1 / 16 (6.25%) 0 / 17 (0.00%) 0 / 16 (0.00%)      occurrences all number 1 0 0 Urinary tract infection      subjects affected / exposed 1 / 16 (6.25%) 0 / 17 (0.00%) 0 / 16 (0.00%)      occurrences all number 1 0 0 Viral upper respiratory tract infection      subjects affected / exposed 0 / 16 (0.00%) 1 / 17 (5.88%) 0 / 16 (0.00%)      occurrences all number 0 1 0 Metabolism and nutrition disorders Hypertriglyceridaemia      subjects affected / exposed 0 / 16 (0.00%) 1 / 17 (5.88%) 0 / 16 (0.00%)      occurrences all number 0 1 0

Adverse events Top of page

More information Top of page
Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? Yes
Date	Amendment
10 Oct 2013	Reduced lower limit of UACR incl. criteria from 200 to 50 mg/g; error correction; further clarifications.
03 Jan 2014	Widening of eGRF incl. criteria from 30-60 to 27-62 mL/min/1.73m2; increase of > serum potassium incl. criteria from 5.0 to 5.2 mmol/L; error correction, further clarifications.
21 May 2014	Former primary UACR objective now secondary objective and safety & tolerability now primary obj.; sample size modified accordingly.
Interruptions (globally)
Were there any global interruptions to the trial? No
Limitations and caveats
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
None reported

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