Clinical Trial Results:
EFFECTS OF BENFOTIAMINE ON INTRAEPIDERMAL NERVE FIBER DENSITY (IENFD) AND DIABETIC NEUROPATHY IN SUBJECTS WITH SENSORIMOTOR DIABETIC POLYNEUROPATHY: A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, PARALLEL GROUP PILOT STUDY OVER 12 MONTHS
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Summary
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EudraCT number |
2013-001058-85 |
Trial protocol |
DE |
Global end of trial date |
07 Sep 2015
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Results information
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Results version number |
v1 |
This version publication date |
13 Dec 2016
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First version publication date |
13 Dec 2016
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Other versions |
v2 |
Summary report(s) |
Development Safety Update Report |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
WOE_2013_SB
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01868191 | ||
WHO universal trial number (UTN) |
U1111-1140-6958 | ||
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Sponsors
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Sponsor organisation name |
Woerwag Pharma GmbH & Co. KG
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Sponsor organisation address |
Calwer Strasse 7, Boeblingen, Germany, 71034
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Public contact |
Priv.-Doz. Dr. med. Ovidiu Alin Stirban, Himmelgeister Landstrasse 174
40589 Duesseldorf, Germany
, 0049 2191465140, stirban@web.de
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Scientific contact |
Priv.-Doz. Dr. med. Ovidiu Alin Stirban
, Himmelgeister Landstrasse 174
40589 Duesseldorf, Germany
, 0049 2191465140, stirban@web.de
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
19 Apr 2016
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
07 Sep 2015
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The aim of the present study was to assess before, as well as 6 and 12 months following a therapy with benfotiamine the influence of therapy on intraepidermal nerve fiber density (an early marker of nerve damage) in 22 people with type 1 or 2 diabetes mellitus and diabetic sensorimotor polyneuropathy.
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Protection of trial subjects |
The trial was not initiated before the protocol and all other relevant documents according to German GCP Ordinance had been reviewed, and received favourable opinion from the local Independent Ethics Committee (IEC) and approval by the Competent Authority, respectively.
Should a protocol amendment be made that needed IEC favourable opinion and/or authority approval, the changes in the protocol were not to be instituted until the amendment had been reviewed and received favourable opinion by the local IEC, and approval by the Competent Authority. A protocol amendment intended to eliminate an apparent immediate hazard to subjects could have been implemented immediately providing that the regulatory authority and IEC were notified as soon as possible and an approval would have been requested.
The constitution of the IEC met the requirements of ICH GCP and of the participating country. The IEC performed all duties outlined by the requirements of ICH GCP and of the participating country.
Prior to subject participation in the trial, written informed consent was obtained from each subject according to ICH GCP and to the regulatory and legal requirements of the participating country. Each signature was personally dated by each signatory and the informed consent and any additional subject information form retained by the investigator as part of the trial records. A signed copy of the informed consent and any additional subject information was given to each subject.
The subject was informed that his/her personal trial-related data would be used in accordance with the local data protection law. The level of disclosure was also explained to the subject.
The subject was informed that his / her medical records could be examined by authorised monitors or Clinical Quality Assurance auditors appointed by the sponsor, by appropriate IEC members, and by inspectors from regulatory authorities.
Should a protocol amendment become necessary, the subject
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Background therapy |
Benfotiamine 300 mg was approved on 23.06.2005 for the treatment or prophylaxis of clinical manifest vitamin B1 deficiency if a dietary supplementation is not effective. Though, benfotiamine is used for many years in the treatment of diabetic and alcoholic polyneuropathies. Clinical trials have been performed with benfotiamine for the treatment of diabetic polyneuropathy, alcoholic polyneuropathy, alleviation of endothelial dysfunction in subjects with type 2 diabetes or in healthy smokers and treatment of diabetic nephropathy. Study durations were up to 2 years at a dose of 300 mg/day and the highest doses were 1050 mg for 3 days and 900 mg/day administered for 12 weeks. | ||
Evidence for comparator |
Placebo tablets were provided in a blinded manner by the Sponsor for the 12 months therapy. | ||
Actual start date of recruitment |
30 Apr 2013
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Germany: 22
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Worldwide total number of subjects |
22
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EEA total number of subjects |
22
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
16
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From 65 to 84 years |
6
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85 years and over |
0
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Recruitment
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Recruitment details |
Subjects were recruited from the patients of the Diabetes Schwerpunktpraxis Essen (Camillo-Sitte Platz 1, 45136 Essen) and all study-related activities took place there. | |||||||||
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Pre-assignment
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Screening details |
It was planned that 22 participants with T1DM or T2DM on a stable regimen of antidiabetic treatment with no possibility of therapy intensification, with DSP, between 18 and 75 years of age, with a BMI between 25 and 45 kg/m2, HbA1c ≤9.5 % will be randomized, ensuring 18 completers (at least 9 in each group) at 6 months. | |||||||||
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Period 1
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Period 1 title |
Duration of study participation (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||
Roles blinded |
Subject, Investigator, Monitor | |||||||||
Blinding implementation details |
The medication was provided in a blinded manner by the Sponsor for the 12 months therapy, along with emergency envelops for unblinding single participants.
Tablets packaged:
Benfotiamin 300 mg: 1 tablet
Placebo : 1 tablet
Approximately 13.5 months (12.5-15 months), including 5 ambulatory and 3
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Group 1 | |||||||||
Arm description |
Benfotiamine 600 mg/day for 3 months followed by benfotiamine 300 mg/day for the rest of the study duration | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Benfotiamine 300 mg
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
The recommended daily dose for the treatment of neuropathies is 300 mg, but doses as high as 900 mg/day have been given for 3 months and doses of 300 mg/day for 2 years. Therefore it was decided to administer 600 mg/day for 3 months and decrease the dose to 300 mg/day for the next 9 months.
Study medication was administered in a blinded manner. The first administration was undertaken by subjects on an outpatient basis in the morning of day 2 after being instructed with regard to the procedure and receiving the medication at Visit 2 (day 1), Visit 3 (day 91±7) for the next at least 100 days (3 months + 1 week) and at Visit 5 (day 181±7) for the next 6 months and 1 week. The medication was taken as one tablet in the morning and one in the evening (before meals) until Visit 3 (600 mg/day) and one tablet in the morning afterwards (300 mg/day).
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Arm title
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Group 2 | |||||||||
Arm description |
Placebo | |||||||||
Arm type |
Placebo | |||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Placebo (identical appearance to benfotiamine)
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Baseline characteristics reporting groups
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Reporting group title |
Duration of study participation
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Group 1
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Reporting group description |
Benfotiamine 600 mg/day for 3 months followed by benfotiamine 300 mg/day for the rest of the study duration | ||
Reporting group title |
Group 2
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Reporting group description |
Placebo | ||
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End point title |
Primary | |||||||||
End point description |
Change from baseline in IENFD after 6 months of benfotiamine treatment compared to placebo.
Change from baseline in IENFD after 12 months of benfotiamine treatment compared to placebo.
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End point type |
Primary
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End point timeframe |
Study participation
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Statistical analysis title |
Double blinded | |||||||||
Comparison groups |
Group 1 v Group 2
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Number of subjects included in analysis |
22
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
< 0.05 | |||||||||
Method |
Chi-squared | |||||||||
Parameter type |
Mean difference (final values) | |||||||||
Point estimate |
2
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Confidence interval |
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95% | |||||||||
sides |
2-sided
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lower limit |
1 | |||||||||
upper limit |
2 | |||||||||
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End point title |
Secondary Pharmacodynamic | ||||||||||||
End point description |
Change from baseline in MNSI questionnaire after 6 months of benfotiamine treatment compared to placebo.
Change from baseline in MNSI examination after 6 months of benfotiamine treatment compared to placebo
Change from baseline in MNSI questionnaire after 12 months of benfotiamine treatment compared to placebo.
Change from baseline in MNSI examination after 12 months of benfotiamine treatment compared to placebo.
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End point type |
Secondary
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End point timeframe |
Study participation
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Secondary Pharmacokinetic | ||||||||||||
End point description |
Change from baseline in plasma thiamine concentration after 6 months of benfotiamine treatment compared to placebo
Change from baseline in plasma thiamine concentration after 12 months of benfotiamine treatment compared to placebo
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End point type |
Secondary
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End point timeframe |
Study participation
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Safety | |||||||||
End point description |
Adverse events
Laboratory safety variables
Physical examination
Vital signs
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End point type |
Other pre-specified
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End point timeframe |
Study participation
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| No statistical analyses for this end point | ||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
The investigator was to submit all SUSARs that occur during the period of observation (from the time the informed consent form is signed until the Follow-up visit), to the Sponsor within 24 hours. The Sponsor was to report within 15 days electronically.
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Adverse event reporting additional description |
7 days after initial report from the investigator and the follow up report will be submitted maximum 8 days later via the notification form. Life threatening SUSARs or such that led to death were to be reported within 7 days.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
4
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Reporting groups
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Reporting group title |
Adverse Events
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Reporting group description |
AEs were collected from the subject enrolment until the last visit. Concomitant illnesses, which existed prior to entry into the clinical study, were not considered AEs unless they increased in frequency or severity, or worsen in nature during the treatment period. Medical occurrences prior to randomisation but after obtaining informed consent were recorded on the Medical History/Current Medical Conditions CRF. The cannula inserted in a forearm vein for the collection of blood samples could have lead to superficial irritation of the vein. This was appropriately treated by the study staff and not reported as an AE in the clinical study report. Skin biopsy could have led to bleeding, local infections, and wound healing or sensitivity disturbances. These will be recorder as AEs. An AE that meets serious criteria should be recorded both on the AE Report Form and on the Serious Adverse Event Report Form. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
