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Clinical Trial Results:
SUPREMES - Sunphenon in progressive forms of multiple sclerosis

Summary
EudraCT number	2008-005213-22
Trial protocol	DE
Global end of trial date	02 Mar 2016

Results information
Results version number	v1(current)
This version publication date	23 Dec 2021
First version publication date	23 Dec 2021
Other versions
Summary report(s)	supremes_result_report

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

SUPREMES-01

ISRCTN number

US NCT number

NCT00799890

WHO universal trial number (UTN)

Sponsor organisation name

Charité- Universitätsmedizin Berlin

Sponsor organisation address

Charitéplatz 1, Berlin, Germany, 10117

Public contact

Prof. Friedemann Paul, Charité - NeuroCure Clinical Research Center Charitéplatz 1, 10117 Berlin, +49 30 450639705, friedemann.paul@charite.de

Scientific contact

Prof. Friedemann Paul , Charité - NeuroCure Clinical Research Center Charitéplatz 1, 10117 Berlin, +49 30 450639705, friedemann.paul@charite.de

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

10 May 2019

Is this the analysis of the primary completion data?

Yes

Primary completion date

02 Mar 2016

Global end of trial reached?

Yes

Global end of trial date

02 Mar 2016

Was the trial ended prematurely?

Main objective of the trial

To evaluate efficacy and safety of Sunphenon EGCg in progressive forms of multiple sclerosis after a 36 months treatment compared to the placebo-group, primary outcome criteria being reduction of Brain Parenchymal Fraction (atrophy)

Protection of trial subjects

Safety: Vital signs, Physical examination, ECG, laboratory tests, occurence of (severe) adverse events in both arm and for more parameter see manuscript

Background therapy

Evidence for comparator

Actual start date of recruitment

08 May 2009

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 61

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Start: 08.05.2009; End: 08.05.2012; Subjects assessed of eligibility (screening) = 79; Screening failure =8; Subjects declined to participants = 10;

Screening details

Eligibility criteria comprised fulfillment of the revised McDonald criteria for MS and the diagnosis of PPMS or SPMS, Expanded Diability Status Scale score of 3 to 8 and relapse-free period of at least 30 days before randomization. Exclusion criteria were relapsing-remitting from MS, a major systemic or CNS disease, laboratory abnormalities.

Period 1 title

Baseline to 36 months

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Control placebo group

Arm description

Subjects treated with Placebo

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Subjects received placebo (identical with study drug apart from active ingredient)

EGCG

Arm description

Subjects treated with Sunphenon

Arm type

Experimental

Investigational medicinal product name

Sunphenon

Investigational medicinal product code

Other name

Sunphenon EGCg

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Subjects received 0-3 month: 200mg daily (1x in the morning), after 3 to 6 months: 400mg (2x 200mg times daily), after 6 to 18 months: 600 mg daily (400 mg in the morning, 200mg in the evening), after 18 to 30 months: 800 mg (2x 400mg times daily) and after 30 to 36 month: 1200 mg (3x 400 mg times daily)

Number of subjects in period 1	Control placebo group	EGCG
Started	31	30
Completed	19	18
Not completed	12	12
Adverse event, non-fatal	-	3
personal reasons	10	5
non-compliance	-	2
Protocol deviation	2	2

Period 2 title

open-label extension

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Control placebo group with EGCG

Arm description

Patients initially treated with placebo, started with EGCG in the 12 month open label extension

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

treatment starts with daily 1x 200mg capsule(1-0-0). After 3 months to 400mg daily (2x200mg, 2-0-0). After 6 months to 600mg (3x1 200mg capsules, 2-0-1). After 18 months to 800mg (2x2 200mg capsules, 2-0-2). After 30 months to 1200mg daily ( 3x2 200mg, 2-2-2)

Investigational medicinal product name

Sunphenon Epigallocatechin-3-Gallte (EGCG

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Ocular use

Dosage and administration details

Patients initially treated with placebo who decided to participate in the 12 moth open-label extension started treatment with EGCG capsules 200 mg daily (1x 200mg in the morning) and escalated every 2 weeks for 200mg, reaching 1200mg after 10 weeks (3 times daily 2 capsules with 200mg each).

EGCG+OE

Arm description

Continue 1200mg daily treatment for 12 months

Arm type

Experimental

Investigational medicinal product name

Sunphenon

Investigational medicinal product code

Other name

Sunphenon EGCg

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Sunphenon Eigallocatechin-3-Gallate (EGCG). Sunphenon EGCG capsules 200mg daily ( 1x 200mg, 1-0-0). They were escalated after 3 months to 400mg daily (2x 200mg, 2-0-0). After 6 months to 600mg daily (3x1 200mg, 2-0-1),after 18 months to 800mg daily (4x400mg, 2-0-2), after 30months to 1200mg daily (6x200mg, 2-2-2) until the end of the study at 36 month. For the patients treated with EGCG the dosage was maintained also in the open label extension until month 48 if they participated.

Number of subjects in period 2	Control placebo group with EGCG	EGCG+OE
Started	19	18
Completed	15	17
Not completed	4	1
Physician decision	2	-
personal reasons	2	1

Baseline characteristics

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Reporting group title

Control placebo group

Reporting group description

Subjects treated with Placebo

Reporting group title

EGCG

Reporting group description

Subjects treated with Sunphenon

Reporting group values	Control placebo group	EGCG	Total
Number of subjects	31	30	61
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	31	30	61
From 65-84 years	0	0	0
85 years and over	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	48.84 ± 7.56	49.50 ± 7.70	-
Gender categorical
Units: Subjects
Women	13	14	27
Men	18	16	34
disease type
Diagnosis: Secondary progressive multiple sclerosis (SPMS) primary progressive multiple sclerosis (PPMS)
Units: Subjects
PPMS	12	11	23
SPMS	19	19	38
Expanded Disability Status Scale
Units: Score
median (inter-quartile range (Q1-Q3))	6 (3.0 to 7.0)	6 (3.0 to 6.0)	-
Expanded Disability Status Scale
Units: Score
arithmetic mean (standard deviation)	5.29 ± 1.2	5.5 ± 1.3	-
Disease duration
Units: year
arithmetic mean (standard deviation)	9.42 ± 6.18	11.08 ± 8.98	-
Duration of Progression
Units: years
arithmetic mean (standard deviation)	5.05 ± 3.66	6.48 ± 5.13	-
MSFC Z-score
Multiple Sclerosis Functional Composite
Units: score
arithmetic mean (standard deviation)	0.01 ± 0.64	0.15 ± 0.58	-
PASAT
Paced Auditory Serial Addition Test
Units: Score
arithmetic mean (standard deviation)	42.23 ± 12.53	43.30 ± 11.90	-
TWT average speed
Timed 25-Foot Walk Test
Units: seconds
arithmetic mean (standard deviation)	11.72 ± 11.73	12.65 ± 8.74	-
9-HPT average
9-Hole-Peg Test
Units: seconds
arithmetic mean (standard deviation)	30.90 ± 9.95	30.53 ± 14.25	-
Brain parenchymal fraction
BPF
Units: Score
arithmetic mean (standard deviation)	0.7008 ± 0.0415	0.7067 ± 0.0571	-
CEL count
Contrast enhancing lesions
Units: Count
arithmetic mean (standard deviation)	0.48 ± 2.00	0.25 ± 0.52	-
CEL volume
Contrast enhancing lesions
Units: ml
arithmetic mean (standard deviation)	0.05 ± 0.07	0.05 ± 0.05	-
T2w lesion count
Units: count
arithmetic mean (standard deviation)	44.19 ± 26.97	41.30 ± 22.29	-
T2w lesion volume
Units: ml
arithmetic mean (standard deviation)	15.64 ± 14.46	18.42 ± 17.07	-

End points

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Reporting group title

Control placebo group

Reporting group description

Subjects treated with Placebo

Reporting group title

EGCG

Reporting group description

Subjects treated with Sunphenon

Reporting group title

Control placebo group with EGCG

Reporting group description

Patients initially treated with placebo, started with EGCG in the 12 month open label extension

Reporting group title

EGCG+OE

Reporting group description

Continue 1200mg daily treatment for 12 months

Primary: Brain parenchymal fraction change from baseline to month 36

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End point title

Brain parenchymal fraction change from baseline to month 36

End point description

Decrease in brain volume, brain parenchymal fraction (BPF) after 36 months

End point type

Primary

End point timeframe

From baseline to month 36

End point values	Control placebo group	EGCG
Number of subjects analysed	19	19
Units: percentage, volume
arithmetic mean (standard deviation)
BPF	0.6867 ± 0.0439	0.6943 ± 0.0502
change from baseline	0.0078 ± 0.0159	0.0092 ± 0.0152
Percent brain volume	-0.8013 ± 1.1996	-0.5659 ± 0.9818

Mann-Whitney test

Statistical analysis description

The primary end point was the change of BPF from baseline to month 36

Comparison groups

EGCG v Control placebo group

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

< 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: Expanded Disability Status Scale

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End point title

Expanded Disability Status Scale

End point description

Secondary clinical outcome measurments were disability progression as measured by EDSS and confirmed progression (CDP) defined as a 1-point increase in the EDSS if the baselinbe score was 3.0-5.5, or 0.5-point increase if the baseline score was 6.0 and above, confirmed at a scheduled visit 6 months later.

End point type

Secondary

End point timeframe

from baseline to month 36

End point values	Control placebo group	EGCG
Number of subjects analysed	19	19
Units: Score	20	19

No statistical analyses for this end point

Secondary: EDSS Month 36

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End point title

EDSS Month 36

End point description

End point type

Secondary

End point timeframe

36 months

End point values	Control placebo group	EGCG
Number of subjects analysed	19	19
Units: score
arithmetic mean (full range (min-max))
Median	5.73 (3.5 to 8.0)	6.08 (3.0 to 8.0)

No statistical analyses for this end point

Secondary: EDSS Change from baseline

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End point title

EDSS Change from baseline

End point description

End point type

Secondary

End point timeframe

36 months

End point values	Control placebo group	EGCG
Number of subjects analysed	19	19
Units: score
arithmetic mean (standard deviation)
change	0.5750 ± 0.9904	0.2631 ± 0.4524

No statistical analyses for this end point

Secondary: T2w and CE lesions

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End point title

T2w and CE lesions

End point description

End point type

Secondary

End point timeframe

36 months

End point values	Control placebo group	EGCG
Number of subjects analysed	19	19
Units: volume
arithmetic mean (standard deviation)
Number of T2w-lesions	39.32 ± 19.28	35.21 ± 16.84
T2w-lesions chane from baselin	3.7894 ± 4.8828	1.5263 ± 4.2343
Volume of T2w-lesions (ml)	16.9076 ± 17.2964	17.5741 ± 16.4686
T2w-lesions change from baseline (ml)	0.5243 ± 2.3606	1.0439 ± 1.4783
Number of CEL	0.13 ± 0.342	0.00 ± 0.00
Volume of CEL (CEL)	0.0029 ± 0.0096	0.00 ± 0.00

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

day of assesment to month 36

Adverse event reporting additional description

None of the SAEs were considered related to the study drug. All occurred due to hospitalization of the study participants for various reasons (Table 3 of the report). The most common AEs were flu-like infections, urinary tract infections, fractures and contusions after all and elevated enzymes.

Assessment type

Systematic

Dictionary name

own

Dictionary version

Reporting group title

EGCG

Reporting group description

see manuscript page 11

Reporting group title

Placebo

Reporting group description

Serious adverse events	EGCG	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	11 / 30 (36.67%)	11 / 31 (35.48%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Injury, poisoning and procedural complications
Fracture
subjects affected / exposed	3 / 30 (10.00%)	3 / 31 (9.68%)
occurrences causally related to treatment / all	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Fall with headache
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 30 (3.33%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Vascular fragility
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 30 (3.33%)	1 / 31 (3.23%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Surgery
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 30 (0.00%)	2 / 31 (6.45%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Nervous system disorder
subjects affected / exposed	6 / 30 (20.00%)	4 / 31 (12.90%)
occurrences causally related to treatment / all	0 / 6	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Multiocular pain syndrom
subjects affected / exposed	2 / 30 (6.67%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Micturition dysfunction
subjects affected / exposed	2 / 30 (6.67%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Bronchopneumonia
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 30 (3.33%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Injection Abscess
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 30 (0.00%)	1 / 31 (3.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 3%

Non-serious adverse events	EGCG	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	29 / 30 (96.67%)	28 / 31 (90.32%)
Investigations
Overall
Additional description: The common AEs (>3%) was smiliar in both groups. The most common AEs were flu like infections, urinary tract infections, fracture and contusions after fall and elevated liver enzymes, for which there was no statistical difference between the groups.
subjects affected / exposed	29 / 30 (96.67%)	28 / 31 (90.32%)
occurrences all number	1	1

More information

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Were there any global substantial amendments to the protocol? Yes

28 Sep 2011

The study was initially planned as double-blind pilot study with recalculation of sample size with a total of 60 patients. At the end of the blinded phase ( afther 36 month of study), the unblinded recalculation of sample size, was not carried out a continuation of the study did not seem realistic die to recruitment problems.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
SUPREMES - Sunphenon in progressive forms of multiple sclerosis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Brain parenchymal fraction change from baseline to month 36

Primary: Brain parenchymal fraction change from baseline to month 36

Secondary: Expanded Disability Status Scale

Secondary: Expanded Disability Status Scale

Secondary: EDSS Month 36

Secondary: EDSS Month 36

Secondary: EDSS Change from baseline

Secondary: EDSS Change from baseline

Secondary: T2w and CE lesions

Secondary: T2w and CE lesions

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: SUPREMES - Sunphenon in progressive forms of multiple sclerosis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Brain parenchymal fraction change from baseline to month 36

Primary: Brain parenchymal fraction change from baseline to month 36

Secondary: Expanded Disability Status Scale

Secondary: Expanded Disability Status Scale

Secondary: EDSS Month 36

Secondary: EDSS Month 36

Secondary: EDSS Change from baseline

Secondary: EDSS Change from baseline

Secondary: T2w and CE lesions

Secondary: T2w and CE lesions

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
SUPREMES - Sunphenon in progressive forms of multiple sclerosis