Polyphenon E, non-futile at neuroprotection in multiple sclerosis but unpredictably hepatotoxic

Phase I single group and phase II randomized placebo-controlled studies

Jesus Lovera, Alexander Ramos, Deidre Devier, Virginia Garrison, Blake Kovner, Tara Reza, Dennis Koop, William Rooney, Anne Foundas, Dennis Bourdette

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

OBJECTIVES: Phase I (PhI): assess the safety of Polyphenon E in people with multiple sclerosis (MS) and determine the futility of Polyphenon E as a neuroprotective agent. Correlate plasma levels of EGCG with neuroprotective effects. Phase II (PhII): Further assess safety and confirm the neuroprotective effects of Polyphenon E.

DESIGN: PhI: single group futility study. PhII: parallel group randomized double-blind placebo-controlled study.

PARTICIPANTS: Recruitment area (both studies): LSU MS Center, New Orleans, LA and general public from surrounding areas. Inclusion criteria (both studies): 1) MS per 2005 McDonald criteria; 2) relapsing remitting or secondary progressive MS; 3) stable for six months prior to enrollment on either no therapy or glatiramer acetate (GA) for the PhI study and on either on GA or Interferon β for the PhII study. Exclusion criteria (both studies): 1) complete bone marrow ablation or alentuzumab use at any time; 2) mitoxantrone, cyclophosphamide, natalizumab or fingolimod use in the prior nine months; 3) liver problems or significant medical problems.

INTERVENTIONS: PhI: Polyphenon E, a green tea extract containing 50% of the antioxidant Epigallocatechin-gallate (EGCG), two capsules twice daily (200mg of EGCG per capsule; total daily dose 800mg) for six months. PhII: Polyphenon E or matching placebo capsules, same dose for one year. Only the research pharmacist knew treatment assignment and she randomized participants (one-to-one, stratified by GA or Interferon β, blocks of 4 or 6). Outcome evaluators did not discuss side effects with participants.

OUTCOME MEASURES: PhI: 1) adverse events (AE); 2) futility: decrease in N-acetyl aspartate (NAA) from baseline to six months of 10% or more; 3) association between EGCG plasma levels and change in NAA. PhII: 1) AEs; 2) difference in the rate of change of NAA-levels over twelve months.We measured NAA using a point resolved magnetic resonance spectroscopic imaging sequence (TE30/TR2000) on a 10cm×10cm×1cm volume of interest (VOI) located just superior to the lateral ventricles. The field of view was 16×16 resulting in 1cm(3) voxels. We quantified NAA and creatine/phosphocreatine (Cr) levels using LCModel for post-processing.

RESULTS: PhI: Ten participants enrolled and completed all assessments with no serious AEs. One discontinued therapy due to grade (G) I abnormal liver function tests (LFTs). We included all participants in the analysis. NAA adjusted for creatine increased by 10% [95% CI(3.4%,16.2%), p<0.01] rejecting the futility endpoint. PhII: Thirteen participants enrolled and twelve started treatment. The DSMB stopped the study because 5/7 participants on Polyphenon E had abnormal LFTs (G I, and 1G III). Median time to onset of abnormal LFTs was 20 weeks [Inter-Quartile Range (IQR) (10,23)]. Only two participants completed the six-month visit, so we could not analyze the NAA levels. PhI participants took capsules from lot 189I1107 while 6/7 PhII participants took capsules from a new lot (L0206306). Both lots had similar levels of EGCG but differed in the levels of minor catechins. There were no significant differences between the lots on participants' median free EGCG plasma levels at either 3h or 8h as well as conjugated EGCG levels at 3h (all p>0.4, Wilcoxon exact test). Free EGCG levels at 8h correlated with changes in NAA adjusted by water content. A 1ng/ml higher EGCG plasma concentration correlated with a 0.9% increase in NAA[95% CI(0.5%,1.4%), visit*level interaction F=14.4, p<0.001]. However, EGCG plasma concentrations did not correlate with NAA adjusted by creatine (1ng/ml higher EGCG was associated with 0.02%,[95% CI(-0.27%,0.3%) change in NAA, p>0.5]). There was a trend towards an increase in creatine levels (referenced to water content) from baseline to exit (1 5% increase, [95% CI(-6%,17%), p=0.4]). The free EGCG levels at 8hours correlated significantly with change in creatine levels (1ng/ml higher EGCG level at 8h was associated with a 1.1% increase in creatine [95% CI(0.6%,1.6%)]). Thus it is possible that the discrepancy between the correlation of the EGCG 8h levels with NAA changes referenced to water and the 8h EGCG levels with NAA changes referenced to creatine was due to a change in creatine among the subjects with higher EGCG levels. Conjugated 3h and 8h levels and free 3h levels did not correlate with NAA changes (all p >0.5).

CONCLUSIONS/CLASSIFICATION OF EVIDENCE: Class III evidence: Polyphenon E at a dose of 400mg of EGCG twice a day is not futile at increasing brain NAA levels. Class I evidence: some lots of Polyphenon E have a high risk of hepatotoxicity.

FUNDING: National Center for Complementary and Alternative Medicine K23AT004433, National Multiple Sclerosis Society RG4816-A-1 and National Institute of General Medical Sciences 1 U54 GM104940. Mitsui Norin provided Polyphenon E and placebo and their representative reviewed the manuscript prior to publication. Mitsui Norin was not involved in other aspects of the study. The decision to submit the manuscript remained with the investigators.

REGISTRATION: NCT00836719 and NCT01451723

Original languageEnglish (US)
Pages (from-to)46-52
Number of pages7
JournalJournal of the Neurological Sciences
Volume358
Issue number1-2
DOIs
StatePublished - Nov 15 2015

Fingerprint

Multiple Sclerosis
Placebos
Creatine
Medical Futility
Neuroprotective Agents
Capsules
Manuscripts
Interferons
National Institute of General Medical Sciences (U.S.)
N-acetylaspartate
polyphenon E
Neuroprotection
epigallocatechin gallate
Water
Chronic Progressive Multiple Sclerosis
Safety
Mitoxantrone
Phosphocreatine
Lateral Ventricles
Liver Function Tests

Keywords

  • EGCG
  • Green tea
  • Hepatotoxicity
  • Liver toxicity
  • Magnetic resonance spectroscopy
  • Multiple sclerosis
  • N-acetyl-aspartate
  • Polyphenon E

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Polyphenon E, non-futile at neuroprotection in multiple sclerosis but unpredictably hepatotoxic : Phase I single group and phase II randomized placebo-controlled studies. / Lovera, Jesus; Ramos, Alexander; Devier, Deidre; Garrison, Virginia; Kovner, Blake; Reza, Tara; Koop, Dennis; Rooney, William; Foundas, Anne; Bourdette, Dennis.

In: Journal of the Neurological Sciences, Vol. 358, No. 1-2, 15.11.2015, p. 46-52.

Research output: Contribution to journalArticle

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title = "Polyphenon E, non-futile at neuroprotection in multiple sclerosis but unpredictably hepatotoxic: Phase I single group and phase II randomized placebo-controlled studies",
abstract = "OBJECTIVES: Phase I (PhI): assess the safety of Polyphenon E in people with multiple sclerosis (MS) and determine the futility of Polyphenon E as a neuroprotective agent. Correlate plasma levels of EGCG with neuroprotective effects. Phase II (PhII): Further assess safety and confirm the neuroprotective effects of Polyphenon E.DESIGN: PhI: single group futility study. PhII: parallel group randomized double-blind placebo-controlled study.PARTICIPANTS: Recruitment area (both studies): LSU MS Center, New Orleans, LA and general public from surrounding areas. Inclusion criteria (both studies): 1) MS per 2005 McDonald criteria; 2) relapsing remitting or secondary progressive MS; 3) stable for six months prior to enrollment on either no therapy or glatiramer acetate (GA) for the PhI study and on either on GA or Interferon β for the PhII study. Exclusion criteria (both studies): 1) complete bone marrow ablation or alentuzumab use at any time; 2) mitoxantrone, cyclophosphamide, natalizumab or fingolimod use in the prior nine months; 3) liver problems or significant medical problems.INTERVENTIONS: PhI: Polyphenon E, a green tea extract containing 50{\%} of the antioxidant Epigallocatechin-gallate (EGCG), two capsules twice daily (200mg of EGCG per capsule; total daily dose 800mg) for six months. PhII: Polyphenon E or matching placebo capsules, same dose for one year. Only the research pharmacist knew treatment assignment and she randomized participants (one-to-one, stratified by GA or Interferon β, blocks of 4 or 6). Outcome evaluators did not discuss side effects with participants.OUTCOME MEASURES: PhI: 1) adverse events (AE); 2) futility: decrease in N-acetyl aspartate (NAA) from baseline to six months of 10{\%} or more; 3) association between EGCG plasma levels and change in NAA. PhII: 1) AEs; 2) difference in the rate of change of NAA-levels over twelve months.We measured NAA using a point resolved magnetic resonance spectroscopic imaging sequence (TE30/TR2000) on a 10cm×10cm×1cm volume of interest (VOI) located just superior to the lateral ventricles. The field of view was 16×16 resulting in 1cm(3) voxels. We quantified NAA and creatine/phosphocreatine (Cr) levels using LCModel for post-processing.RESULTS: PhI: Ten participants enrolled and completed all assessments with no serious AEs. One discontinued therapy due to grade (G) I abnormal liver function tests (LFTs). We included all participants in the analysis. NAA adjusted for creatine increased by 10{\%} [95{\%} CI(3.4{\%},16.2{\%}), p<0.01] rejecting the futility endpoint. PhII: Thirteen participants enrolled and twelve started treatment. The DSMB stopped the study because 5/7 participants on Polyphenon E had abnormal LFTs (G I, and 1G III). Median time to onset of abnormal LFTs was 20 weeks [Inter-Quartile Range (IQR) (10,23)]. Only two participants completed the six-month visit, so we could not analyze the NAA levels. PhI participants took capsules from lot 189I1107 while 6/7 PhII participants took capsules from a new lot (L0206306). Both lots had similar levels of EGCG but differed in the levels of minor catechins. There were no significant differences between the lots on participants' median free EGCG plasma levels at either 3h or 8h as well as conjugated EGCG levels at 3h (all p>0.4, Wilcoxon exact test). Free EGCG levels at 8h correlated with changes in NAA adjusted by water content. A 1ng/ml higher EGCG plasma concentration correlated with a 0.9{\%} increase in NAA[95{\%} CI(0.5{\%},1.4{\%}), visit*level interaction F=14.4, p<0.001]. However, EGCG plasma concentrations did not correlate with NAA adjusted by creatine (1ng/ml higher EGCG was associated with 0.02{\%},[95{\%} CI(-0.27{\%},0.3{\%}) change in NAA, p>0.5]). There was a trend towards an increase in creatine levels (referenced to water content) from baseline to exit (1 5{\%} increase, [95{\%} CI(-6{\%},17{\%}), p=0.4]). The free EGCG levels at 8hours correlated significantly with change in creatine levels (1ng/ml higher EGCG level at 8h was associated with a 1.1{\%} increase in creatine [95{\%} CI(0.6{\%},1.6{\%})]). Thus it is possible that the discrepancy between the correlation of the EGCG 8h levels with NAA changes referenced to water and the 8h EGCG levels with NAA changes referenced to creatine was due to a change in creatine among the subjects with higher EGCG levels. Conjugated 3h and 8h levels and free 3h levels did not correlate with NAA changes (all p >0.5).CONCLUSIONS/CLASSIFICATION OF EVIDENCE: Class III evidence: Polyphenon E at a dose of 400mg of EGCG twice a day is not futile at increasing brain NAA levels. Class I evidence: some lots of Polyphenon E have a high risk of hepatotoxicity.FUNDING: National Center for Complementary and Alternative Medicine K23AT004433, National Multiple Sclerosis Society RG4816-A-1 and National Institute of General Medical Sciences 1 U54 GM104940. Mitsui Norin provided Polyphenon E and placebo and their representative reviewed the manuscript prior to publication. Mitsui Norin was not involved in other aspects of the study. The decision to submit the manuscript remained with the investigators.REGISTRATION: NCT00836719 and NCT01451723",
keywords = "EGCG, Green tea, Hepatotoxicity, Liver toxicity, Magnetic resonance spectroscopy, Multiple sclerosis, N-acetyl-aspartate, Polyphenon E",
author = "Jesus Lovera and Alexander Ramos and Deidre Devier and Virginia Garrison and Blake Kovner and Tara Reza and Dennis Koop and William Rooney and Anne Foundas and Dennis Bourdette",
year = "2015",
month = "11",
day = "15",
doi = "10.1016/j.jns.2015.08.006",
language = "English (US)",
volume = "358",
pages = "46--52",
journal = "Journal of the Neurological Sciences",
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TY - JOUR

T1 - Polyphenon E, non-futile at neuroprotection in multiple sclerosis but unpredictably hepatotoxic

T2 - Phase I single group and phase II randomized placebo-controlled studies

AU - Lovera, Jesus

AU - Ramos, Alexander

AU - Devier, Deidre

AU - Garrison, Virginia

AU - Kovner, Blake

AU - Reza, Tara

AU - Koop, Dennis

AU - Rooney, William

AU - Foundas, Anne

AU - Bourdette, Dennis

PY - 2015/11/15

Y1 - 2015/11/15

N2 - OBJECTIVES: Phase I (PhI): assess the safety of Polyphenon E in people with multiple sclerosis (MS) and determine the futility of Polyphenon E as a neuroprotective agent. Correlate plasma levels of EGCG with neuroprotective effects. Phase II (PhII): Further assess safety and confirm the neuroprotective effects of Polyphenon E.DESIGN: PhI: single group futility study. PhII: parallel group randomized double-blind placebo-controlled study.PARTICIPANTS: Recruitment area (both studies): LSU MS Center, New Orleans, LA and general public from surrounding areas. Inclusion criteria (both studies): 1) MS per 2005 McDonald criteria; 2) relapsing remitting or secondary progressive MS; 3) stable for six months prior to enrollment on either no therapy or glatiramer acetate (GA) for the PhI study and on either on GA or Interferon β for the PhII study. Exclusion criteria (both studies): 1) complete bone marrow ablation or alentuzumab use at any time; 2) mitoxantrone, cyclophosphamide, natalizumab or fingolimod use in the prior nine months; 3) liver problems or significant medical problems.INTERVENTIONS: PhI: Polyphenon E, a green tea extract containing 50% of the antioxidant Epigallocatechin-gallate (EGCG), two capsules twice daily (200mg of EGCG per capsule; total daily dose 800mg) for six months. PhII: Polyphenon E or matching placebo capsules, same dose for one year. Only the research pharmacist knew treatment assignment and she randomized participants (one-to-one, stratified by GA or Interferon β, blocks of 4 or 6). Outcome evaluators did not discuss side effects with participants.OUTCOME MEASURES: PhI: 1) adverse events (AE); 2) futility: decrease in N-acetyl aspartate (NAA) from baseline to six months of 10% or more; 3) association between EGCG plasma levels and change in NAA. PhII: 1) AEs; 2) difference in the rate of change of NAA-levels over twelve months.We measured NAA using a point resolved magnetic resonance spectroscopic imaging sequence (TE30/TR2000) on a 10cm×10cm×1cm volume of interest (VOI) located just superior to the lateral ventricles. The field of view was 16×16 resulting in 1cm(3) voxels. We quantified NAA and creatine/phosphocreatine (Cr) levels using LCModel for post-processing.RESULTS: PhI: Ten participants enrolled and completed all assessments with no serious AEs. One discontinued therapy due to grade (G) I abnormal liver function tests (LFTs). We included all participants in the analysis. NAA adjusted for creatine increased by 10% [95% CI(3.4%,16.2%), p<0.01] rejecting the futility endpoint. PhII: Thirteen participants enrolled and twelve started treatment. The DSMB stopped the study because 5/7 participants on Polyphenon E had abnormal LFTs (G I, and 1G III). Median time to onset of abnormal LFTs was 20 weeks [Inter-Quartile Range (IQR) (10,23)]. Only two participants completed the six-month visit, so we could not analyze the NAA levels. PhI participants took capsules from lot 189I1107 while 6/7 PhII participants took capsules from a new lot (L0206306). Both lots had similar levels of EGCG but differed in the levels of minor catechins. There were no significant differences between the lots on participants' median free EGCG plasma levels at either 3h or 8h as well as conjugated EGCG levels at 3h (all p>0.4, Wilcoxon exact test). Free EGCG levels at 8h correlated with changes in NAA adjusted by water content. A 1ng/ml higher EGCG plasma concentration correlated with a 0.9% increase in NAA[95% CI(0.5%,1.4%), visit*level interaction F=14.4, p<0.001]. However, EGCG plasma concentrations did not correlate with NAA adjusted by creatine (1ng/ml higher EGCG was associated with 0.02%,[95% CI(-0.27%,0.3%) change in NAA, p>0.5]). There was a trend towards an increase in creatine levels (referenced to water content) from baseline to exit (1 5% increase, [95% CI(-6%,17%), p=0.4]). The free EGCG levels at 8hours correlated significantly with change in creatine levels (1ng/ml higher EGCG level at 8h was associated with a 1.1% increase in creatine [95% CI(0.6%,1.6%)]). Thus it is possible that the discrepancy between the correlation of the EGCG 8h levels with NAA changes referenced to water and the 8h EGCG levels with NAA changes referenced to creatine was due to a change in creatine among the subjects with higher EGCG levels. Conjugated 3h and 8h levels and free 3h levels did not correlate with NAA changes (all p >0.5).CONCLUSIONS/CLASSIFICATION OF EVIDENCE: Class III evidence: Polyphenon E at a dose of 400mg of EGCG twice a day is not futile at increasing brain NAA levels. Class I evidence: some lots of Polyphenon E have a high risk of hepatotoxicity.FUNDING: National Center for Complementary and Alternative Medicine K23AT004433, National Multiple Sclerosis Society RG4816-A-1 and National Institute of General Medical Sciences 1 U54 GM104940. Mitsui Norin provided Polyphenon E and placebo and their representative reviewed the manuscript prior to publication. Mitsui Norin was not involved in other aspects of the study. The decision to submit the manuscript remained with the investigators.REGISTRATION: NCT00836719 and NCT01451723

AB - OBJECTIVES: Phase I (PhI): assess the safety of Polyphenon E in people with multiple sclerosis (MS) and determine the futility of Polyphenon E as a neuroprotective agent. Correlate plasma levels of EGCG with neuroprotective effects. Phase II (PhII): Further assess safety and confirm the neuroprotective effects of Polyphenon E.DESIGN: PhI: single group futility study. PhII: parallel group randomized double-blind placebo-controlled study.PARTICIPANTS: Recruitment area (both studies): LSU MS Center, New Orleans, LA and general public from surrounding areas. Inclusion criteria (both studies): 1) MS per 2005 McDonald criteria; 2) relapsing remitting or secondary progressive MS; 3) stable for six months prior to enrollment on either no therapy or glatiramer acetate (GA) for the PhI study and on either on GA or Interferon β for the PhII study. Exclusion criteria (both studies): 1) complete bone marrow ablation or alentuzumab use at any time; 2) mitoxantrone, cyclophosphamide, natalizumab or fingolimod use in the prior nine months; 3) liver problems or significant medical problems.INTERVENTIONS: PhI: Polyphenon E, a green tea extract containing 50% of the antioxidant Epigallocatechin-gallate (EGCG), two capsules twice daily (200mg of EGCG per capsule; total daily dose 800mg) for six months. PhII: Polyphenon E or matching placebo capsules, same dose for one year. Only the research pharmacist knew treatment assignment and she randomized participants (one-to-one, stratified by GA or Interferon β, blocks of 4 or 6). Outcome evaluators did not discuss side effects with participants.OUTCOME MEASURES: PhI: 1) adverse events (AE); 2) futility: decrease in N-acetyl aspartate (NAA) from baseline to six months of 10% or more; 3) association between EGCG plasma levels and change in NAA. PhII: 1) AEs; 2) difference in the rate of change of NAA-levels over twelve months.We measured NAA using a point resolved magnetic resonance spectroscopic imaging sequence (TE30/TR2000) on a 10cm×10cm×1cm volume of interest (VOI) located just superior to the lateral ventricles. The field of view was 16×16 resulting in 1cm(3) voxels. We quantified NAA and creatine/phosphocreatine (Cr) levels using LCModel for post-processing.RESULTS: PhI: Ten participants enrolled and completed all assessments with no serious AEs. One discontinued therapy due to grade (G) I abnormal liver function tests (LFTs). We included all participants in the analysis. NAA adjusted for creatine increased by 10% [95% CI(3.4%,16.2%), p<0.01] rejecting the futility endpoint. PhII: Thirteen participants enrolled and twelve started treatment. The DSMB stopped the study because 5/7 participants on Polyphenon E had abnormal LFTs (G I, and 1G III). Median time to onset of abnormal LFTs was 20 weeks [Inter-Quartile Range (IQR) (10,23)]. Only two participants completed the six-month visit, so we could not analyze the NAA levels. PhI participants took capsules from lot 189I1107 while 6/7 PhII participants took capsules from a new lot (L0206306). Both lots had similar levels of EGCG but differed in the levels of minor catechins. There were no significant differences between the lots on participants' median free EGCG plasma levels at either 3h or 8h as well as conjugated EGCG levels at 3h (all p>0.4, Wilcoxon exact test). Free EGCG levels at 8h correlated with changes in NAA adjusted by water content. A 1ng/ml higher EGCG plasma concentration correlated with a 0.9% increase in NAA[95% CI(0.5%,1.4%), visit*level interaction F=14.4, p<0.001]. However, EGCG plasma concentrations did not correlate with NAA adjusted by creatine (1ng/ml higher EGCG was associated with 0.02%,[95% CI(-0.27%,0.3%) change in NAA, p>0.5]). There was a trend towards an increase in creatine levels (referenced to water content) from baseline to exit (1 5% increase, [95% CI(-6%,17%), p=0.4]). The free EGCG levels at 8hours correlated significantly with change in creatine levels (1ng/ml higher EGCG level at 8h was associated with a 1.1% increase in creatine [95% CI(0.6%,1.6%)]). Thus it is possible that the discrepancy between the correlation of the EGCG 8h levels with NAA changes referenced to water and the 8h EGCG levels with NAA changes referenced to creatine was due to a change in creatine among the subjects with higher EGCG levels. Conjugated 3h and 8h levels and free 3h levels did not correlate with NAA changes (all p >0.5).CONCLUSIONS/CLASSIFICATION OF EVIDENCE: Class III evidence: Polyphenon E at a dose of 400mg of EGCG twice a day is not futile at increasing brain NAA levels. Class I evidence: some lots of Polyphenon E have a high risk of hepatotoxicity.FUNDING: National Center for Complementary and Alternative Medicine K23AT004433, National Multiple Sclerosis Society RG4816-A-1 and National Institute of General Medical Sciences 1 U54 GM104940. Mitsui Norin provided Polyphenon E and placebo and their representative reviewed the manuscript prior to publication. Mitsui Norin was not involved in other aspects of the study. The decision to submit the manuscript remained with the investigators.REGISTRATION: NCT00836719 and NCT01451723

KW - EGCG

KW - Green tea

KW - Hepatotoxicity

KW - Liver toxicity

KW - Magnetic resonance spectroscopy

KW - Multiple sclerosis

KW - N-acetyl-aspartate

KW - Polyphenon E

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U2 - 10.1016/j.jns.2015.08.006

DO - 10.1016/j.jns.2015.08.006

M3 - Article

VL - 358

SP - 46

EP - 52

JO - Journal of the Neurological Sciences

JF - Journal of the Neurological Sciences

SN - 0022-510X

IS - 1-2

ER -