Epigallocatechingallate (EGCG) in Cardiac AL Amyloidosis (EpiCardiAL)

• Rate of adverse events [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  The secondary objectives are to assess the safety of EGCG in cardiac AL amyloidosis, to determine whether EGCG can prevent or delay cardiac progression and to compare survival of patients receiving EGCG compared to subjects receiving SST.
• Rate of cardiac progression [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  The secondary objectives are to assess the safety of EGCG in cardiac AL amyloidosis, to determine whether EGCG can prevent or delay cardiac progression and to compare survival of patients receiving EGCG compared to subjects receiving SST.
• Time to cardiac progression [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  The secondary objectives are to assess the safety of EGCG in cardiac AL amyloidosis, to determine whether EGCG can prevent or delay cardiac progression and to compare survival of patients receiving EGCG compared to subjects receiving SST.
• Rate of cardiac events [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  The secondary objectives are to assess the safety of EGCG in cardiac AL amyloidosis, to determine whether EGCG can prevent or delay cardiac progression and to compare survival of patients receiving EGCG compared to subjects receiving SST.
• Time to cardiac events [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  The secondary objectives are to assess the safety of EGCG in cardiac AL amyloidosis, to determine whether EGCG can prevent or delay cardiac progression and to compare survival of patients receiving EGCG compared to subjects receiving SST.
• Survival [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  The secondary objectives are to assess the safety of EGCG in cardiac AL amyloidosis, to determine whether EGCG can prevent or delay cardiac progression and to compare survival of patients receiving EGCG compared to subjects receiving SST.

In a proportion of patients with AL amyloidosis there is no improvement of cardiac function despite hematologic response to treatment. The aim of the study is to assess whether treatment with EGCG increases the rate of cardiac response in patients with AL amyloidosis who completed chemotherapy.

This will be a phase II open-label randomized trial. Patients with AL amyloidosis and cardiac involvement who have achieved at least partial hematologic response after chemotherapy will be randomized to receive standard supportive therapy (SST) or SST plus Epigallocatechin gallate (EGCG). After giving written informed consent, the patients will be evaluated for eligibility. Briefly, the subjects with a biopsy-proven diagnosis of AL amyloidosis who achieved at least partial response after chemotherapy, who are not planned to receive further chemotherapy and who have significant cardiac dysfunction will be considered eligible. The patients will be stratified according to the quality of hematologic response and to the severity of cardiac involvement. Following stratification, the patients will be randomized to receive SST or SST plus EGCG. The study comprises 3 periods: screening (including stratification and randomization), treatment (with evaluations of response every 2 months) followed by the end-of-treatment evaluation and follow-up. Therapy will continue for up to 1 year. After treatment patients will be followed for 3 years.

• Drug: Diuretics (plus antiarrhythmic drugs, i.e. amiodarone, in case of complex ventricular arrhithmias)
  Antiarrhythmic drugs (i.e. amiodarone), angiotensins which transform inhibitor enzymes, and/or beta-blockers if tolerated.
• Drug: Diuretics (plus antiarrhythmic drugs, i.e. amiodarone, in case of complex ventricular arrhythmias) plus EGCG

  Antiarrhythmic drugs (i.e. amiodarone), angiotensins which transform inhibitor enzymes, and/or beta-blockers if tolerated.

  EGCG, 675 mg/day, oral, for one year.

• Active Comparator: Arm A
  The patients will be divided into 4 strata according to cardiac dysfunction and to the quality of hematologic response. After stratification the patients will be randomized (1:1) within each stratum to receive Standard Therapy alone (Arm A) or Standard Therapy plus Investigational Drug (Arm B).
  Intervention: Drug: Diuretics (plus antiarrhythmic drugs, i.e. amiodarone, in case of complex ventricular arrhithmias)
• Experimental: Arm B
  The patients will be divided into 4 strata according to cardiac dysfunction and to the quality of hematologic response. After stratification the patients will be randomized (1:1) within each stratum to receive Standard Therapy alone (Arm A) or Standard Therapy plus Investigational Drug (Arm B)
  Intervention: Drug: Diuretics (plus antiarrhythmic drugs, i.e. amiodarone, in case of complex ventricular arrhythmias) plus EGCG

• Dispenzieri A, Gertz MA, Kyle RA, Lacy MQ, Burritt MF, Therneau TM, Greipp PR, Witzig TE, Lust JA, Rajkumar SV, Fonseca R, Zeldenrust SR, McGregor CG, Jaffe AS. Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic amyloidosis. J Clin Oncol. 2004 Sep 15;22(18):3751-7.
• Hunstein W. Epigallocathechin-3-gallate in AL amyloidosis: a new therapeutic option? Blood. 2007 Sep 15;110(6):2216. No abstract available.
• Mereles D, Wanker EE, Katus HA. Therapy effects of green tea in a patient with systemic light-chain amyloidosis. Clin Res Cardiol. 2008 May;97(5):341-4. Epub 2008 Mar 3. No abstract available.
• Palladini G, Campana C, Klersy C, Balduini A, Vadacca G, Perfetti V, Perlini S, Obici L, Ascari E, d'Eril GM, Moratti R, Merlini G. Serum N-terminal pro-brain natriuretic peptide is a sensitive marker of myocardial dysfunction in AL amyloidosis. Circulation. 2003 May 20;107(19):2440-5. Epub 2003 Apr 28.

Inclusion Criteria:

• Diagnosis of AL amyloidosis.
• Age ≥18 years.
• The patients must have been treated for AL amyloidosis attaining hematologic response.
• Evidence of cardiac involvement at echocardiography (mean left ventricular wall thickness >12 mm in the absence of other causes).
• NT-proBNP ≥650 ng/L

Exclusion Criteria:

• Non-AL (e.g. familial, senile) amyloidosis.
• Concomitant non-amyloid related clinically significant cardiac diseases.
• Need of further chemotherapy for AL amyloidosis.
• Estimated glomerular filtration rate (eGFR) <30 mL/min per 1.73 m2.
• Uncontrolled infection.
• Inability to give informed consent.
• Previous or ongoing psychiatric illness (excluding reactive depression).
• Pregnant or nursing women.