Ignite Creation Date:
2024-05-06 @ 11:15 AM
Last Modification Date:
2024-10-26 @ 12:42 PM
Study NCT ID:
NCT03474458
Status:
TERMINATED
Last Update Posted:
2024-07-11
First Post:
2018-03-16
Brief Title:
A Trial of Doxycycline vs Standard Supportive Therapy in Newly-diagnosed Cardiac AL Amyloidosis Patients Undergoing Bortezomib-based Therapy
Sponsor:
Fondazione IRCCS Policlinico San Matteo di Pavia
Organization:
Fondazione IRCCS Policlinico San Matteo di Pavia
Study Overview
Official Title:
A Randomized Phase IIIII Trial of Doxycycline vs Standard Supportive Therapy in Newly-diagnosed Cardiac AL Amyloidosis Patients Undergoing Bortezomib-based Therapy
Status:
TERMINATED
Status Verified Date:
2024-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
difficulty in recruitment
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Systemic amyloidoses are rare diseases affecting approximately 1 in 100000 persons each year
In systemic amyloidoses abnormal proteins deposit in bodily organs and severely impair their function causing death if not treated effectively Light chain AL amyloidosis is caused by a usually small population of plasma cells the cells that produce antibodies These cells produce part of antibodies the light chains LC that form amyloid deposits Almost every organ with the exception of the brain can be affected by AL amyloidosis The heart is involved in three fourths of patients and is responsible for almost all the deaths occurring in the first 6 months after diagnosis Current therapy of AL amyloidosis is based on drugs targeting the plasma cells producing the amyloid-forming LC At present most patients receive a powerful anti-plasma cell drug bortezomib as part of their initial treatment However bortezomib-based therapy can improve heart involvement only in less than one third of patients with AL amyloidosis and many patients approximately one third still die within 12 months from diagnosis Early cardiac deaths remain an acute unmet need and the major determinant of overall outcome in this disease Thus there is the need of alternative means to treat heart involvement in AL amyloidosis Doxycycline is a widely used well tolerated antibiotic that has been marketed for decades and used to treat a number of different infectious diseases caused by bacteria This molecule has been extensively studied in the laboratory in animal models and more recently in small studies involving patients for its potential of improving cardiac damage in amyloidosis These studies showed that doxycycline disrupts amyloid deposits reduces the amyloid load in a mouse model and counteracts the toxicity exerted by amyloid-forming LCs on C elegans a worm whose pharynx is used as a model resembling human heart In a small clinical study doxycycline was given to patients with cardiac AL amyloidosis during treatment for their underlying plasma cell disease This resulted in a remarkable improvement of survival compared to matched historical controls ie similar patients who had received only anti-plasma cell therapy without doxycycline in the past Based on these promising preliminary results we designed the present clinical trial to assess whether the addition of doxycycline to anti-plasma cell therapy can improve survival in patients with cardiac AL amyloidosis who were not previously treated The rate of survival at 12 months will be compared in patients receiving doxycycline and in controls receiving standard antibiotic therapy together with anti-plasma cell therapy Patients will be assessed for parameters of plasma cell disease heart involvement and possible involvement of other organs as well as for quality of life To make sure that patients who will receive doxycycline and those who will not have comparable severity of cardiac disease patients will be stratified according to the stage of cardiac involvement Patients with very advanced heart dysfunction will not be enrolled in the trial because preliminary data indicate that doxycycline is of little or no benefit in these subjects Patients will be randomized to receive doxycycline or standard antibiotics in combination with anti-plasma cell therapy Bortezomib-based treatment directed against plasma cells will be delivered according to each participating institutions guidelines Doxycycline will be administered at a dosage of 100 mg two times a day which is usual in the treatment of bacterial diseases Standard antibiotics will be delivered according to each participating institutions guidelines provided that drugs of the same class as doxycycline are not administered in the control arm Patients will be provided a diary to record possible adverse events and will be instructed accordingly Patients will be evaluated at trial centers every 2 months for treatment efficacy and toxicity In case of unsatisfactory response second-line therapy will be initiated In the absence of unacceptable toxicity doxycycline administration will be continued for the entire duration of follow-up 12 months
In systemic amyloidoses abnormal proteins deposit in bodily organs and severely impair their function causing death if not treated effectively Light chain AL amyloidosis is caused by a usually small population of plasma cells the cells that produce antibodies These cells produce part of antibodies the light chains LC that form amyloid deposits Almost every organ with the exception of the brain can be affected by AL amyloidosis The heart is involved in three fourths of patients and is responsible for almost all the deaths occurring in the first 6 months after diagnosis Current therapy of AL amyloidosis is based on drugs targeting the plasma cells producing the amyloid-forming LC At present most patients receive a powerful anti-plasma cell drug bortezomib as part of their initial treatment However bortezomib-based therapy can improve heart involvement only in less than one third of patients with AL amyloidosis and many patients approximately one third still die within 12 months from diagnosis Early cardiac deaths remain an acute unmet need and the major determinant of overall outcome in this disease Thus there is the need of alternative means to treat heart involvement in AL amyloidosis Doxycycline is a widely used well tolerated antibiotic that has been marketed for decades and used to treat a number of different infectious diseases caused by bacteria This molecule has been extensively studied in the laboratory in animal models and more recently in small studies involving patients for its potential of improving cardiac damage in amyloidosis These studies showed that doxycycline disrupts amyloid deposits reduces the amyloid load in a mouse model and counteracts the toxicity exerted by amyloid-forming LCs on C elegans a worm whose pharynx is used as a model resembling human heart In a small clinical study doxycycline was given to patients with cardiac AL amyloidosis during treatment for their underlying plasma cell disease This resulted in a remarkable improvement of survival compared to matched historical controls ie similar patients who had received only anti-plasma cell therapy without doxycycline in the past Based on these promising preliminary results we designed the present clinical trial to assess whether the addition of doxycycline to anti-plasma cell therapy can improve survival in patients with cardiac AL amyloidosis who were not previously treated The rate of survival at 12 months will be compared in patients receiving doxycycline and in controls receiving standard antibiotic therapy together with anti-plasma cell therapy Patients will be assessed for parameters of plasma cell disease heart involvement and possible involvement of other organs as well as for quality of life To make sure that patients who will receive doxycycline and those who will not have comparable severity of cardiac disease patients will be stratified according to the stage of cardiac involvement Patients with very advanced heart dysfunction will not be enrolled in the trial because preliminary data indicate that doxycycline is of little or no benefit in these subjects Patients will be randomized to receive doxycycline or standard antibiotics in combination with anti-plasma cell therapy Bortezomib-based treatment directed against plasma cells will be delivered according to each participating institutions guidelines Doxycycline will be administered at a dosage of 100 mg two times a day which is usual in the treatment of bacterial diseases Standard antibiotics will be delivered according to each participating institutions guidelines provided that drugs of the same class as doxycycline are not administered in the control arm Patients will be provided a diary to record possible adverse events and will be instructed accordingly Patients will be evaluated at trial centers every 2 months for treatment efficacy and toxicity In case of unsatisfactory response second-line therapy will be initiated In the absence of unacceptable toxicity doxycycline administration will be continued for the entire duration of follow-up 12 months
Detailed Description:
None
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None