Clinical Trials Register

Summary
EudraCT Number:	2017-002210-31
Sponsor's Protocol Code Number:	AC-012-EU
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2019-01-24
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2017-002210-31

A.3

Full title of the trial

A randomized phase II/III trial of doxycycline vs. standard supportive therapy in newly-diagnosed cardiac AL amyloidosis patients undergoing bortezomib-based therapy

Randomisierte Phase II/III Studie mit Doxycyclin oder einer Standard Supportivtherapie bei neu diagnostizierten Patienten mit kardialer Leichtketten (AL-) Amyloidose, die mit einer Bortezomib-haltigen Chemotherapie behandelt werden

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

An allocation by random phase II/III trial of doxycycline in comparison to standard therapy in newly-diagnosed cardiac AL amyloidosis patients with bortezomib-based therapy

A.3.2

Name or abbreviated title of the trial where available

ReDox

A.4.1

Sponsor's protocol code number

AC-012-EU

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Amyloid Center - Biotechnology Research Laboratories Policlinico San Matteo
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	DFG
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Universitätsklinikum Heidelberg
B.5.2	Functional name of contact point	Professor Dr. med. Ute Hegenbart
B.5.3	Address:
B.5.3.1	Street Address	Im Neuenheimer Feld 410
B.5.3.2	Town/ city	Heidelberg
B.5.3.3	Post code	69120
B.5.3.4	Country	Germany
B.5.4	Telephone number	490622156 8030
B.5.5	Fax number	490622156 4659
B.5.6	E-mail	Ute.Hegenbart@med.uni-heidelberg.de

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	DoxyHEXAL® tabs 100 mg Tabletten Wirkstoff Doxycyclin Zugelassen ab 18. November 2018
D.2.1.1.2	Name of the Marketing Authorisation holder	HEXAL AG
D.2.1.2	Country which granted the Marketing Authorisation	Germany
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	DoxyHEXAL® tabs 100 mg Tabletten
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DOXYCYCLINE
D.3.9.1	CAS number	564-25-0
D.3.9.4	EV Substance Code	SUB06393MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Light chain (AL) amyloidosis is a protein conformational disease, caused by a small bone
marrow plasma cell clone producing light chains (LCs) that undergo conformational changes,
aggregate and deposit in tissues in the form of amyloid fibrils. This process causes dysfunction
of the organs involved and leads to death if not effectively treated.

E.1.1.1

Medical condition in easily understood language

Light chain (AL) amyloidosis is a protein conformational disease, caused by a small bone
marrow plasma cell clone producing light chains (LCs) that undergo changes in their conformation.

E.1.1.2

Therapeutic area

Not possible to specify

MedDRA Classification

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The trial aims at establishing whether the addition of the antibiotic
doxycycline to anti-plasma cell therapy can reduce early mortality
in newly-diagnosed patients with cardiac AL amyloidosis.
Cardiac involvement is responsible for almost all the early deaths
in AL amyloidosis. Therapy solely aimed at the underlying disease
can rescue only a minority of patients with cardiac AL amyloidosis,
whose treatment remains a largely unmet need. The severity of
cardiac involvement is accurately assessed by a staging system
based on cardiac biomarkers. Patients with stage II/IIIa cardiac
involvement will be enrolled in this study.

E.2.2

Secondary objectives of the trial

Not applicable

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• newly-diagnosed AL amyloidosis
• stage II/IIIa heart involvement
• age >18 years
• planned bortezomib-based therapy
• total bilirubin <1.5 × upper reference limit (url),
• patients with Gilbert disease who have a total bilirubin,
predominantly unconjugated >1.5 × url without any other
liver function test abnormalities are still eligible
• alkaline phosphatase <5 × url
• alanine aminotransferase <3 × url

E.4

Principal exclusion criteria

non-AL amyloidosis
· previous treatment for AL amyloidosis
· pregnant or nursing women
· uncontrolled infection
· active malignancy
· known hypersensitivity to doxycycline, bortezomib, boron,
or mannitol
· treatment with drugs potentially affecting doxycycline
absorption
· significant acute gastrointestinal symptoms
· active peptic ulceration and/or esophageal reflux disease
· contraindications to bortezomib based therapy

E.5 End points

E.5.1

Primary end point(s)

proportion surviving at 12 months

E.5.1.1

Timepoint(s) of evaluation of this end point

12 months after beginning of the Treatment phase

E.5.2

Secondary end point(s)

safety, i.e. rate of severe (CTCAE v5.0) grade 3 or greater
adverse events)
· rate of infective adverse events of any grade
· cardiac response (as per consensus criteria) at 2, 4, 6 and 12
months
· hematologic response (as per consensus criteria) at 2, 4, 6
and 12 months
· renal response (as per consensus criteria) at 2, 4, 6 and 12
months

E.5.2.1

Timepoint(s) of evaluation of this end point

12 months after beginning of the Treatment phase

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Canada

Turkey

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The study will end when the last subject discontinues study treatment and completes the
6-Month Follow-up Visit.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

120

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

120

F.4.2.2

In the whole clinical trial

120

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

At the discretion of the treating physician and when it is deemed to be in the patient’s best
interest; in particular, patients can be removed from the study if they do not meet study
criteria of a progression but they did not reach CR, VGPR or organ response and the local
clinicians wish to give further treatment (these patients will be considered censored for the
purpose of the survival analysis).

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-05-31

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-05-20

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2022-04-14

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