Clinical Trials Register

Summary
EudraCT Number:	2020-004828-42
Sponsor's Protocol Code Number:	ATOS-016R
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-10-26
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

Sweden - MPA

A.2

EudraCT number

2020-004828-42

A.3

Full title of the trial

A Phase 2, Randomized, Double-blinded, Placebo - controlled, Dose Response Study of Oral (Z)-endoxifen in Premenopausal Women with Measurable Breast Density

A.3.1

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

A Phase 2, Randomized, Double-blinded, Placebo - controlled, Dose Response Study of Oral (Z)-endoxifen in Premenopausal Women with Measurable Breast Density

A.4.1

Sponsor's protocol code number

ATOS-016R

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	Atossa Therapeutics Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Atossa Therapeutics Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Atossa Therapeutics Inc.
B.5.2	Functional name of contact point	Heather Fraser, VP Clinical
B.5.3	Address:
B.5.3.1	Street Address	107 Spring Street
B.5.3.2	Town/ city	Seattle
B.5.3.3	Post code	WA 98104
B.5.3.4	Country	United States
B.5.6	E-mail	heather.fraser@atossainc.com

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	No
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	(Z)-endoxifen
D.3.4	Pharmaceutical form	Capsule
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	(Z)-Endoxifen
D.3.9.1	CAS number	112093-28-4
D.3.9.3	Other descriptive name	4_[(Z)-1-[4-[2-(methylamino)ethoxy]phenyl]-2-phenylbut-1-enyl]phenol
D.3.9.4	EV Substance Code	SUB193570
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
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.IMP: 2
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	No
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	(Z)-endoxifen
D.3.4	Pharmaceutical form	Capsule
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	(Z)-Endoxifen
D.3.9.1	CAS number	112093-28-4
D.3.9.3	Other descriptive name	4_[(Z)-1-[4-[2-(methylamino)ethoxy]phenyl]-2-phenylbut-1-enyl]phenol
D.3.9.4	EV Substance Code	SUB193570
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

The mammographic density reduction in healthy women

E.1.1.1

Medical condition in easily understood language

Mammographic breast tissue density reduction

E.1.1.2

Therapeutic area

Body processes [G] - Physiological processes [G07]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To determine the dose-response relationship of daily oral (Z) endoxifen by measurement of mammographic breast density area (cm2) reduction.

E.2.2

Secondary objectives of the trial

The secondary objective of this study is to assess the safety and tolerability of daily oral (Z)-endoxifen.

The exploratory objectives of this study are:
-To determine if daily oral (Z)-endoxifen for a maximum of six months results in at least a one category reduction in the BI-RADS® scale
-To determine the durability of (Z)-endoxifen on breast density response at 24 months post standard of care screening mammogram (difference between end of treatment and 24-month breast density)
-To evaluate the levels of endoxifen over time and correlate endoxifen values to density change

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. 40-55 year old premenopausal women (defined as having at least one menstruation during the prior 12 months; women whose status is questionable in the mind of the PI will have an FSH test to confirm (FSH<26 U/L))
2. Women of childbearing potential using a highly effective method of birth control throughout the study period and willing to comply with monthly pregnancy testing
3. Screening mammogram performed within 3 month of study inclusion
4. Mammographic density assessed as BI-RADS® score B, C, or D
5. Must have given written informed consent before any study-related activities are carried out and must be able to understand the full nature and purpose of the trial, including possible risks and adverse effects

E.4

Principal exclusion criteria

1. Mammographic BI-RADS® malignancy code ≥3 at baseline mammography
2. Any previous diagnosis of breast cancer, including carcinoma in situ, or any other cancer (non-melanoma skin cancer and in situ cancer of the cervix are not exclusion criteria)
3. A history of breast surgery, e.g., reduction or enlargement, which might affect mammographic density measurements
4. Current medical conditions:
a. APC (activated protein C) resistance, an inherited coagulation disorder
b. Systolic pressure higher than 160 mm Hg or diastolic higher than 100 mm Hg
c. Cataract(s)
d. Uncontrolled diabetes (defined as HbA1c >50 mmol/mol)
e. Abnormal lab values deemed clinically significant by Investigator
5. BMI > 30
6. Women who have an increased risk of venous thrombosis due to immobilization, e.g., using wheelchair
7. Agents that have the potential to decrease endoxifen levels through increased metabolic clearance:
a. Certain anti-epileptic therapies (carbamazepine, fenytoin, fenobarbital, lamotrigine)
b. Certain antibiotics (rifamycins)
c. St John’s wort (in Swedish: johannesört)
d. Certain HIV medications (efavirenz, ritonavir)
8. Lactating, pregnant, or plan to become pregnant in the next year
9. History of thromboembolic disease such as embolus, deep vein thrombosis, stroke, TIA (transient ischemic attack) or myocardial infarction
10. Allergy to endoxifen or any of its components
11. Previous treatment with an anti-oestrogen, including experimental drug studies (e.g., Karma CREME, Karisma-1 or Karisma-2)
12. Current, or within prior 6 months, use of hormone replacement therapy to treat menopausal symptoms
13. Prescribed and regular use of anticoagulants (defined as substances included in group B01A in the ATC-system)
14. Participation in another investigational clinical trial in the last 6 months
15. Not willing or able to understand the study information and/or informed consent

E.5 End points

E.5.1

Primary end point(s)

Change of mammographic density area (cm2) assessed by iCAD® software after 6 months of daily
(Z) endoxifen treatment.

E.5.1.1

Timepoint(s) of evaluation of this end point

6 months

E.5.2

Secondary end point(s)

Change from baseline of safety and tolerability of daily oral (Z)-endoxifen by subject responses to the BCPT Eight Symptom Scale (BESS) questionnaire and AE collection.
Change from baseline of clinical assessments and laboratory tests (Clinical chemistry, haematology, coagulation, urinalysis).
Change of mammographic density area (cm2) assessed by iCAD® software after 3 months of daily (Z)-endoxifen treatment.
Change of mammographic density area (cm2) assessed by Stratus software after 3 and 6 months of daily (Z)-endoxifen treatment.

E.5.2.1

Timepoint(s) of evaluation of this end point

3, 6 months

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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)

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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)

E.8.2.2

Placebo

Yes

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

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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

LVLS

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

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

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:

240

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

F.3 Group of trial subjects

F.3.1

Healthy volunteers

Yes

F.3.2

Patients

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

240

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)

None.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Södersjukhuset AB, Breast and Mammographic unit

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-06-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-08-30

P. End of Trial
P.	End of Trial Status	Ongoing

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