Clinical Trials Register

Summary
EudraCT Number:	2012-001831-30
Sponsor's Protocol Code Number:	ISIS420915-CS2
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-06-19
Trial results	View 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

Italy - Italian Medicines Agency

A.2

EudraCT number

2012-001831-30

A.3

Full title of the trial

A Phase 2/3 Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of ISIS 420915 in Patients with Familial Amyloid Polyneuropathy

A.3.1

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

A controlled study to assess the effectiveness and safety of study drug, ISIS 420915, in patients with Familial Amyloid Polyneuropathy

A.3.2

Name or abbreviated title of the trial where available

ISIS 420915-CS2

A.4.1

Sponsor's protocol code number

ISIS420915-CS2

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	Isis Pharmaceuticals, 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	Isis Pharmaceuticals
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	Isis Pharmaceuticals, Inc.
B.5.2	Functional name of contact point	Matt R. Buck
B.5.3	Address:
B.5.3.1	Street Address	2855 Gazelle Ct.
B.5.3.2	Town/ city	Carlsbad
B.5.3.3	Post code	92010
B.5.3.4	Country	United States
B.5.4	Telephone number	011760603-2684
B.5.5	Fax number	011760603-3891
B.5.6	E-mail	mbuck@isisph.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	Human Transthyretin Antisense Oligonucleotide
D.3.2	Product code	ISIS 420915
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ISIS 420915
D.3.9.2	Current sponsor code	ISIS 420915
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
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	Yes
D.3.11.13.1	Other medicinal product type	Antisense Oligonucleotide

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	Solution for injection
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Familial Amyloid Polyneuropathy

E.1.1.1

Medical condition in easily understood language

Familial Amyloid Polyneuropathy

E.1.1.2

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10057949
E.1.2	Term	Familial amyloid polyneuropathy
E.1.2	System Organ Class	100000004850

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

To evaluate the efficacy of ISIS 420915 as compared to palcebo, given for 65 weeks, as measured by the change from baseline in the modified Neuropathy Impairment Score +7 (mNIS+7) and inthe Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire total score, in patients with FAP.

E.2.2

Secondary objectives of the trial

To evaluate the efficacy of ISIS 420915 as compared to placebo based on the change from baseline in the following measures:
• Norfolk QOL-DN questionnaire symptoms domain score in Stage 1 patients and Norfolk QOL-DN questionnaire physical functioning/large fiber neuropathy domain score in Stage 2 patients
• Modified body mass index (mBMI) and body mass index (BMI)
• NIS and modified +7
• NIS+7

To evaluate the pharmacodynamic (PD) effect of ISIS 420915 as compared to placebo, based on the change from baseline in transthyretin (TTR) and retinol binding protein 4 (RBP4).

To evaluate the safety and tolerability of ISIS 420915.

To evaluate the plasma trough levels of ISIS 420915 in all patients and to evaluate the plasma pharmacokinetic parameters of ISIS 420915 in a subset of patients.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Stage 1 and Stage 2 FAP patients with the following:
a. NIS score >15 and <85
b. Ability to walk unaided or with the use of no more than one stick/cane
c. Documented transthyretin variant by genotyping
d. Documented amyloid deposit by biopsy

2. Willingness to take vitamin A supplements

3. Aged 18 to 75 years old at the time of informed consent

4. Satisfy the following:
a. Females: Non-pregnant and non-lactating; surgically sterile, post-menopausal, abstinent, or if engaged in sexual relations of child-bearing potential, patient is using an acceptable contraceptive method for 4 weeks prior to, during, and for 3 months after the last dose of Study Drug
b. Males: Surgically sterile, abstinent, or if engaged in sexual relations of child-bearing potential, patient is utilizing an acceptable contraceptive method during and for 3 months after the last dose of Study Drug

5. Must have given written informed consent (signed and dated) and any authorizations required by local law and be able to comply with all study requirements

E.4

Principal exclusion criteria

1. Unwillingness to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator

2. Screening laboratory results as follows, or any other clinically significant abnormalities in screening laboratory values that would render a patient unsuitable for inclusion:
a. ALT/AST >1.9 x ULN
b. Bilirubin ≥1.5 x ULN (patients with bilirubin ≥1.5 x ULN may be allowed on study following discussion with the Study Medical Monitor if indirect bilirubin only is elevated,ALT/AST is not greater than the ULN and genetic testing confirming Gilbert’s disease)
c. Platelets <100 x 109/L
d. Persistently positive (2 out of 3 consecutive tests ≥1+) for protein on urine dipstick. In the event of a positive test eligibility may be confirmed by a quantitative total urine protein measurement of <1.0 g/24 hours
e. Persistently positive (2 out of 3 consecutive tests ≥ trace positive) for blood on urine dipstick. In the event of a positive test eligibility may be confirmed with urine microscopy showing <5 red blood cells per high power field
f. TSH values outside normal range

3. Retinol level at screen < LLN

4. QTcF >470 msec (average of triplicates). QTcF values >470 msec should be confirmed by Sponsor central ECG reader. Patients with a left bundle branch block or pacemaker will not be eligible if QTcF >500 msec (QTcF values >500 msec should be confirmed by Sponsor entral ECG reader)

5. Uncontrolled hypertension (blood pressure >160/100)

6. Positive test result for human immunodeficiency virus (HIV), hepatitis B or hepatitis C

7. Karnofsky performance status ≤50

8. Renal insufficiency as defined by estimated creatinine clearance calculated according to the formula of CKD-EPI <45 mL/min/1.73 m2 at screen. If the calculated creatinine clearance is thought to be artificially low, a 24-hour urine creatinine clearance can be completed with prior Sponsor approval

9. Known type 1 or type 2 diabetes mellitus

10. Other causes of sensorimotor or autonomic neuropathy (e.g., autoimmune disease)

11. Treatment with another investigational drug, biological agent, or device within three-months of screening, or five half-lives of study agent, whichever is longer

12. If previously treated with Vyndaqel® must have discontinued treatment for 2 weeks prior to Study Day 1. If previously treated with Diflunisal, must have discontinued treatment for 3 days prior to Study Day 1

13. Previous treatment with any oligonucleotide or siRNA within 12 months of screening

14. Prior liver transplant or anticipated liver transplant within 1 year of screening

15. New York Heart Association (NYHA) functional classification of ≥3

16. Acute coronary syndrome or major surgery within 3 months of screening

17. Known Primary Amyloidosis

18. Known Leptomeningeal Amyloidosis

19. Anticipated survival less than 2 years

20. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1

21. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated

22. Have any other conditions, which, in the opinion of the Investigator would make the patient unsuitable for inclusion, or could interfere with the patient participating in or completing the study

E.5 End points

E.5.1

Primary end point(s)

Change in mNIS+7 score from baseline to Week 66 and the change in the Norfolk QOL-DN questionnaire total score from baseline to Week 66

E.5.1.1

Timepoint(s) of evaluation of this end point

66 Weeks

E.5.2

Secondary end point(s)

• Change in the Norfolk QOL-DN questionnaire symptoms domain score (Stage 1 patients only) and Norfolk QOL-DN questionnaire physical functioning/large fiber neuropathy domain score (Stage 2 patients only) from baseline to Week 66)

• Change in the mBMI and BMI from baseline to Week 65

• Change in NIS and modified +7 from baseline to Week 66

• Change in NIS+7 score from baseline to Week 66

E.5.2.1

Timepoint(s) of evaluation of this end point

66 Weeks

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

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

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

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in 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

Brazil

France

Germany

Italy

Portugal

United Kingdom

United States

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

LSLV

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

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:

165

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

113

F.4.2.2

In the whole clinical trial

195

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)

Standard of Care or patients may choose to participate in the proposed Open Label Extension trial.

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

2013-07-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-07-01

P. End of Trial
P.	End of Trial Status	Completed

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