Clinical Trials Register

Summary
EudraCT Number:	2021-000688-57
Sponsor's Protocol Code Number:	AROAPOC3-2002
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2021-10-11
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

Poland - Office for Medicinal Products

A.2

EudraCT number

2021-000688-57

A.3

Full title of the trial

A Double-blind, Placebo-Controlled Phase 2b Study to Evaluate the Efficacy and Safety of ARO-APOC3 in Adults with Mixed Dyslipidemia

Prowadzone metodą podwójnie ślepej próby z grupą kontrolną otrzymującą placebo, badanie fazy IIb mające na celu ocenę skuteczności i bezpieczeństwa stosowania ARO-APOC3 u osób dorosłych z dyslipidemią mieszaną

A.3.1

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

A study to understand the safety and effectiveness of ARO-APOC3 in Adults with Mixed Dyslipidemia

Badanie mające na celu zrozumienie bezpieczeństwa i skuteczności stosowania ARO-APOC3 u dorosłych z dyslipidemią mieszaną

A.4.1

Sponsor's protocol code number

AROAPOC3-2002

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT04998201

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	Arrowhead 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	Arrowhead Pharmaceuticals, 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	Arrowhead Pharmaceuticals, Inc.
B.5.2	Functional name of contact point	Armine Balian
B.5.3	Address:
B.5.3.1	Street Address	177 East Colorado Boulevard, Suite 700
B.5.3.2	Town/ city	Pasadena
B.5.3.3	Post code	91105
B.5.3.4	Country	United States
B.5.4	Telephone number	+16263043400
B.5.5	Fax number	+16263043401
B.5.6	E-mail	abalian@arrowheadpharma.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	ARO-APOC3 Injection
D.3.2	Product code	ARO-APOC3
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	To Be Determined
D.3.9.1	CAS number	2379776-40-4
D.3.9.2	Current sponsor code	ADS-005
D.3.9.3	Other descriptive name	Synthetic double-stranded siRNA oligonucleotide directed against apolipoprotein C-III mRNA and covalently linked to a ligand containing three N-acetylgalactosamine residues
D.3.9.4	EV Substance Code	SUB208166
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	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	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

Mixed Dyslipidemia

E.1.1.1

Medical condition in easily understood language

high LDL cholesterol and triglyceride levels

E.1.1.2

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	26.0
E.1.2	Level	LLT
E.1.2	Classification code	10027763
E.1.2	Term	Mixed hyperlipidemia
E.1.2	System Organ Class	100000004850

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of the study is to evaluate the safety and efficacy of ARO-APOC3 in adults with mixed dyslipidemia (MD) and to select a dose and dosing regimen for later stage clinical studies in this patient population.

E.2.2

Secondary objectives of the trial

Not applicable

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Pharmacokinetics, Optional Genotype, and Future Research studies.

E.3

Principal inclusion criteria

To be eligible for enrollment, participants must meet all the following inclusion criteria:
1. Males or nonpregnant (who do not plan to become pregnant), nonlactating females ≥18 years of age;
2. Based on medical history, prior evidence of TG ≥150 mg/dL or 1.69 mmol/L and ≤499 mg/dL or 5.64 mmol/L;
3. A mean fasting TG level of ≥150 mg/dL (≥1.69 mmol/L) and ≤499 mg/dL (5.64 mmol/L) collected at two separate and consecutive visits and at least 7 days apart and no more than 17 days apart during the Screening period;
4. Fasting levels at Screening of non-HDL-C ≥100 mg/dL (2.59 mmol/L), OR LDL-C ≥70 mg/dL (1.8 mmol/L) after at least 2 weeks of stable diet and 4 weeks on stable optimal statin therapy (unless documented as statin intolerant as defined in Section 8.4);
5. Able and willing to provide written informed consent prior to the performance of any study-specific procedures;
6. Willing to follow diet counseling as per Investigator judgment based on local standard of care; and
7. Participants of childbearing potential must agree to use highly effective contraception during the study and for at least 24 weeks following the last dose of IP. Males must agree to not donate sperm during the study and for at least 24 weeks following the last dose of IP.
Females must agree to not donate eggs during the study and for at least 24 weeks following the last dose of IP.
8. Women of childbearing potential on hormonal contraceptives must be stable on the medication for ≥2 menstrual cycles prior to Day 1;
9. Participants taking any of the following medications must be on a stable regimen for the specified duration prior to collection of Screening visit (S2) laboratory tests and for the duration of study participation:

Medication: Time on stable regimen prior to collection of Screening visit (S2) laboratory tests
• Lipid lowering therapies (including statins): ≥ 4 weeks
• Beta-blockers, thiazide diuretics: ≥ 4 weeks
• Fibrates: ≥ 6 weeks
• PCSK9 inhibitors: ≥ 8 weeks
• Retinoids: ≥ 8 weeks
• Atypical antipsychotics: ≥ 12 weeks
• Diabetes mellitus medications: ≥ 12 weeks
• Oral estrogens, tamoxifen, raloxifene: ≥ 16 weeks
• Immunosuppressants: ≥ 24 weeks
• Thyroid hormone replacement therapy: ≥ 12 weeks
• Anticoagulation therapy: ≥ 12 weeks
• Testosterone replacement therapy: ≥ 16 weeks

NOTE: All laboratory tests used as inclusion criteria will be assessed by a central laboratory and may be repeated once and the repeat value may be used for inclusion purposes. Local laboratory testing may be permitted in limited circumstances and only with prior Sponsor approval.

E.4

Principal exclusion criteria

Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study:
1. Current use or use within last 365 days from Day 1 of any hepatocyte targeted siRNA or antisense oligonucleotide molecule;
2. Active pancreatitis within 12 weeks prior to Day 1;
3. Any planned bariatric surgery or similar procedures to induce weight loss during the period starting at consent through the end of the study;
4. History of major surgery within 12 weeks of Day 1 or planned major surgery during the study
5. Planned coronary intervention (such as stent placement or heart bypass) during the study;
6. History of acute coronary syndrome event within 24 weeks of Day 1
7. New York Heart Association (NYHA) Class II, III, or IV heart failure or last known ejection fraction of <30%;
8. Uncontrolled hypertension (sitting blood pressure >160/100 mmHg at Screening); participant may be re-screened once hypertension is controlled;
9. History of hemorrhagic stroke within 24 weeks of Day 1;
10. History of bleeding diathesis or coagulopathy;
11. Current diagnosis of nephrotic syndrome;
12. Any of the following laboratory values at Screening:
a. Hepatic: ALT or AST >2× ULN at Screening,
b. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 (using the Modification of Diet in Renal Disease [MDRD] equation) at Screening,
c. HbA1c >9.0% (or >75 mmol/mol IFCC units) at Screening ;
d. Spot urine protein/spot urine creatinine ratio >3 grams per day;
e. Clinically significant abnormality in PT, aPTT, or INR;
13. Systemic use of corticosteroids or anabolic steroids within 4 weeks prior to Day 1 or planned use during the study (stable doses of testosterone replacement therapy ≥16 weeks prior to Screening [Visit S2] is permitted for a documented history of hypogonadism [low testosterone] as verified in subject health records);
14. Blood donation of 50 to 499 mL within 4 weeks of Screening (Visit S2) or of >499 mL within 8 weeks of Screening (Visit S2) laboratory collection;
15. Known history of human immunodeficiency virus infection.
16. Seropositive (hepatitis B surface antigen [HBsAg] +) for hepatitis B virus (HBV) or hepatitis C virus (HCV) (HCV seropositivity requires positive test for antibodies confirmed with positive test for HCV RNA);
17. Clinical evidence of uncontrolled hypothyroidism or hyperthyroidism, as per Investigator’s judgment;
18. History of malignancy within the last 2 years prior to the date of consent requiring systemic treatment except for adequately treated basal cell carcinoma, squamous cell skin cancer, superficial bladder tumors, or in situ cervical cancer. Currently receiving systemic cancer treatment(s) or, in the Investigator's opinion, at risk of relapse for recent cancer;
19. Use of an investigational agent or device within 30 days or within 5 half-lives, based on plasma pharmacokinetics (PK) (whichever is longer) prior to Day 1 or current participation in an interventional investigational study. Participants previously exposed to ARO-APOC3 or ARO-ANG3 will require a washout period of at least 1 year from last dose;
20. Unwilling to limit alcohol consumption to within moderate limits for the duration of the study, as follows: not more than 14 units per week (1 unit = 80 mL of wine, 200 mL of beer, or 25 mL of 40% alcohol);
21. Any concomitant medical or psychiatric condition or social situation or any other situation that, in the Investigator’s judgment, would make it difficult to comply with protocol requirements or put the participant at additional safety risk.

All laboratory tests used as exclusion criteria may be repeated once and the repeat value may be used for exclusion purposes.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of the study is:
• Percent change from baseline at Week 24 in fasting TG.

E.5.1.1

Timepoint(s) of evaluation of this end point

24 weeks

E.5.2

Secondary end point(s)

The following are the secondary endpoints to be evaluated in this study:
• Percent change from baseline at each scheduled assessment in fasting TG;
• Percent change from baseline at Week 24 and over time through Week 48 in apolipoprotein (Apo)C-III;
• Percent change from baseline at Week 24 and over time through Week 48 in fasting non-HDL-C;
• Percent change from baseline at Week 24 and over time through Week 48 in fasting HDL C;
• Percent change from baseline at Week 24 and over time through Week 48 in fasting total ApoB;
• Percent change from baseline at Week 24 and over time through Week 48 in fasting LDL-C using ultracentrifugation;
• Subject incidence of TEAEs

E.5.2.1

Timepoint(s) of evaluation of this end point

24 and 48 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

Yes

E.6.10

Pharmacogenetic

Yes

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

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

Australia

Canada

New Zealand

United States

Hungary

Poland

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

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:

256

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

124

F.4.2.2

In the whole clinical trial

320

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)

After Week 48, participants will be eligible and invited to consent and continue in an open-label extension study. All placebo participants who opt to continue will switch to active drug during the extension study. After discontinuation from the study the participants will be treated by their physician according to standard medical practice with the standard of care treatment.

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

2022-01-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-09-21

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-08-14

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