Clinical Trials Register

Summary
EudraCT Number:	2022-002538-14
Sponsor's Protocol Code Number:	218672
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2022-11-04
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2022-002538-14

A.3

Full title of the trial

17-beta-Hydroxysteroid Dehydrogenase type 13 Minimization for the treatment of NASH (HORIZON): A Double-Blind, Placebo-Controlled Phase 2b Study to Evaluate the Efficacy and Safety of GSK4532990 in Adults with Pre-Cirrhotic Non-Alcoholic Steatohepatitis

A.3.1

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

Phase 2b Study of GSK4532990 in Adults with Nonalcoholic Steatohepatitis (NASH)

A.3.2

Name or abbreviated title of the trial where available

Phase 2b Study of GSK4532990 in Adults with NASH (HORIZON)

A.4.1

Sponsor's protocol code number

218672

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	GlaxoSmithKline Research & Development Limited
B.1.3.4	Country	United Kingdom
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	GlaxoSmithKline Research & Development Limited
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	GlaxoSmithKline Research & Development Limited
B.5.2	Functional name of contact point	Clinical Trial Help Desk
B.5.3	Address:
B.5.3.1	Street Address	980 Great West Road
B.5.3.2	Town/ city	Brentford, Middlesex
B.5.3.3	Post code	TW8 9GS
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+442089909733
B.5.6	E-mail	GSKClinicalSupportHD@gsk.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	GSK4532990 Injection, 200 mg/mL
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	N/A
D.3.9.1	CAS number	2409783-35-1
D.3.9.2	Current sponsor code	GSK4532990A
D.3.9.3	Other descriptive name	ADS-006 sodium
D.3.9.4	EV Substance Code	SUB258556
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

Nonalcoholic steatohepatitis (NASH)

E.1.1.1

Medical condition in easily understood language

Nonalcoholic steatohepatitis (NASH) is a condition in which fat builds up in your liver. NASH causes inflammation, damage and scarring of the liver.

E.1.1.2

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	24.1
E.1.2	Level	PT
E.1.2	Classification code	10053219
E.1.2	Term	Non-alcoholic steatohepatitis
E.1.2	System Organ Class	10019805 - Hepatobiliary disorders

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 evaluate whether GSK4532990 can cause one (or both) of fibrosis regression and/or NASH resolution in participants with NASH and bridging (F3) fibrosis.

E.2.2

Secondary objectives of the trial

To evaluate GSK4532990 treatment effects on blood-based and imaging markers of liver fat, liver injury, and liver fibrosis in participants with NASH and bridging (F3) fibrosis.

To assess the safety and tolerability of GSK4532990 in participants with NASH and bridging (F3) fibrosis.

To evaluate the pharmacokinetics of GSK4532990.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

As previously approved, with the following addition.
A female participant is eligible to participate, if she is not pregnant or breastfeeding and one of the following conditions applies:
• Is a woman of nonchildbearing potential (WONCBP) as defined in Section 10.4
Contraception and Barrier Guidance
OR
• Is a WOCBP and using a contraceptive method that is highly effective, with a failure rate of <1%, as described in Section 10.4. Contraceptive measures must start from the time of negative serum pregnancy test at screening and at least 28 days before first administration of study intervention. Contraceptive measures should then continue during the
study intervention period, and for at least 18 weeks after the last administration of study intervention. The investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated in relationship to the first dose of study intervention).
o A WOCBP must have a negative highly sensitive pregnancy test (serum or urine as required by local regulations) within 24 hours before the first dose of study intervention, see Section 8.2.5 Pregnancy Testing.
Additional requirements for pregnancy testing during and after study intervention are in Section 8.2.5.
The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy

E.4

Principal exclusion criteria

Criterion 1 has been deleted,
Woman of Non-childbearing Potential (WONCBP)
Women in the following categories are considered WONCBP:
1. Premenarchal: Tanner stage 1 (prepubertal)
2. Permanently sterile due to one of the following procedures:
a) Documented hysterectomy
b) Documented bilateral salpingectomy
c) Documented bilateral oophorectomy
• For permanently sterile individuals due to an alternate medical cause other than
the above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal dysgenesis),
investigator discretion should be applied to determining study entry.
If reproductive status is questionable, additional evaluation should be considered.
Criterion 9 has been amended:
Any history of chronic kidney disease or kidney impairment defined by current hemodialysis/hemofiltration or an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 (using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation). (Based on central laboratory measurements; 1 repeat test is allowed).
The following exclusion criteria (23, 26, 36, 37 & 38) have been added Variable doses (including newly starting or stopping) of any of the following medications for ≥6 months prior to the baseline liver biopsy (either historical biopsy or biopsy taken at Screening 3): glucagon-like peptide-1 (GLP-1) agonists, PPAR agonists (e.g., pioglitazone, saroglitazar), sodium glucose cotransporter 2 (SGLT2) inhibitors; thyroid hormone receptor agonists; farnesoid X receptor (FXR) agonists; or Vitamin E (at doses greater than or equal to 800 IU/day)
Any history of anaphylaxis or hypersensitivity to GSK4532990 or any of the constituents of the injection.
Any history of anaphylaxis or hypersensitivity to GSK4532990 or any of the constituents of the injection.
Clinical suspicion of rhabdomyolysis.
Clinical suspicion of bleeding episode related to low blood fibrinogen level.
QTc >450 msec or QTc >480 msec in participants with bundle branch block.

E.5 End points

E.5.1

Primary end point(s)

• Achieving ≥ 1 stage improvement in histological fibrosis (Clinical Research Network [CRN] scoring) with no worsening of NASH (defined as no increase in the NAFLD Activity Score [NAS] for steatosis, ballooning, or inflammation) at 52 weeks.
• Achieving NASH resolution with no worsening of fibrosis (defined as no increase in CRN fibrosis score) at 52 weeks. Resolution of NASH is defined as a ballooning score of 0 and an inflammation score of 0-1.

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 52

E.5.2

Secondary end point(s)

• Change from baseline in Pro-C3 at 24 weeks and 52 weeks.
• Change from baseline in liver fat using MRI-PDFF at 24 weeks and 52 weeks.
• Change from baseline in liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE™) at 24 weeks and 52 weeks.
• Change from baseline in Enhanced Liver Fibrosis (ELF™) Score and its individual components (HA, PIIINP, TIMP-1) at 24 weeks and 52 weeks.
• Achieving ≥30% reduction from baseline in MRI-PDFF at 24 weeks.
• Achieving ≥30% reduction from baseline in MRI-PDFF at 52 weeks.
• Change from baseline in ALT, AST and GGT at 24 weeks and 52 weeks.

Clinical assessments including, but not limited to:
• Occurrence of AEs and SAEs,
• Change from baseline in vital signs at each Visit,
• Change from baseline in key laboratory measurements at each Visit.

• In a subset of participants with intensive PK sampling: plasma pharmacokinetic (PK) parameters of GSK4532990 including area under the concentration-time curve from time zero (pre-dose) to the last quantifiable concentration (AUC0-t), maximum observed concentration (Cmax), time of occurrence of Cmax (tmax), apparent terminal phase half-life (t1/2), apparent clearance (CL/F), and apparent terminal phase volume of distribution (Vz/F).
• Occurrence of anti-drug antibodies (ADA) to GSK4532990.

E.5.2.1

Timepoint(s) of evaluation of this end point

52 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

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

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)

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

Argentina

Belgium

Canada

France

Greece

India

Italy

Japan

Korea, Republic of

Mexico

Spain

Turkey

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

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:

204

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

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

F.4.2.2

In the whole clinical trial

246

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 the trial, on-going management of disease will be provided by the subjects’ healthcare providers or their pre-trial status.

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

2023-01-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2023-02-13

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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