Clinical Trials Register

Summary
EudraCT Number:	2023-000785-33
Sponsor's Protocol Code Number:	HST20-CL01
Clinical Trial Type:	Outside EU/EEA
Date on which this record was first entered in the EudraCT database:	2023-08-18
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
H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED

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A. Protocol Information

A.2

EudraCT number

2023-000785-33

A.3

Full title of the trial

A Phase 2 Open-label, Dose Escalation Study of HST5040 in Subjects with Propionic or Methylmalonic Acidemia Followed by a 6-Month, Randomized, Double-blind, Placebo-controlled, 2-Period Crossover Study and an Open-label, Long-term Extension Study

A.3.1

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

Study of HST5040 in Subjects With Propionic or Methylmalonic Acidemia (HERO)

A.4.1

Sponsor's protocol code number

HST20-CL01

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT04732429

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/254/2023

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	HemoShear Therapeutics
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	HemoShear Therapeutics
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	HemoShear Therapeutics
B.5.2	Functional name of contact point	Mavis Waller
B.5.3	Address:
B.5.3.1	Street Address	501 Locust Avenue, Suite 301
B.5.3.2	Town/ city	Charlottesville, Virginia
B.5.3.3	Post code	22902
B.5.3.4	Country	United States
B.5.4	Telephone number	1833975-3559
B.5.6	E-mail	waller@hemoshear.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.3.2	Product code	HST5040
D.3.4	Pharmaceutical form	Oral liquid
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	Dimebutic acid
D.3.9.1	CAS number	595-37-9
D.3.9.2	Current sponsor code	HST5040
D.3.9.4	EV Substance Code	SUB33307
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	8.4
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.3.2	Product code	HST5040
D.3.4	Pharmaceutical form	Oral liquid
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	Dimebutic acid
D.3.9.1	CAS number	595-37-9
D.3.9.2	Current sponsor code	HST5040
D.3.9.4	EV Substance Code	SUB33307
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	59
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	Oral liquid
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

Methylmalonic Acidemia (MMA)
Propionic Acidemia (PA)

E.1.1.1

Medical condition in easily understood language

Methylmalonic Acidemia (MMA)
Propionic Acidemia (PA)

E.1.1.2

Therapeutic area

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

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

An interventional study to assess the safety, PK, and efficacy of HST5040 in 12 subjects - 6 with Methylmalonic Acidemia (MMA) and 6 with Propionic Acidemia (PA). The study consists of 3 parts:

Part A: Open-label, within-subject, dose escalation study in PA and MMA subjects ≥ 2 years old to identify a safe and pharmacologically active (optimal) dose of HST5040 for use in Part B. Subjects will continue in a Part A open-label extension until all subjects complete Part A and the optimal dose of HST5040 is identified for use in Part B.

Part B: 6-month, randomized, double-blind, placebo-controlled, 2-period crossover in the same subjects from Part A to evaluate safety and efficacy of the optimal dose of HST5040 in addition to standard of care (SoC).

Part C: All subjects will be offered participation in an open-label long-term extension study.

This study will determine whether HST5040 can improve levels of disease-associated toxins that accumulate in patients with PA and MMA.

E.2.2

Secondary objectives of the trial

Not applicable

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

* Confirmed diagnosis of symptomatic PA or MMA (Mutase)
* Ages ≥ 2 years old.
* History of Inadequate metabolic control while receiving standard of care (SoC).
* Plasma MCA concentration > 3x upper limit of normal of the reference range at screening.
* Stable supplementation dose of carnitine for at least 1 week prior to the entry in the study.

E.4

Principal exclusion criteria

* Moderate-to-severely impaired cardiac function with LVEF < 40% by ECHO.
* Clinically significant arrhythmia by Holter monitor.
* QTcF > 450 msec
* Moderate to severe chronic kidney disease with estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2.
* Exposure to any investigational therapy within the past 6 months prior to study entry.
* Exposure to gene therapy for PA or MMA at any time prior to study entry.
* History of organ transplantation
* History of severe allergic or anaphylactic reactions to any of the components of HST5040.

E.5 End points

E.5.1

Primary end point(s)

Part A:
Determine the optimal dose(s) and regimen of HST5040 in PA and MMA subjects ≥ 2 years old
• Safety: Evaluate the safety of 3 dose levels of HST5040 administered orally or per gastrostomy tube twice daily (po/pg BID) in subjects with PA or MMA for a minimum of 4 weeks at each dose level per subject
• Pharmacokinetics (PK): Evaluate the systemic exposure to support the dose and dosing regimen of HST5040
• Efficacy: Evaluate the pharmacodynamics (PD) response to HST5040 in PA and MMA subjects through improvements in the 2-methylcitric acid (MCA) level

Part B:
Evaluate the safety and efficacy at the optimal dose(s) and regimen determined in Part A (within subject dose escalation)
• Safety: Evaluate the safety of HST5040 in PA and MMA subjects
• Efficacy: Evaluate the PD response to HST5040 in PA and MMA subjects through improvements in MCA levels

E.5.1.1

Timepoint(s) of evaluation of this end point

6 months

E.5.2

Secondary end point(s)

Part A:
• Evaluate the PD response to HST5040 in PA and MMA subjects through improvements in other disease-related biomarkers and tricarboxylic acid cycle function (TCA)
• Evaluate the total number of acute metabolic decompensation events requiring an ER visit or hospitalization
• Evaluate the total number of hospital days required for treatment/resolution of acute metabolic decompensation
• Evaluate the total number of episodes and days requiring use of a home emergency treatment protocol for acute metabolic decompensations
• Evaluate changes in hematologic parameters
• Evaluate changes in the route and amount of dietary intake
• Evaluate the effects of HST5040 on the QTc interval
• Evaluate changes in Health-related Quality of Life (HRQOL) and global assessments
• Evaluate changes in LVEF
• Evaluate whether PD biomarkers return to baseline levels during the washout period

Part B
• Evaluate the PD response to HST5040 in PA and MMA subjects through improvements in other disease-related biomarkers and TCA cycle function
• Evaluate the total number of acute metabolic decompensation events requiring an ER visit or hospitalization
• Evaluate the total number of hospital days and ER visits required for treatment/resolution of acute metabolic decompensation
• Evaluate the total number of episodes and days requiring use of a home emergency treatment protocol for acute metabolic decompensations
• Evaluate changes in hematologic parameters
• Evaluate changes in the route and amount of dietary intake
• Evaluate changes in QTcF and LVEF
• Evaluate changes in HRQOL and global assessments
• Evaluate changes in neurocognitive and developmental function
• Characterize the PK of HST5040

E.5.2.1

Timepoint(s) of evaluation of this end point

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

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

E.8.1.6

Cross over

Yes

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

Will this trial be conducted at a single site globally?

E.8.4

Will this trial be conducted at multiple sites globally?

Yes

E.8.6 Trial involving sites outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

Yes

E.8.6.3

Specify the countries outside of the EEA in which trial sites are planned

Australia

Saudi Arabia

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.8.9.2

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

Yes

F.1.1

Number of subjects for this age range:

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)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

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

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Informed Consent Form is provided to the parents of the child explaining full details of the proposed trial. Parents will sign the informed consent in agreement for their child to participate in the study.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.2

For a multinational trial

F.4.2.2

In the whole clinical trial

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	Rady Children's Hospital
G.4.3.4	Network Country	United States
G.4 Investigator Network to be involved in the Trial: 2
G.4.1	Name of Organisation	Yale
G.4.3.4	Network Country	United States
G.4 Investigator Network to be involved in the Trial: 3
G.4.1	Name of Organisation	Children's National Health System
G.4.3.4	Network Country	United States
G.4 Investigator Network to be involved in the Trial: 4
G.4.1	Name of Organisation	Emory University School of Medicine
G.4.3.4	Network Country	United States
G.4 Investigator Network to be involved in the Trial: 5
G.4.1	Name of Organisation	Ann & Robert H. Lurie Children's Hospital of Chicago
G.4.3.4	Network Country	United States
G.4 Investigator Network to be involved in the Trial: 6
G.4.1	Name of Organisation	Boston Children's Hospital
G.4.3.4	Network Country	United States
G.4 Investigator Network to be involved in the Trial: 7
G.4.1	Name of Organisation	Helen DeVos Children's Hospital
G.4.3.4	Network Country	United States
G.4 Investigator Network to be involved in the Trial: 8
G.4.1	Name of Organisation	University of Minnesota
G.4.3.4	Network Country	United States
G.4 Investigator Network to be involved in the Trial: 9
G.4.1	Name of Organisation	Children's Mercy Hospital Kansas City
G.4.3.4	Network Country	United States
G.4 Investigator Network to be involved in the Trial: 10
G.4.1	Name of Organisation	University of Pittsburgh Medical Center - Children's Hospital of Pittsburgh
G.4.3.4	Network Country	United States
G.4 Investigator Network to be involved in the Trial: 11
G.4.1	Name of Organisation	Vanderbilt University Medical Center
G.4.3.4	Network Country	United States
G.4 Investigator Network to be involved in the Trial: 12
G.4.1	Name of Organisation	University of Utah Hospital
G.4.3.4	Network Country	United States
G.4 Investigator Network to be involved in the Trial: 13
G.4.1	Name of Organisation	Nationwide Children's Hospital
G.4.3.4	Network Country	United States
G.4 Investigator Network to be involved in the Trial: 14
G.4.1	Name of Organisation	University of Texas Health Science Center at Houston
G.4.3.4	Network Country	United States
G.4 Investigator Network to be involved in the Trial: 15
G.4.1	Name of Organisation	Royal Children's Hospital Melbourne
G.4.3.4	Network Country	Australia
G.4 Investigator Network to be involved in the Trial: 16
G.4.1	Name of Organisation	King Faisal Specialist Hospital & Research Centre
G.4.3.4	Network Country	Saudi Arabia

H.4 Third Country in which the Trial was first authorised
H.4.1	Third Country in which the trial was first authorised:	United States

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