Clinical Trials Register

Summary
EudraCT Number:	2022-000491-18
Sponsor's Protocol Code Number:	AT-007-1005
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2022-05-09
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

Czechia - SUKL

A.2

EudraCT number

2022-000491-18

A.3

Full title of the trial

A Randomized, Double-Blind, Placebo-Controlled, Two-Part Study to Evaluate the Pharmacodynamic Efficacy and Clinical Benefit of AT 007 in Patients with Sorbitol Dehydrogenase (SORD) Deficiency

Randomizovaná, dvojitě zaslepená, placebem kontrolovaná, dvoudílná studie hodnotící farmakodynamickou účinnost a klinický přínos přípravku AT-007 u pacientů s deficitem sorbitoldehydrogenázy (SORD)

A.3.1

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

A phase 3 study to evaluate efficacy and clinical benefit of AT-007 with Sorbitol Dehydrogenase (SORD) Deficiency

Studie fáze 3 k vyhodnocení účinnosti a klinického přínosu AT-007 s deficitem sorbitoldehydrogenázy (SORD)

A.4.1

Sponsor's protocol code number

AT-007-1005

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	Applied 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	Applied 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	Applied Therapeutics Inc.
B.5.2	Functional name of contact point	Management
B.5.3	Address:
B.5.3.1	Street Address	545 Fifth Avenue \| Suite 1400
B.5.3.2	Town/ city	New York
B.5.3.3	Post code	10017
B.5.3.4	Country	United States
B.5.4	Telephone number	+1212220-9226
B.5.6	E-mail	rperfetti@appliedtherapeutics.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	Govorestat
D.3.2	Product code	AT-007
D.3.4	Pharmaceutical form	Oral suspension
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	Govorestat
D.3.9.1	CAS number	2170729-29-8
D.3.9.2	Current sponsor code	AT-007
D.3.9.3	Other descriptive name	S292
D.3.9.4	EV Substance Code	SUB213868
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	100
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 suspension
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

SoRbitol Dehydrogenase (SORD) DEficiency

E.1.1.1

Medical condition in easily understood language

Progressive and debilitating hereditary neuropathy that affects peripheral nerves and motor neurons, resulting in significant disability, loss of sensory function and decreased mobility.

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10029328
E.1.2	Term	Neuropathy
E.1.2	System Organ Class	100000004852

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

Clinical Outcome Objectives:

• To evaluate the effect of long-term (24 months) administration of AT-007 on the 10 m walk/run test (10MWRT) in patients with SORD Deficiency 16 to 55 years of age

Pharmacodynamic/Biomarker Objectives:
• To evaluate the effect of long-term (12 months) administration of AT-007 on the levels of blood sorbitol in patients with SORD Deficiency
• To evaluate the effect of long-term (12 months) administration of AT-007 on the levels of blood sorbitol in patients with SORD Deficiency

E.2.2

Secondary objectives of the trial

Clinical Outcome Objectives:
• To evaluate the effect of long-term (24 months) administration of AT-007 on the Charcot Marie Tooth Health Index (CMTHI) score in patients with SORD Deficiency
• To evaluate the safety of long-term administration and pharmacokinetic (PK) parameters of AT 007 in patients with SORD Deficiency

Pharmacodynamic/Biomarker Objectives:
• To evaluate the effect of long-term (12 months) administration of AT-007 on the CMT-related magnetic resonance imaging (MRI) parameters of disease progression inpatients with SORD Deficiency
• To evaluate the effect of long-term (24 months) administration of AT-007 on the levels of blood sorbitol in patients with SORD Deficiency
• To evaluate the effect of long-term administration (24 months only if Month 12 between-group difference [AT-007 minus placebo] is not statistically significant) of AT-007 on the CMT-related MRI parameters of disease progression in patients with SORD Deficiency

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Willing and able to provide signed and dated informed consent prior to any study-related procedures and willing and able to comply with all study procedures. Consent for minor patients (until the age of 18) must provided by parents or legal representatives.
2. Male and non-pregnant, non-lactating female patients between the ages of 16 and 55 years, inclusive.
3. Females must be of non-childbearing potential (defined as surgically sterile [i.e., had a bilateral tubal ligation, hysterectomy, or bilateral oophorectomy ≥6 months prior to the first dose of study drug] or postmenopausal for ≥1 year [confirmatory follicle-stimulating hormone or FSH test results required] prior to the first dose of study drug) or agree to use a highly effective form of birth control from Screening until 15 days (5 half-lives) after the last dose of study drug.
4. Males must be unable to procreate (defined as surgically sterile [i.e., had a vasectomy ≥6 months prior to Screening]) or must agree to use a highly effective form of birth control from Screening through 105 days (sum of 5-half-life and 90 days interval as per CTFG guidelines) after the last dose of study drug.
5. Clinical diagnosis of CMT2 or dHMN due to SORD Deficiency confirmed by medical record, elevated sorbitol level (>10,000 ng/mL), and gene analysis report confirming a pathogenic mutations in both the paternal and maternal SORD alleles (can be homozygous for the same mutation or compound heterozygous with two different pathogenic mutations).
6. Patient may be on concomitant medications and dietary supplements; however, they must be on stable doses for at least 1 month prior to Screening and throughout the study. In addition, all over-the-counter (OTC) and/or prescription medications must be reviewed and approved by the Investigator.
7. Willing and able to be confined to the clinical research unit (CRU) as required by the protocol.

E.4

Principal exclusion criteria

1. Carrier of a single heterozygous mutation of the SORD gene
2. 10MWRT classified as very severe disease (e.g. 10MWRT >15 seconds to complete OR unable to complete 10MWRT without the use of an assistive device such as a cane/walker/wheelchair).
3. History or presence of clinically significant hematopoietic, renal, hepatic, endocrine (e.g. diabetes), metabolic, pulmonary, neurological (e.g. other neuropathy, myopathy or neuromuscular disorder), psychiatric, cardiovascular, immunological, dermatological, or gastrointestinal diseases that are -at priori- altering the proper evaluation of the safety and efficacy of AT-007; conditions capable of altering the absorption, metabolism, or elimination of drugs; or conditions that constitute a risk factor when taking the study drug and/or impact the conduct or results of the study.
4. Body Mass Index (BMI) >35 kg/m2.
5. BMI < 17 kg/m2.
6. Positive test for hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus (HIV) at Screening or previous treatment for hepatitis B, hepatitis C, or HIV infection.
7. Individuals who smoke or use tobacco or nicotine-containing products.
8. Pregnant, lactating, or not using/not willing to use appropriate means of contraception.
9. Any prior history of substance abuse (including alcohol) or treatment for such.
10. Positive urine drug screen (UDS) for drugs of abuse (amphetamines, barbiturates, benzodiazepines, cocaine, opiates) or cotinine.
11. Prior bilateral ankle stabilization surgery.
12. Impaired renal function or estimated glomerular filtration rate (eGFR) less than 90 mL/min/1.73 m2. Note: The eGFR is an estimation of renal function, and the ultimate decision of whether a patient has normal renal function (and can be included in the study) is at the discretion of the Investigator, assuming there are no safety concerns. Also, because eGFR can vary from day to day based on outside factors, patients can be re-screened for eGFR multiple times to understand the renal function of the patient.
13. Hemoglobin (Hgb) < 10.0 g/dL at Screening.
14. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) or total bilirubin (except in case of Gilbert’s syndrome) > 1.5 x upper limit of normal (ULN) at Screening.
15. Urinary albumin-to-creatinine ratio (UACR) > 30 mg/g at Screening in the presence of elevated creatinine (>2X ULN).
16. History or presence of cardiovascular disorders including myocardial infarction, stroke, uncontrolled hypertension (sitting blood pressure ≥140/90 mmHg), left ventricular (LV) hypertrophy, atrial fibrillation, or valvular heart disease considered clinically significant by the Principal Investigator (PI).
17. Abnormal findings on the Screening 12-lead ECG, such as ST/T wave changes, pathological Q wave changes, or any rhythm other than normal sinus rhythm considered clinically significant by the PI.
18. Evidence of significant active hematological disease and/or cumulative blood donation of 1 unit (500 mL) or more including blood drawn during clinical studies in the last 3 months.
19. History of significant drug allergy or drug hypersensitivity.
20. Investigators, site personnel directly affiliated with this study, and their immediate families (defined as a spouse, parent, child, or sibling, whether biological or legally adopted).
21. Any other condition that, in the opinion of the Investigator, precludes the patient from following and completing the protocol.
22. A clinically significant abnormal finding on the physical exam, medical history, ECG, or clinical laboratory results at Screening, such pose a risk to the well being of the patient during the study.
23. Participation in another clinical study of a different investigational product within 30 days or 5 half-lives, whichever is longer, prior to the first dose of study drug.
24. Use of any OTC medication (including nutritional or dietary supplements, herbal preparations, or vitamins) ≤7 days prior to the first dose of study drug until the last dose of study drug without evaluation and approval by the Investigator.
25. Use of any prescription medication, from 30 days prior to the first dose of study drug until the last dose of study drug without evaluation and approval by the Investigator.
26. Treatment with any sensitive substrates of Breast Cancer Resistance Protein (BCRP) or potent inhibitors of BCRP.
27. Treatment with any sensitive substrates of cytochrome P450 3A4 (CYP3A4), CYP2B6, CYP2C19, or CYP1A2.
28. Treatment with sensitive substrates of Organic Anion Transporter (OAT)1 and OAT3. Treatment with any drugs potentially associated with transaminase elevations.
30. Potentially nephrotoxic drugs are prohibited

Please refer to main protocol and synopsis for full list of exclusion criteria

E.5 End points

E.5.1

Primary end point(s)

Clinical Outcomes Analyses: 10MWRT

Pharmacodynamic and Biomarker Analyses: Blood sorbitol

E.5.1.1

Timepoint(s) of evaluation of this end point

Clinical Outcomes Analyses: 24 months

Pharmacodynamic and Biomarker Analyses: 12 months

E.5.2

Secondary end point(s)

Clinical Outcomes Analyses: CMTHI

Pharmacodynamic and Biomarker Analyses:
CMT related MRI parameters of disease progression
Blood sorbitol

E.5.2.1

Timepoint(s) of evaluation of this end point

Clinical Outcomes Analyses: 24 months

Pharmacodynamic and Biomarker Analyses:

12 months
24 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

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)

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

Yes

E.8.4

The trial involves multiple sites in the 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

United States

Czechia

Italy

United Kingdom

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 months

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:	10
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	Yes
F.1.1.6.1	Number of subjects for this age range:	10
F.1.2	Adults (18-64 years)	Yes
F.1.2.1	Number of subjects for this age range:	62
F.1.3	Elderly (>=65 years)	No
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	20
F.4.2	For a multinational trial
F.4.2.1	In the EEA	72
F.4.2.2	In the whole clinical trial	72

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

2022-08-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-09-14

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

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