Clinical Trials Register

Summary
EudraCT Number:	2022-002301-24
Sponsor's Protocol Code Number:	NMD670-02-0001
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:	2023-01-19
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

2022-002301-24

A.3

Full title of the trial

A Phase 2, randomised, double-blind, placebo-controlled, 2-way crossover study to evaluate the efficacy, safety, and tolerability of NMD670 in ambulatory adults with Type 3 spinal muscular atrophy

A.3.1

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

Safety and efficacy of NMD670 in ambulatory adult patients with Type 3 spinal muscular atrophy (SYNAPSE-SMA)

A.4.1

Sponsor's protocol code number

NMD670-02-0001

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	NMD Pharma A/S
B.1.3.4	Country	Denmark
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	NMD Pharma A/S
B.4.2	Country	Denmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Parexel International
B.5.2	Functional name of contact point	Clinical Trials Information
B.5.3	Address:
B.5.3.1	Street Address	70 Sir John Rogerson's Quay
B.5.3.2	Town/ city	Dublin
B.5.3.3	Post code	2
B.5.3.4	Country	Ireland
B.5.6	E-mail	clinicaltrial.enquiries@parexel.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	NMD670
D.3.4	Pharmaceutical form	Film-coated tablet
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.3.9.1	CAS number	2354321-33-6
D.3.9.2	Current sponsor code	NMD670
D.3.9.3	Other descriptive name	NMD670
D.3.9.4	EV Substance Code	SUB208279
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
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.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	NMD670
D.3.4	Pharmaceutical form	Film-coated tablet
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.3.9.1	CAS number	2354321-33-6
D.3.9.2	Current sponsor code	NMD670
D.3.9.3	Other descriptive name	NMD670
D.3.9.4	EV Substance Code	SUB208279
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	300
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	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
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

Type 3 spinal muscular atrophy

E.1.1.1

Medical condition in easily understood language

spinal muscular atrophy - an inherited condition that makes the muscles weaker and causes problems with movement.

E.1.1.2

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

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	10079415
E.1.2	Term	Spinal muscular atrophy type III
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

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 assess changes in muscle strength and function after NMD670 400 mg bid for 21 days, compared with placebo, in participants with SMA

E.2.2

Secondary objectives of the trial

- To assess changes in muscle strength after NMD670 400 mg bid for 21 days, compared with placebo, in participants with SMA
- To further assess changes in muscle strength and function after NMD670 400 mg bid for 21 days, compared with placebo, in participants with SMA
- To assess changes in neuromuscular junction transmission after NDM670 400 mg bid for 21 days, compared with placebo, in participants with SMA
- To assess the safety and tolerability of NMD670, compared with placebo, over 21-day dosing, in participants with SMA

Exploratory objectives:
- To assess changes in patient-reported quality of life and fatigue severity after 21-day dosing of NMD670, compared with placebo, in participants with SMA
- To explore drug exposure after NMD670 400 mg bid for 21 days in participants with SMA

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Participant must be 18 to 75 years of age inclusive, at the time of signing the informed consent.
2. Participants who are with a clinical diagnosis of Type 3 SMA.
3. Participants who are ambulatory, defined as being able to walk at least 50 metres without walking aids at screening during the 6-minute walk test.
4. Participant with genetic confirmation of diagnosis (e.g., homozygous deletion or compound heterozygous deletion and mutation of survival of motor neuron 1 gene [SMN1]).
5. Participant with 3 to 5 copies of survival of motor neuron 2 gene [SMN2].
6. Participants with an MFM-32 dimension 1 (D1) score <80% at screening.
7. Participants with ≥7% CMAP amplitude decrement at screening [RNS].
8. Participant has a body mass index (BMI) within the range 19-35 kg/m2 (inclusive).
9. Participant is male or female.
10. Contraceptive use by men and women must be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
Male Participants:
• A male participant must agree to use a highly effective contraception as detailed in Appendix 4 of this protocol during the intervention period and until the follow-up visit (corresponding to time needed to eliminate study intervention) and refrain from donating sperm during this period.
Female Participants:
• A female participant is eligible to participate if she is not pregnant (see Appendix 4), not breastfeeding, and at least one of the following conditions applies:
o Not a woman of childbearing potential (WOCBP) as defined in Appendix 4.
OR
o A WOCBP who agrees to follow the contraceptive guidance in Appendix 4 during the intervention period and until the follow-up visit (corresponding to time needed to eliminate study intervention).
11. Participant is capable of giving signed informed consent as described in Appendix 1, Section 10.1.3 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

E.4

Principal exclusion criteria

1. Participants with prior surgery or fixed deformity (scoliosis, contractures) which would restrict ability to perform study-related tasks.
2. Participants with other significant disease that may interfere with the interpretation of study data (e.g., other neuromuscular or muscular diseases).
3. Participant with a clinical diagnosis of gout, or with serum uric acid > ULN at screening.
4. Participant with clinically significant electrocardiogram (ECG) abnormalities at screening including PR interval ≥220 msec, irregular rhythms (other than sinus arrhythmia or occasional, rare supraventricular or rare ventricular ectopic beats) in the judgement of the Investigator, or T-wave configurations are not of sufficient quality for assessing QT interval duration.
5. Participant with any of the following abnormalities in QT interval corrected for heart rate using Fridericia’s correction (QTcF) at screening:
a. QTcF >450 msec for male participants without bundle branch block.
b. QTcF >470 msec for female participants without bundle branch block.
c. QTcF >480 msec in participants with bundle branch block.
6. Participant with any of the following:
a. Abnormal liver function test defined as total bilirubin >1.5×ULN (participants with Gilbert's syndrome can be included with total bilirubin >1.5×ULN if direct bilirubin is ≤1.5×ULN and ≤35% of total bilirubin).
b. Current or chronic history of liver disease including (but not limited to) hepatitis virus infections, drug- or alcohol-related liver disease, non-alcoholic steatohepatitis, autoimmune hepatitis, hemochromatosis, Wilson's disease, α-1 antitrypsin deficiency, primary biliary cholangitis, primary sclerosing cholangitis, or any other liver disease
considered clinically significant by the Investigator.
c. Known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
7. Participant with clinically significant laboratory test abnormalities at screening.
8. Participant with breast cancer within the past 10 years or lymphoma, leukaemia, or any malignancy within the past 5 years. An exception of this 5-year requirement is basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease.
9. Participants with ongoing significant psychiatric disorder (e.g., uncontrolled depression, anxiety).
10. Participants with positive drug screen (cocaine, heroin, opiates, and ketamine at screening. Participants will not be excluded from the study if they showed a positive drug screen due to medically prescribed opiates or ketamine.
11. Participants with positive human immunodeficiency virus (HIV) antibody test.
12. Participants with presence of hepatitis B surface antigen (HBsAg) [or hepatitis B core antibody (HBcAb)] at screening or within 3 months prior to first dose of investigational intervention.
13. Participants with positive hepatitis C antibody or ribonucleic acid (RNA) test result at screening or within 3 months prior to Day 1.
NOTE: Participants with hepatitis C with positive hepatitis C antibody could be enrolled, if a negative hepatitis C RNA test is obtained.
14. Participants with a clinically significant history of allergic conditions (including drug allergies and anaphylactic reactions) or hypersensitivity to any component of the study intervention.
15. Participants with evidence of a lens opacity or cataract, or an inability to undergo the ophthalmologic evaluation, at screening.
16. Participants who have received any prohibited medication within 30 days (or 5 half-lives of the medication, whichever is shorter), or are likely to require treatment with prohibited medications during the study. Prohibited medications are listed in Section 6.9 and include drugs
affecting neuromuscular transmission (such as anticholinergic drugs), drugs showing relevant effect on ClC-1 channel, drugs with potential drug-drug interactions with NMD670. Other current and recent (within 1 month prior to the screening) treatments will be allowed, if judged by the Investigator to have no clinical relevance.
17. Participants received treatment with an investigational medicinal product (IMP) within 30 days (or 5 half-lives of the medication, whichever is longer) prior to Day 1.
18. Participants unable to perform or tolerate electromyography (EMG), according to medical history or at screening.
19. Participants with history of poor compliance with relevant SMA therapy.

E.5 End points

E.5.1

Primary end point(s)

Change from baseline in 6MWT (total distance) after 21-day dosing

E.5.1.1

Timepoint(s) of evaluation of this end point

After 21 day dosing

E.5.2

Secondary end point(s)

Change from baseline in individual muscle groups maximum strength (measured with a dynamometer) after 21-day dosing
Change from baseline after 21-day dosing in:
• 6MWT (fatigue index)
• revised Hammersmith scale score
Change from baseline in jitter and blocking measured via sfEMG after 21-day dosing
AEs, physical examinations, clinical laboratory parameters, vital signs, ECG, C-SSRS

Exploratory:
Change from baseline after 21-day dosing in:
• INQoL score
• FSS
Plasma levels of NMD670 and its metabolite NMD1190

E.5.2.1

Timepoint(s) of evaluation of this end point

After 21 day dosing
During study participation

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

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

Canada

United States

Belgium

Denmark

Germany

Italy

Netherlands

Spain

E.8.7

Trial has a data monitoring committee

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:

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

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)

Standard of care

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

2023-02-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2023-04-26

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

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