2.1.1.1 Clinical trial identifiers

EU trial number:

2024-518875-73-00

Full title (English):

Randomised, double-blind, placebo-controlled study to evaluate the effect of metformin, an AMPK activator, on cognitive measures of progression in Huntington's disease patients.

Public title (English):

Randomised, double-blind, placebo-controlled study to evaluate the effect of metformin, an AMPK activator, on cognitive measures of progression in Huntington's disease patients.

Protocol code:

TEMET-HD

2.1.1.2 Secondary identifying numbers

WHO universal trial number (UTN):

ClinicalTrials.gov identifier (NCT number):

ISRCTN number:

2.1.1.3 Additional registries

2.1.2.1 Transition Trial

EudraCT number:

2016-003783-39

2.1.2.2 Trial Category

Trial phase:

Therapeutic confirmatory (Phase III)

Trial category:

2

Justification for trial category:

Clinical trial phase III

2.1.2.3 Medical Conditions

Medical condition(s) (English):

Huntington Disease

Is the medical condition considered to be a rare disease:

Yes

Therapeutic area:

Diseases [C] - Nervous System Diseases [C10]

2.1.2.4 Medical condition(s) MedDRA information

Version	Level	Classification code	Term name	System organ class

2.1.2.5 Main objective

Trial scope:

Efficacy

Main objective (English):

The main objective of this study is to evaluate the effect of metformin on the scores obtained in different cognitive subtests that make up the Unified Huntington's Disease Rating Scale (UHDRS) and that have been shown to be very sensitive to disease progression from early stages and even in the pre-symptomatic phase.

2.1.2.6 Secondary objective

Secondary objective number	Secondary objective (English)
1	To evaluate the efficacy of metformin on motor function in HD patients after 6 and 12 months of treatment using the UHDRS-TMS (Unified Huntington's Disease Scale Total Motor Score). Evaluation of motor function will include the following tests: OCULAR PURSUIT (horizontal and vertical), SACCADE INITIATION (horizontal and vertical), SACCADE VELOCITY (horizontal and vertical), DYSARTHRIA, TONGUE PROTRUSION, DISTONY (trunk and limbs), CHOREA (face, mouth, trunk and limbs), RETROPULSION TEST, FINGER TAPS (right and left), PRONATE/SUPINATE-HANDS (right and left), LURIA (palm test), ARM RIGIDITY (right and left), BRADY KINESIA-BODY, GAIT (walking difficulties), TANDEM WALKING. These tests have been described by the Huntington Study Group.
2	To evaluate the effect of metformin on functional capacity in HD patients after 6 and 12 months of treatment using the UHDRS-TFC scale. This will be evaluated by means of a questionnaire on the following variables: OCCUPATION, FINANCES, ADLs (activities of daily living), HOUSEHOLD WORK and LEVEL OF CARE.
3	To evaluate the effect of metformin on the degree of independence in HD patients after 6 and 12 months of treatment. This will be evaluated using the UHDRS-FA questionnaire and independence scale where the degree of independence of the subject is scored and evaluated.
4	To evaluate the effect of metformin on behavioural signs and symptoms in HD patients after 6 and 12 months of treatment using the Problem Behaviors AssessmentShort form (PBA-s). Specifically, changes in severity scores on the items of depressed mood, suicidal ideation, anxiety, irritability, aggressiveness, apathy, perseverative behaviour and thinking, obsessive-compulsive behaviour, delusional ideation, hallucinations and disorientation will be evaluated.
5	To evaluate the safety and tolerability of metformin in HD patients during patient participation in the trial by evaluating adverse events (AEs) and clinical laboratory parameters, vital signs, physical examinations and premature discontinuations from the study.
6	To analyse whether there are genetic markers associated with a better (or worse) response to metformin, using pharmacogenetics.
7	To analyse neurofilament light chain protein in peripheral blood as a circulating biomarker.

2.1.2.7 Principal inclusion criteria

Inclusion criteria number	Principal inclusion criteria (English)
1	Positive symptomatic clinical diagnosis of HD.
10	They should be able to travel to the study site, and in the judgement of the investigator, show that they are likely to be able to continue to travel for the duration of the study.
11	Availability and willingness of a carer, informant, or family member to provide information during study visits assessing PBAs. It is recommended that the carer be someone who attends the patient at least 2-3 times per week and for at least 3 hours per occasion. The suitability of the carer should be judged by the researcher.
2	Presence of ≥ 36 CAG repeats (or more) in the huntingtin gene based on centralised CAG analysis.
3	Males or females between 21-65 years of age, inclusive, with an onset of HD at 18 years of age or older.
4	Women of childbearing age (women who are not postmenopausal or who have not undergone surgical sterilisation) should be using a method of contraception for 30 days prior to starting study treatment, and should maintain at least two methods of birth control for the duration of the study and until 30 days after the last dose of treatment is taken.
5	A sum of > 4 points on the UHDRS-TMS scale and a diagnostic confidence level of 4.
6	Independence scale ≥ 75 %.
7	A score on the UHDRS-TFC scale ≥ 8 at the screening visit.
8	Must be able and willing to provide written informed consent prior to any study-related procedures being performed at the screening visit. Patients with a legal guardian must be authorised according to local requirements.
9	They should be able and willing to take oral medication and should be able to comply with study-specific procedures.

2.1.2.8 Principal exclusion criteria

Exclusion criteria number	Principal exclusion criteria (English)
1	Taken metformin in the last three months prior to the start of the study.
10	You have been treated for heart failure or recently had a heart attack, have severe problems with circulation, or have difficulty breathing.
11	Drinking > 6 units/day of alcohol (alcoholism).
12	Has been diagnosed with oncological disease.
13	Presents suicidal propensity, with affirmative response in items 4 or 5 in the C-SSRS in the screening visit.
2	Have diabetes of any type.
3	You are pregnant or breastfeeding.
4	Have any medical condition other than HD (metabolism, kidney function, liver function, heart problems, etc.), or any contraindication against metformin.
5	Having an uncontrolled psychiatric condition.
6	You are allergic to metformin or any of the other ingredients of this medicine.
7	Have renal [creatinine clearance <60 ml/min calculated by Cockcroft - Gault formula] or hepatic problems.
8	Tiene deshidratación, por diarrea prolongada o severa, o ha vomitado varias veces.
9	It presents a serious infection.

2.1.2.9 Primary end points

End point criteria number	Primary end point (English)
1	The tests that make up this subscale are the Symbol Digit Modalities Test, verbal fluency under phonetic command with the letters F, A and S, colour naming, word naming and interference in the Stroop test. The sum of the raw scores obtained makes up the UHDRS cognitive score, which is the primary endpoint of this study.

2.1.2.10 Secondary end points

Secondary end point number	Secondary end point (English)

2.1.2.11 Individual Participant Data (IPD) Sharing statement

Plan to share IPD:

Yes

Plan description:

The primary publication of this study will report the results of the study in accordance with the ‘Uniform Requirements for Manuscripts Submitted to Biomedical Journals’ as set forth by the International Committee of Medical Journal Editors (www.ICMJE.org). Authorship will be limited to those parties with editorial or conceptual input to protocol design, data collection and/or analysis, data interpretation, and manuscript preparation. Additional publications may follow.

2.1.2.12 Participants

Gender:

Male and Female

Age range:

65+ years, 18-64 years

Age range secondary identifier:

Clinical trial group:

Patients

Vulnerable population:

No

2.1.3.1 Study design

Period details:

Number	Period title	Period description	Allocation method	Blinding used	Roles blinded	Blinding implementation details	Arm details

2.2.1.1 Product: DUMMY METFORMINE 850 mg COATED TABLETS

Type

Product

Excluded MSCs

2.2.1.1.1 Product details

Medicinal product name:

DUMMY METFORMINE 850 mg COATED TABLETS

EU medicinal product number/medicinal product unique ID:

N/A

Pharmaceutical form:

N/A

Strength:

Medicinal product other name:

N/A

Is this a specific paediatric formulation:

No

Product authorisation status:

Medicinal product role in trial:

Placebo

Sponsors product code:

2.2.1.1.2 Products characteristics

Medicinal product characteristics:

Other medicinal product:

2.2.1.1.3 Dosage and administration Details

Route of administration:

Maximum duration of treatment:

undefined Week(s)

Maximum daily dose allowed:

Daily dose unit of measure:

Maximum total dose allowed:

Total dose unit of measure:

2.2.1.1.4 Information about the modification of the medicinal product

Has the medicinal product been modified in relation to its Marketing Authorisation:

No

Description of the modification:

2.2.1.1.5 Product classification

Anatomical Therapeutic Chemical (ATC) Codes:

N/A

ATC name:

N/A

ATC level:

N/A

2.2.1.1.6 Product authorisation details

MA holder

N/A

MA authorisation country

Iceland

Marketing authorisation number

N/A

Centralised procedure/MRP/DCP/registration procedure number

2.2.1.1.7 Orphan designation

Does this product have an orphan drug designation:

No

Designation number for orphan drug:

2.2.1.1.8 Active substance

Classification:

Active Substance name:

Active substance name synonyms:

Active Substance other descriptive name:

N/A

EU Active Substance Code:

N/A

Strength:

Status:

2.2.1.1.9 Advanced therapy medicinal product

2.2.1.1.10 Device associated with medicinal product

Product used in combination with a device	Product ID	Device trade name	Description of the device	Type of device	Device has CE mark	Device notified body

2.2.1.1 Compliance with (GMP) for the medicinal product

Authorisation number of manufacturing and import:

6540E

2.2.2.1 Product: Metformina Galenicum 850 mg comprimidos recubiertos con película EFG

Type

Product

Excluded MSCs

2.2.2.1.1 Product details

Medicinal product name:

Metformina Galenicum 850 mg comprimidos recubiertos con película EFG

EU medicinal product number/medicinal product unique ID:

PRD10198393

Pharmaceutical form:

FILM-COATED TABLET

Strength:

Medicinal product other name:

Is this a specific paediatric formulation:

No

Product authorisation status:

Authorised

Medicinal product role in trial:

Test

Sponsors product code:

2.2.2.1.2 Products characteristics

Medicinal product characteristics:

Other

Other medicinal product:

biguanide with antihyperglycaemic effects

2.2.2.1.3 Dosage and administration Details

Route of administration:

ORAL

Maximum duration of treatment:

52 Week(s)

Maximum daily dose allowed:

1700

Daily dose unit of measure:

mg milligram(s)

Maximum total dose allowed:

1700

Total dose unit of measure:

mg milligram(s)

2.2.2.1.4 Information about the modification of the medicinal product

Has the medicinal product been modified in relation to its Marketing Authorisation:

No

Description of the modification:

2.2.2.1.5 Product classification

Anatomical Therapeutic Chemical (ATC) Codes:

A10BA02

ATC name:

METFORMIN

ATC level:

5

2.2.2.1.6 Product authorisation details

MA holder

GALENICUM HEALTH, S.L.

MA authorisation country

Spain

Marketing authorisation number

88536

Centralised procedure/MRP/DCP/registration procedure number

2.2.2.1.7 Orphan designation

Does this product have an orphan drug designation:

No

Designation number for orphan drug:

2.2.2.1.8 Active substance

Classification:

Chemical

Active Substance name:

METFORMIN HYDROCHLORIDE

Active substance name synonyms:

Active Substance other descriptive name:

EU Active Substance Code:

SUB03200MIG

Strength:

Status:

Authorised

2.2.2.1.9 Advanced therapy medicinal product

2.2.2.1.10 Device associated with medicinal product

Product used in combination with a device	Product ID	Device trade name	Description of the device	Type of device	Device has CE mark	Device notified body

2.2.2.1 Compliance with (GMP) for the medicinal product

Authorisation number of manufacturing and import:

6540E