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.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

IIS La Fe

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

10 Dec 2021 → 10 Jun 2025

Decision date (initial)

2024-12-11

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

External identifiers

EU CT number

2024-518875-73-00

EudraCT number

2016-003783-39

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

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.

Secondary objectives 7

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.

Conditions and MedDRA coding

Huntington Disease

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Positive symptomatic clinical diagnosis of HD.
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.
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.

Exclusion criteria 13

1. Taken metformin in the last three months prior to the start of the study.
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.
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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

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.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

IIS La Fe

Sponsor organisation

IIS La Fe

Address

Avenida De Fernando Abril Martorell 106 A 7 Planta

City

Valencia

Postcode

46026

Country

Spain

Scientific contact point

Organisation

IIS La Fe

Contact name

Carmen Peiró Vilaplana

Public contact point

Organisation

IIS La Fe

Contact name

María josé Carrión Martínez

Locations

1 EU/EEA country · 9 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 6 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications