Trial of the Combined Use of Thiamine and Biotin in Patients With Huntington's Disease

NCT ID: NCT04478734

Last Updated: 2025-02-25

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 24 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-04-12
• Study Completion Date: 2025-12-30

Brief Summary

Evaluate the safety and tolerability of combined oral thiamine with biotin therapy in patients with Huntington´s disease in mild to moderate stages and it is intended to evaluate the biological effect of the treatment in the central nervous system of these patients using as the main biomarker the increase in the level of thiamine monophosphate (TMP) in cerebrospinal fluid (CSF) of these patients with Huntington Disease (HD) during a follow-up period of one year.

Our main hypothesis is that combined thiamine-biotin oral therapy is a secure and well-tolerated treatment, potentially capable of modifying the disease course or avoiding the progression of symptoms in early-stages HD patients

Detailed Description

The assessment of the safety and tolerability of the combined oral thiamine and biotin therapy in patients with HD will be performed by:

• Periodic clinical examination and anamnesis directed by a neurologist during face-to-face and non-contact visits.
• The collection of adverse effects during interviews of face-to-face visits to assess tolerability.
• Analytical monitoring with hematological and biochemical control (hepatic and renal function) during the dose escalation period, subsequently being this periodic control every 3 months, from signature of informed consent until the end the follow up.

The evaluation of the biological efficacy of treatment with combined oral thiamine and biotin therapy in increasing thiamine monophosphate (TMP) levels in cerebrospinal fluid (CSF) of patients with HD is to be performed by:

• The determination of thiamine levels: free thiamine, TMP, and thiamine pyrophosphate (TTP) in CSF and blood of patients at the beginning and after the end of the study.
• Comparison of thiamine levels (free, TMP and TTP) between the start and the end of the study in CSF and serum of patients with HD.

The evaluation of the biological efficacy of the treatment with combined oral thiamine and oral biotin therapy in neurodegeneration produced in HD will be performed by:

• Measurement of neurofilament light chain protein (NfL) levels in CSF at the baseline visit and after the end of the treatment.
• The obtained score in the motor and Total Functional Capacity (TFC) section of the Unified Huntington's Disease Rating Scale (UHDRS).
• Measurement of bradykinesia through quantitative motion measurement techniques (Quantitative motor assessment, Q-motor). Q-motor assessment relies on three-dimensional position sensors and pre-calibrated force translators, for standardized movement recording. This measurement will be made to patients in the pre-selection visit, randomization, and quarterly face-to-face visits.
• Score on the quality of life scale (SF-36).
• Variation in the overall clinical impression scale of the patient and the examiner.
• Measurement of the change in the volume of the caudate nucleus, white matter, and cortical thickness, as well as in the change of the Combined cerebral atrophy score. Measurements of cerebral structures will be acquired on magnetic resonance imaging scans (3T) at the baseline visit and after the end of the treatment.

To determine the sample size required to examine secondary and exploratory objectives, we based our estimations on the published thiamine-biotin treatment effects in preclinical HD models, and on the reported differences in CSF thiamine levels between HD patients and healthy subjects (Pico S, et al. 2021). According to the previous results, it is expected that a medium-to-high effect size (0.6 ≤ Cohen's d ≥ 0.8) would be necessary to restore TPP, TMP and Free-thiamine levels in CSF after treatment. Based on the parameter choices, for a desired power of 0.80 and a Type I error rate of 0.05, we estimate that we would need 24 HD patients to detect a standardized mean difference of 0.6. Sample size analysis was conducted using GPower 3.1.9.7 software.

The demographic data collection as well as the information related to all the variables analyzed during the study will be done through an electronic data collection notebook. The notification of adverse effects, severity, and relationship with study medication will be done through an electronic data collection notebook.

All statistical analyses will be conducted using SPSS v.26.0. IBM software and R studio software package. Linear regression will be used when the variables are quantitative (eg, scale measurements, CSF thiamine or NfL levels, among others) controlling for age, sex, CAG repetitions and motor symptom severity (UHDRS and UHDRS-Total Functional Capacity) at baseline as potential confounding variables. Logistic or multinomial regression when the variables are groups (binary or multinomial).

We will examine the association between the severity of disease and CSF thiamine among HD patients by fitting a linear mixed model for each clinical measurement, with age, sex, CAG repetitions and disease severity (UHDRS-TFC) as the covariates.

Magnetic resonance imaging performed during the study will be processed with specific neuroimaging programs for volumetry, diffusion and cortical thickness.

Conditions

Huntington Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Moderate doses

moderate doses of combination therapy applying the minimum average dosage of thiamine and biotin used in patients with BTBGD

Group Type: EXPERIMENTAL

Moderate doses of Thiamine y Biotin

Intervention Type: DRUG

Thiamine 600 mg every day + Biotin 150mg every day

High doses

high doses of the combination therapy applying the average standard dosage of thiamine and biotin used in patients with BTBGD.

Group Type: EXPERIMENTAL

High doses of Thiamine y Biotin

Intervention Type: DRUG

Thiamine 1200 mg every day + Biotin 300mg every day

Interventions

Moderate doses of Thiamine y Biotin

Thiamine 600 mg every day + Biotin 150mg every day

Intervention Type: DRUG

High doses of Thiamine y Biotin

Thiamine 1200 mg every day + Biotin 300mg every day

Intervention Type: DRUG

Other Intervention Names

moderate doses of combination therapy; high doses of the combination therapy

Eligibility Criteria

Inclusion Criteria

• Patients of legal age with manifest Huntington's disease with motor symptoms (chorea, dystonia or bradykinesia) and/or neuropsychiatric; and genetic confirmation of a number of repetitions of the cytosine-adenine-guanine trinucleotide (CAG triplet) in the HTT gene (coding for HTT) greater than or equal to 39
• Patients should be capable of giving informed consent and attending the planned visit of the study.
• Women of childbearing age should obtain a negative result in the serum or urine pregnancy test at the screening visit. They must also accept the use of appropriate contraceptive methods during the course of the clinical trial and men who have a partner of childbearing age, accept the use of contraceptive methods

Exclusion Criteria

• Medical comorbidities considered clinically significant by the clinical judgment of the investigators.
• Pregnancy or lactation
• Patients with HD dependents on the basic routine daily life activities (UHDRS TFC < 7) or a severe cognitive decline.
• Active psychosis at the moment of the screening evaluation.
• Severe renal failure.
• Patients previously treated with thiamine and/or biotin or enrolled in other HD clinical trial with oligonucleotide antisense (IONIS-HTTRX (RG6042).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Fundación Pública Andaluza para la gestión de la Investigación en Sevilla

OTHER

Sponsor Role: lead

Ciberned (Centro de Investigación Biomédica en Red)

UNKNOWN

Sponsor Role: collaborator

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Pablo Mir Rivera, MD/PhD

Role: STUDY_DIRECTOR

Institute of Biomedicine of Seville (IBiS)

Clara M. Rosso Fernández

Role: PRINCIPAL_INVESTIGATOR

Virgen del Rocío University Hospital Research and Clinical Trials Unit

Locations

Hospital Universitario de San Sebastián

San Sebastián, San Sebastian, Spain

Site Status: RECRUITING

Virgen del Rocío Hospital

Seville, Seville, Spain

Site Status: RECRUITING

Hospital Ramón y Cajal

Madrid, , Spain

Site Status: RECRUITING

Countries

Spain

Central Contacts

Pablo Mir Rivera, MD/PhD

Role: CONTACT

pmir@us.es

+34 955923039

Clara M. Rosso Fernández, MD/PhD

Role: CONTACT

claram.rosso.sspa@juntadeandalucia.es

+34 955012144

Facility Contacts

Javier Ruiz Martinez, MD

Role: primary

javier.ruizmartinez@osakidetza.eus

(0034) 943007027

Pablo Mir Rivera, MD/PhD

Role: primary

pmir@us.es

+34955923039

José Luis López-Sendón, MD

Role: primary

jlsendonmoreno@salud.madrid.org

0034 913368013

Other Identifiers

HUNTIAM

Identifier Type: -

Identifier Source: org_study_id