Aim stated in the publication

“We aimed to assess the safety and efficacy of levacetylleucine for paediatric and adult patients with ataxia-telangiectasia.” (opens the source at this quote in a new tab)

Purpose and primary objective in the trial protocol

“The primary purpose of the study is to evaluate the safety and efficacy of N-Acetyl-L-Leucine (IB1001) in the treatment of Ataxia-Telangiectasia (A-T)” (opens the source at this quote in a new tab)
“The primary objective is to evaluate the efficacy of N-Acetyl-L-Leucine based on the Scale for the Assessment and Rating of Ataxia (SARA) for the chronic treatment of A-T.” (opens the source at this quote in a new tab)

Secondary and exploratory objectives in the trial protocol

“To assess the clinical efficacy of N-Acetyl-L-Leucine on neurological signs, symptoms, functioning, and quality of life for patients with A-T;” (opens the source at this quote in a new tab)
“To evaluate the safety and tolerability of N-Acetyl-L-Leucine in weight-tiered doses in patients with A-T” (opens the source at this quote in a new tab)
“To characterize the pharmacokinetics (PK) of N-Acetyl-L-Leucine in patients with A-T” (opens the source at this quote in a new tab)

Symptomatic parent study and long-term extension phase

“The IB1001-303 clinical trial was separated into two study phases to enable the investigation of the symptomatic (parent study) and long-term (open-label extension phase) safety and efficacy of levacetylleucine.” (opens the source at this quote in a new tab)
“The results of the parent study are reported below and are closed to new participants. The extension phase is ongoing.” (opens the source at this quote in a new tab)

Objective stated in the registry record

“The objective of this study is to evaluate the safety, tolerability and efficacy of N-acetyl-L-leucine (IB1001) compared to standard of care.” (opens the source at this quote in a new tab)

Countries and number of centers

“In this phase 3, randomised, double-blind, placebo-controlled crossover trial, participants were enrolled across ten research hospitals in Germany, Slovakia, Spain, Switzerland, the UK, and the USA.” (opens the source at this quote in a new tab)

Screening and enrollment period

“Between March 18, 2025 and June 30, 2025, 77 participants with a genetically confirmed diagnosis of ataxia-telangiectasia were screened for inclusion.” (opens the source at this quote in a new tab)

Participating centers named in the publication

“We thank the study teams and co-investigators from Comenius University in Bratislava, Hospital La Paz Madrid, Justus Liebig University Giessen, Massachusetts General Hospital, Nottingham University Hospital NHS Trust, Royal Papworth NHS Foundation Trust, University Hospital of L. Pasteur Kosice, University of Bern, University of Cologne, and UTHealth Houston.” (opens the source at this quote in a new tab)

Study locations in the registry record

Facility	City	Country
“University of California Los Angeles”	“Los Angeles”	“United States”
“Massachusetts General Hospital”	“Boston”	“United States”
“The University of Texas Health (UT Health)”	“Houston”	“United States”
“University of Cologne”	“Cologne”	“Germany”
“University of Giessen”	“Giessen”	“Germany”
“Comenius University Bratislava”	“Bratislava”	“Slovakia”
“University Hospital L. Pasteur”	“Košice”	“Slovakia”
“Hospital Universitario La Paz”	“Madrid”	“Spain”
“University of Bern”	“Bern”	“Switzerland”
“Royal Papworth Hospital”	“Cambridge”	“United Kingdom”
“University of Nottingham”	“Nottingham”	“United Kingdom”

Study dates in the registry record

Field	Registry value
Study start (actual)	“2025-03-18”
Primary completion (estimated)	“2027-12-31”
Study completion (estimated)	“2028-06-01”
First posted	“2024-11-04”
Last update posted	“2025-07-03”

European Union trial start and recruitment start by member state

Member state	Decision date	Trial start date	Recruitment start date
Germany	“25/03/2025”	“13/05/2025”	“13/05/2025”
Spain	“25/03/2025”	“13/05/2025”	“29/05/2025”
Slovakia	“26/03/2025”	“13/05/2025”	“19/05/2025”

Planned number of centers and participants traveling from other countries

“The trial will be conducted at a total of approximately 9 centers in Germany, Slovakia, Spain, Switzerland, the United Kingdom (UK), and the United States (US), which must meet the structural and personnel requirements for performing the planned regular trial-related investigations.” (opens the source at this quote in a new tab)
“Note: It is permitted that patients from other countries (e.g. who do not live in a country where there are designated study centers) are allowed to travel from abroad to the study centers with permission from the Sponsor.” (opens the source at this quote in a new tab)

Prescribing information: randomized, double-blind, placebo-controlled, two-period crossover design

“The safety and efficacy of AQNEURSA for the treatment of ataxia in patients with A-T were evaluated in a randomized, double-blind, placebo-controlled, two-period crossover study that evaluated the efficacy of AQNEURSA in 73 patients (Trial 2; NCT06673056).” (opens the prescribing information at this quote)
“Patients were assessed over a 2-week baseline period. Patients were then randomized in a 1:1 ratio to one of the two treatment sequences:” (opens the prescribing information at this quote)
“Treatment Sequence 1 (N=36): AQNEURSA in Treatment Period I, followed by immediate crossover to placebo in Treatment Period II” (opens the prescribing information at this quote)
“Treatment Sequence 2 (N=37): placebo in Treatment Period I, followed by immediate crossover to AQNEURSA in Treatment Period II.” (opens the prescribing information at this quote)

Baseline period, treatment periods, and visit schedule

“The study consisted of a baseline period followed by two 12-week treatment periods (figure 1). In the baseline period, there were two visits, which occurred 14–21 days apart. At the second baseline visit (visit 2), eligible patients were randomly assigned to receive either levacetylleucine or placebo in period 1, which they immediately commenced and received for 84–91 days. At the end of the first treatment period (visit 4), patients immediately crossed over to receive the opposite study drug in period 2 for 84–91 days. Two visits occurred in each period (period 1: visit 3 and 4; period 2: visit 5 and 6).” (opens the source at this quote in a new tab)

Duration of participation in the parent study

“The study duration for all patients, from the first day of dosing with treatment (IB1001 or placebo) (Visit 2) to the final follow-up visit (Visit 6), is expected to be approximately 168 days.” (opens the source at this quote in a new tab)

Randomization method

“Randomisation was done centrally by Medpace, a clinical research organisation, with the use of computerised interactive response technology.” (opens the source at this quote in a new tab)
“The study used a permuted block design for randomisation of four-patient block sizes. The live randomisation list was generated by an independent statistician based on the approved randomisation plan.” (opens the source at this quote in a new tab)
“As the trial was a crossover design, in which each patient received levacetylleucine and placebo and therefore served as their own control, no stratification by age was done.” (opens the source at this quote in a new tab)

Masking

“All participants, investigators, and assessors were blinded to group assignment.” (opens the source at this quote in a new tab)
“Patients, their families, the study team, the principal investigator, and the sponsor were blinded to the randomisation scheme and the sequences to which each patient was assigned until after database lock and study unblinding.” (opens the source at this quote in a new tab)
“The success of masking was not formally assessed, given its high potential to introduce bias and lead to misinterpretations of participant and caregiver perceptions and responses.” (opens the source at this quote in a new tab)

Design summary in the registry record

“Randomized, placebo-controlled, double-blind, crossover, multi-center, study with 1:1 randomization of IB1001 plus SOC for 12-weeks versus placebo plus SOC for 12-weeks, followed by open-label extension study.” (opens the source at this quote in a new tab)

Immediate crossover without a washout period: rationale in the trial protocol

“At the end of Treatment Period I (Visit 4), patients will immediately crossover to receive the opposite treatment (IB1001 or placebo) during Treatment Period II.” (opens the source at this quote in a new tab)
“Based on the study, the optimal statistical method for analyzing the SARA primary endpoint was found to be analysis of covariance comparing the mean of the SARA difference (the end of Treatment Period I (Visit 4) minus the mean SARA at the end of Treatment Period II (Visit 6)) between the two treatment sequences with Baseline SARA (Visit 2) as a covariate.” (opens the source at this quote in a new tab)
“Note: Methods 1 and 2 do not require a washout period between treatment periods 1 and 2.” (opens the source at this quote in a new tab)
“Based on these results, Method 2 is utilized as the basis for the primary analysis for this study. This method not only maximizes the study power but helps ensure the feasibility of recruitment and the retention of subjects in the trial by minimizing the time patients are required to be without unlicensed alternatives.” (opens the source at this quote in a new tab)

Screening pathways for participants with and without recent use of prohibited medications

“A urine sample will be taken at Visit 1 to detect N-Acetyl-D-Leucine. Provided the patient’s level of N-Acetyl-D-Leucine is below the permitted threshold, the initial screening visit will be confirmed as Visit 1 (Baseline 1).” (opens the source at this quote in a new tab)
“Note – at European trial sites (Spain, German, and Slovakia), only naïve patients may be enrolled in the trial.” (opens the source at this quote in a new tab)
“Patients are eligible to return for a second screening visit after a minimum of 42 days washout.” (opens the source at this quote in a new tab)

Open-label extension phase

“Patients who completed the study (visit 6) were eligible to continue into an open-label extension phase, which is ongoing.” (opens the source at this quote in a new tab)

“The Extension Phase currently guarantees patients access to IB1001 for one year, followed by a 42-day washout period.” (opens the source at this quote in a new tab)
“The Extension Phase will collect information on the long-term safety, tolerability, pharmacokinetics (PK), and efficacy of IB1001 as a treatment for A-T for the purpose of further assessing the risk/ benefit balance of the investigational medicinal product in the proposed clinical setting.” (opens the source at this quote in a new tab)

Data monitoring and availability of the protocol and statistical analysis plan

“The safety, integrity, and feasibility of the trial were also monitored by an independent data safety monitoring board consisting of two clinicians and a statistician.” (opens the source at this quote in a new tab)
“The study protocol and statistical analysis plan are available in the appendix (pp 13–162, 164–227).” (opens the source at this quote in a new tab)

Funding and role of the sponsor

“The funder collaborated with authors during study design but had no role in data collection, data analysis, data interpretation, or writing of the report.” (opens the source at this quote in a new tab)
“The study was funded by IntraBio.” (opens the source at this quote in a new tab)
“Finally, we thank Taylor Fields for her leadership of and dedication to the levacetylleucine development programme and for assistance in carrying out clinical trials and for writing and editorial assistance with the manuscript.” (opens the source at this quote in a new tab)

FDA description of the trial

“The effectiveness of Aqneursa was evaluated in a randomized, double-blind, placebo-controlled, two-period crossover study (NCT06673056) of 73 patients aged 4 years or older with a confirmed diagnosis of ataxia-telangiectasia. Patients were randomly assigned to receive Aqneursa followed by placebo, or placebo followed by Aqneursa, with each treatment period lasting 12 weeks.” (opens the source at this quote in a new tab)

Master protocol published for the Niemann-Pick disease type C trial: rationale for the crossover design

“Details of the methods, rationale, design, and oversight of the master study protocol have been previously published.” (opens the source at this quote in a new tab)

“Given the extreme heterogeneity of the disease, a crossover study design is utilized so that each patient serves as their own control and the clinical meaningfulness of the effect can be assessed for each patient.” (opens the source at this quote in a new tab)

Prescribing information: age, diagnosis, and ataxia at baseline

“To be eligible for the study, patients had to be aged 4 years or older with a confirmed diagnosis of A-T. Patients were required to have at least mild ataxia at baseline. Ataxia may be comprised of multiple signs and symptoms, including gait ataxia, truncal ataxia, oculomotor ataxia, and difficulties with balance, speech, and hand coordination.” (opens the prescribing information at this quote)

Key inclusion criteria: genetic confirmation, ataxia severity, and body weight

“Eligible patients were aged 4 years or older with a genetically confirmed diagnosis of ataxia-telangiectasia; had a SARA score of 7–34 and were either within the 2–7 range of the gait subtest of the SARA scale or were able to perform the 9-hole peg test with their dominant hand in a time of 20–150 sec; and weighed 15 kg or more at screening.” (opens the source at this quote in a new tab)

Inclusion criteria in the registry record

“Male or female aged ≥4 years with a genetically confirmed diagnosis of A-T at the time of signing informed consent.” (opens the source at this quote in a new tab)
“A SARA score of 7 ≤ X ≤ 34 points (out of 40) AND” (opens the source at this quote in a new tab)
“Within the 2-7 range (0-8 range) of the Gait subtest of the SARA scale OR ii. Be able to perform the 9-Hole Peg Test with Dominant Hand (9HPT-D) (SCAFI subtest) in 20 ≤ X ≤150 seconds.” (opens the source at this quote in a new tab)
“Weight ≥15 kg at screening.” (opens the source at this quote in a new tab)

Inclusion criteria: stable background medications and therapies

“Patients are willing to disclose their existing medications/therapies for (the symptoms) of A-T, including those on the prohibited medication list.” (opens the source at this quote in a new tab)
“The Investigator does not believe the medication/therapy will interfere with the study protocol/results” (opens the source at this quote in a new tab)
“Patients have been on a stable dose/duration and type of therapy for at least 42 days before Visit 1 (Baseline 1)” (opens the source at this quote in a new tab)
“Patients are willing to maintain a stable dose/do not change their therapy throughout the duration of the study.” (opens the source at this quote in a new tab)

Inclusion criteria: contraception

“Females of childbearing potential, defined as a premenopausal female capable of becoming pregnant, will be included if they are either sexually inactive (sexually abstinent for 14 days prior to the first dose and confirm to continue through 28 days after the last dose) or using one of the following highly effective contraceptives” (opens the source at this quote in a new tab)
“Non-vasectomized male patient agrees to use a condom with spermicide during the study until 90 days beyond the last dose of study medication and the female partner agrees to comply with inclusion criteria 3 or 4.” (opens the source at this quote in a new tab)

Exclusion criteria

“Simultaneous participation in another clinical study or participation in any clinical study involving administration of an investigational medicinal product (IMP; 'study drug') for at least 42 days prior to Visit 1.” (opens the source at this quote in a new tab)
“Patients with a physical or psychiatric condition which, at the investigator's discretion and in consultation with the Medical Monitor and Sponsor (as applicable), may put the patient at risk, may confound the study results, or may interfere with the patient's participation in the clinical study, i.e. reliably perform study assessments.” (opens the source at this quote in a new tab)
“Known or persistent use, misuse, or dependency of medication, drugs, or alcohol.” (opens the source at this quote in a new tab)
“Current or planned pregnancy or women who are breastfeeding.” (opens the source at this quote in a new tab)
“Patients with severe vision or hearing impairment (that is not corrected by glasses or hearing aids) that, at the investigator's discretion, interferes with their ability to perform study assessments.” (opens the source at this quote in a new tab)
“Patients who have been diagnosed with arthritis or other musculoskeletal disorders affecting joints, muscles, ligaments, and/or nerves that by themselves affects patient's mobility and, at the investigator's discretion, interferes with their ability to perform study assessments.” (opens the source at this quote in a new tab)

Exclusion criteria: washout of prohibited medications

“Patients unwilling and/or not able to undergo a 42-day washout period from any of the following prohibited medication prior to Visit 1 (Baseline 1) and remain without prohibited medication through Visit 6.” (opens the source at this quote in a new tab)
“N-Acetyl-DL-Leucine (e.g. Tanganil®);” (opens the source at this quote in a new tab)
“N-Acetyl-L-Leucine (prohibited if not provided as IMP in the IB1001-303 trial);” (opens the source at this quote in a new tab)
“Sulfasalazine;” (opens the source at this quote in a new tab)
“Rosuvastatin.” (opens the source at this quote in a new tab)

Exclusion criteria: prohibited medications at European Union sites

“Patients at EU trial sites who have had any of the following prohibited medication 42-days prior to Visit 1 (Baseline 1) and unwilling and/or not able to remain without prohibited medication through Visit 6.” (opens the source at this quote in a new tab)

Minimum recruitment in pediatric age groups

“Note: a minimum of 3 patients in the age group 4 to 11 years, and 3 patients in the age group 12-17 years need to be recruited to the study.” (opens the source at this quote in a new tab)

Prescribing information: dosage and duration in Trial 2

“AQNEURSA and placebo were administered orally with or without food for 12 weeks in each period. Patients weighing ≥35 kg received 4 gram per day (as 2 gram morning dose, 1 gram afternoon dose, and 1 gram evening dose).” (opens the prescribing information at this quote)

Weight-tiered dosing in the trial protocol

“Patients weighing 15 to <25 kg will take 2 g per day: 1 g in the morning and 1 g in the evening.” (opens the source at this quote in a new tab)
“Patients aged weighing 25 to <35 kg will take 3 g per day: 1 g in the morning, 1 g in the afternoon, and 1 g in the evening.” (opens the source at this quote in a new tab)
“Patients weighing ≥35 kg will take 4 g per day: 2 g in the morning, 1g in the afternoon and 1 g in the evening (as per patients aged ≥13).” (opens the source at this quote in a new tab)
“In the event a patient changes weight category over the course of the parent study, their daily dose will not change from the initial dosing assigned at Visit 2.” (opens the source at this quote in a new tab)

Dose per kilogram for participants weighing less than 35 kg

“patients weighing less than 35 kg received weight-tiered doses two or three times per day based on approximately 0·1 g/kg per day” (opens the source at this quote in a new tab)

Formulation and preparation

“Oral administration (granule in a sachet for suspension in water, orange juice, or almond milk). Patients will receive a total daily dose of 2-4 g/day based on weight-tiered doses.” (opens the source at this quote in a new tab)

“To prepare a sachet: One sachet should be suspended (poured) into 40 mL water (or orange juice or almond milk) i.e., approximately quarter of a glass of water (or orange juice or almond milk).” (opens the source at this quote in a new tab)
“If a patient misses a dose of study drug, the patient should wait and take the next dose according to the treatment schedule.” (opens the source at this quote in a new tab)

Matching placebo

“The placebo was developed to have the same colour, taste, appearance, and solubility properties as the active agent, and both were packaged identically as granules in a sachet for suspension in 40 mL of water, orange juice, or almond milk, administered with identical dosing regimens.” (opens the source at this quote in a new tab)

“Excipients the IB1001 sachet (namely isomalt, hypromellose, and strawberry flavor).” (opens the source at this quote in a new tab)
“Excipients the placebo sachet (namely isomalt, hypromellose, strawberry flavor, citric acid, microcrystalline cellulose, lactose, denatonium benzoate).” (opens the source at this quote in a new tab)

Treatment exposure in Trial 2

“The mean (SD) treatment duration of AQNEURSA was 84.5 (11.2) days (9 min, 97 max); the mean (SD) treatment duration on placebo was 85.5 (3.6) days (77 min, 94 max).” (opens the prescribing information at this quote)

Adherence

“Adherence was high, as shown by treatment compliance and regular urine analyses for prohibited medication (per exclusion criteria).” (opens the source at this quote in a new tab)

Concomitant medications and therapies

“Medication not listed in this table may be permitted, at the discretion of the investigator, as long as there is no interference with the study objectives or patient safety. Doses of medications and therapies used for (the symptoms of) A-T should remain as constant as possible (at the investigator’s discretion) throughout the trial.” (opens the source at this quote in a new tab)
“Note: Drug interactions with substrates of transporters MDR1, BCRP, or BSEP cannot be excluded as N-Acetyl-L-Leucine is an inhibitor of these transporters in vitro. Sulfasalazine and rosuvastatin are included under prohibited medications, whereas substrates of MDR1 and BSEP and other substrates of BCRP may be used at the discretion of the investigator.” (opens the source at this quote in a new tab)

Primary endpoint defined in the trial protocol

“The primary endpoint is defined as the total SARA value at the end of Period I (Visit 4) versus the end of Period II (Visit 6).” (opens the source at this quote in a new tab)
“The validated SARA scale will be used as the primary endpoint.” (opens the source at this quote in a new tab)
“In all jurisdictions besides the United States” (opens the source at this quote in a new tab)

Primary outcome measure in the registry record

“The Scale for Assessment and Rating of Ataxia has 8 items that are related to gait, stance, sitting, speech, finger-chase test, nose-finger test, fast alternating movements, and heel-shin test. The range is 0-40 points, with a lower score representing neurological improvement and a higher score representing neurological worsening.” (opens the source at this quote in a new tab)
“End of Period I (week 12) vs. End of Period 2 (week 24)” (opens the source at this quote in a new tab)

SARA items, score range, and meaningful change as described by the investigators

“The primary endpoint was the SARA, an eight-item (gait, stance, sitting, speech disturbance, finger chase, nose-finger test, fast alternating hand movement, and heel-shin slide) clinical rating scale ranging from 0 to 40, in which 0 is the best neurological status and 40 the worst.” (opens the source at this quote in a new tab)
“for which a 1-point change has been validated as representing a clinically meaningful change in functioning (gain or loss of complex function which is relevant to the patient's everyday life).” (opens the source at this quote in a new tab)

SARA development and validation in spinocerebellar ataxia

“The authors devised the Scale for the Assessment and Rating of Ataxia (SARA) and tested it in two trials of 167 and 119 patients with spinocerebellar ataxia.” (opens the source at this quote in a new tab)
“Interrater reliability was high, with an intraclass coefficient (ICC) of 0.98. Test-retest reliability was high with an ICC of 0.90. Internal consistency was high as indicated by Cronbach's alpha of 0.94.” (opens the source at this quote in a new tab)
“The Scale for the Assessment and Rating of Ataxia is a reliable and valid measure of ataxia, making it an appropriate primary outcome measure for clinical trials.” (opens the source at this quote in a new tab)

SARA reliability and validity in ataxias other than spinocerebellar ataxia

“To this end, 64 patients with various ataxia disorders or stable cerebellar lesions were rated independently by two investigators.” (opens the source at this quote in a new tab)
“Inter-rater and intrarater reliability were very high with ICCs of 0.98 and 0.99. Internal consistency was high indicated by Cronbach's alpha of 0.97.” (opens the source at this quote in a new tab)
“The results suggest that SARA is a reliable and valid measure of ataxia in non-SCA ataxia patients.” (opens the source at this quote in a new tab)

SARA in children: age dependency of scores and of interobserver agreement

“In typically developing children, age was the only variable that revealed a relationship with SARA scores (p<0.001). The youngest children revealed the highest scores and the highest variation in scores (<8y; p<0.001). After 11 years of age, pediatric scores approached adult outcomes.” (opens the source at this quote in a new tab)
“In typically developing European children, both SARA scores and interobserver agreement are age-dependent.” (opens the source at this quote in a new tab)

“ICARS, SARA, BARS and PEG-board test outcomes were age-dependent until 12.5, 10, 11, and 11.5 years of age respectively.” (opens the source at this quote in a new tab)
“In healthy children, ataxia rating scales are reliable, but should include age-dependent interpretation in children up to 12 years of age.” (opens the source at this quote in a new tab)

SARA in ataxia-telangiectasia: recommendation of a rating-scale review panel

“for ataxia telangiectasia: ICARS and SARA;” (opens the source at this quote in a new tab)
“The main limitations of these instruments include the limited assessment of patients in the more severe end of the spectrum and children.” (opens the source at this quote in a new tab)

SARA in ataxia-telangiectasia: validation status and correlation with a disease-specific scale in adults

“However, the SARA score remains unvalidated specifically for use in A-T and is not without its limitations.” (opens the source at this quote in a new tab)
“The weighting of the total score is also disproportionately influenced by the gait domain. Many classical A-T patients lose ambulation by their teenage years, and it is unclear how this influences the assessment of disease progression in non-ambulant patients who continue to report clinical deterioration” (opens the source at this quote in a new tab)
“We found a strong correlation between A-T NEST and the established SARA score, validating the use of A-T NEST and SARA in capturing the natural history of A-T patients.” (opens the source at this quote in a new tab)

SARA in ataxia-telangiectasia: annual progression in adults

“We analysed longitudinal Scale for the Assessment and Rating of Ataxia (SARA) data from the largest published adult AT cohort to date (n = 82, age > 16 years).” (opens the source at this quote in a new tab)
“Neurological impairment progressed with a mean SARA increase of 0.38 points/year.” (opens the source at this quote in a new tab)
“SARA remains a useful outcome measure but may underestimate progression in advanced disease and non-cerebellar domains.” (opens the source at this quote in a new tab)

Minimal clinically important difference of the SARA: thresholds cited by the investigators

“Multiple studies have investigated a minimally clinically important difference on the SARA scale, ranging from 1 to 1·5 points” (opens the source at this quote in a new tab)

Minimal clinically important difference of the SARA: 1-point threshold derived from levacetylleucine trials in lysosomal storage disorders

“We analyzed data from three clinical trial cohorts (IB1001-201, IB1001-202, and IB1001-301) of patients with Niemann–Pick disease type C (NPC) and GM2 Gangliosidoses (Tay–Sachs and Sandhoff disease) comprising 122 patients and 703 visits.” (opens the source at this quote in a new tab)
“Further qualitative analyses of the patient/caregiver interviews demonstrated a 1-point or greater change on SARA to be a clinically meaningful improvement which is directly relevant to the patient’s everyday functioning and quality of life.” (opens the source at this quote in a new tab)
“A 1-point change represents a clinically meaningful transition reflecting the gain or loss of complex function.” (opens the source at this quote in a new tab)

Minimal clinically important difference of the SARA: 1.5-point threshold in cerebellar ataxias

“Sixty-two individuals with cerebellar ataxias participated in a home-exercise clinical trial.” (opens the source at this quote in a new tab)
“The MCID for SARA using anchor-based method was 1.75. The distribution-based method and distribution-based mapping identified a median MCID score of 1.23.” (opens the source at this quote in a new tab)
“Synthesizing methods, we determined an MCID of 1.5 points.” (opens the source at this quote in a new tab)

Responsiveness of the SARA over one year in spinocerebellar ataxia

“Within the 1-year follow-up period, SARA, INAS, and SCAFI but not EQVAS indicated worsening in the whole group and in the groups with subjective (PGI) worsening.” (opens the source at this quote in a new tab)
“SARA and EQVAS performed best to distinguish groups classified as worse by PGI.” (opens the source at this quote in a new tab)

Functional SARA: definition in the prescribing information

“The primary efficacy outcome was assessed using a modified version of the Scale for Assessment and Rating of Ataxia (SARA), referred to as the functional SARA (fSARA). The SARA is a clinical assessment tool that assesses gait, stability, speech, and upper and lower limb coordination across 8 individual domains. The fSARA consists only of gait, sitting, stance, and speech disturbance domains of the original SARA with modifications to the scoring responses. Each domain was rescored from 0 to 4, where 0 is the best neurological status and 4 the worst, with a total score ranging from 0 to 16.” (opens the prescribing information at this quote)
“Efficacy was demonstrated using a modified version of the SARA, referred to as the functional SARA (fSARA) [see Clinical Studies (14.1)]. The fSARA score was assessed at baseline, 6 weeks, 12 weeks (the end of Period I), 18 weeks, and 24 weeks (the end of Period II).” (opens the prescribing information at this quote)

Functional SARA: key secondary endpoint for the United States in the trial protocol

“In the US, in line with discussion with the US Food and Drug Administration (FDA), additional endpoints have been designated as key secondary endpoints: the Investigator and Caregiver CGI-I from Visit 2 to Visit 4 and the functional SARA (f-SARA) assessment.” (opens the source at this quote in a new tab)
“The f-SARA was developed for a clinical trial with troriluzole in patients with Spinocerebellar Ataxia (SCAs).” (opens the source at this quote in a new tab)
“Note: The scoring domains of the f-SARA are not published. Therefore, the f-SARA is not administered separately to the original SARA scale but rather rescored based on the original SARA assessment based on a template provided by the FDA for rescoring the domains from 0 to 4 points.” (opens the source at this quote in a new tab)

Functional SARA: inclusion at FDA request as described by the investigators

“At the request of the US Food and Drug Administration (FDA), in the USA, the FDA functional SARA (f-SARA), which consisted of the axial domains (gait, stance, sitting, speech disturbance) rescored on a scale ranging from 0 to 16, in which 0 is the best neurological status and 16 is the worst, was included as a secondary endpoint.” (opens the source at this quote in a new tab)

Functional SARA: FDA rationale for domain selection and rescoring in the Niemann-Pick disease type C review

“The Agency recommended an fSARA which focuses on four domains: gait, stance, sitting, and speech disturbance. For these four domains, the Agency recommended a modification to the scoring so that each domain has five possible scores: 0 (normal), 1, 2, 3, and 4 (worst severity); thus, the total fSARA score ranges from 0 to 16.” (opens the source at this quote in a new tab)
“Consistent with Agency’s approach in other rare progressive neurodegenerative indications (Potashman et al. 2024b), several domains of the SARA (finger chase, nose to finger, fast alternating hand movements, heel to shin slide) assess neurologic exam findings.” (opens the source at this quote in a new tab)
“These neurologic exam findings do not directly assess the patient’s ability to function, nor do they reflect clinically meaningful change in a patient’s ability to perform daily functions, making them unsuitable for inclusion in a primary efficacy endpoint to convey clinical benefit.” (opens the source at this quote in a new tab)
“Scoring of the SARA domains varies (e.g., gait comprises 9 levels, speech comprises 7 levels), which interferes with the interpretation of the total score.” (opens the source at this quote in a new tab)
“As the Applicant did not revise the response categories of the SARA domains, the Agency rescored to create the same number of response categories across each domain (Table 23) to ensure equal representation of each domain in the total score and interpretability of a 1-point change as clinically meaningful (Potashman et al. 2024a).” (opens the source at this quote in a new tab)

Functional SARA: FDA-recommended rescoring of the four SARA domains

SARA domain	Original item score	Modified domain score
Gait	“0 = Normal, no difficulties in walking, turning and walking tandem (up to one misstep allowed)”	“0”
Gait	“1 = Slight difficulties, only visible when walking 10 consecutive steps in tandem”	“1”
Gait	“2 = Clearly abnormal, tandem walking >10 steps not possible”	“1”
Gait	“3 = Considerable staggering, difficulties in half-turn, but without support”	“2”
Gait	“4 = Marked staggering, intermittent support of the wall required”	“2”
Gait	“5 = Severe staggering, permanent support of one stick or light support by one arm required”	“2”
Gait	“6 = Walking >10 m only with strong support (two special sticks or stroller or accompanying person)”	“3”
Gait	“7 = Walking <10 m only with strong support (two special sticks or stroller or accompanying person)”	“3”
Gait	“8 = Unable to walk, even supported”	“4”
Stance	“0 = Normal, able to stand in tandem for >10 s”	“0”
Stance	“1 = Able to stand with feet together without sway, but not in tandem for >10s”	“1”
Stance	“2 = Able to stand with feet together for >10 s, but only with sway”	“1”
Stance	“3 = Able to stand for >10 s without support in natural position, but not with feet together”	“2”
Stance	“4 = Able to stand for >10 s in natural position only with intermittent support”	“3”
Stance	“5 = Able to stand >10 s in natural position only with constant support of one arm”	“3”
Stance	“6 = Unable to stand for >10 s even with constant support of one arm”	“4”
Sitting	“0 = Normal, no difficulties sitting >10 sec”	“0”
Sitting	“1 = Slight difficulties, intermittent sway”	“1”
Sitting	“2 = Constant sway, but able to sit >10 s without support”	“2”
Sitting	“3 = Able to sit for >10 s only with intermittent support”	“3”
Sitting	“4 = Unable to sit for >10 s without continuous support”	“4”
Speech disturbance	“0 = Normal”	“0”
Speech disturbance	“1 = Suggestion of speech disturbance”	“1”
Speech disturbance	“2 = Impaired speech, but easy to understand”	“1”
Speech disturbance	“3 = Occasional words difficult to understand”	“2”
Speech disturbance	“4 = Many words difficult to understand”	“3”
Speech disturbance	“5 = Only single words understandable”	“4”
Speech disturbance	“6 = Speech unintelligible / anarthria”	“4”

Functional SARA: FDA interpretation of a 1-point change and correlation with the SARA in the Niemann-Pick disease type C trial

“such that a 1-point change in any fSARA domain is indicative of a meaningful change (either improvement or worsening) to patients with NPC” (opens the source at this quote in a new tab)
“Furthermore, because each domain in the fSARA represents an important aspect of daily functioning, improvement in any domain regardless of the absence of change/presence of worsening in other domains provides independent evidence of meaningful clinical benefit to patients.” (opens the source at this quote in a new tab)
“The estimated pairwise Spearman correlations between fSARA, mSARA, and SARA total score at baseline were ≥0.91.” (opens the source at this quote in a new tab)

Functional SARA: origin and content validity in spinocerebellar ataxia

“The resulting modification of the SARA, the functional SARA (f-SARA), is a 4-item scale that assesses Gait, Stance, Sitting, and Speech. Each of the 4 items is rated on an ordinal scale from 0 to 4, where 0 indicates normal or unimpaired function, and higher responses indicate progressive impairment. The total f-SARA score is the sum of the 4 individual items (16 points).” (opens the source at this quote in a new tab)
“The f-SARA was developed based on recommendations from a regulatory body to capture unequivocal and compelling changes that might be functionally meaningful and reflect treatment effect in individuals with SCA.” (opens the source at this quote in a new tab)
“HCPs with previous f-SARA exposure considered that a 1- to 2-point change on the f-SARA total score and a 1-point change on the item score was meaningful.” (opens the source at this quote in a new tab)

Functional SARA: psychometric properties and meaningful change threshold in spinocerebellar ataxia

“The ICC was 0.91 (0.88–0.93) for the f-SARA in the cohort consisting of all SCA subjects and ranged from 0.73 (0.65–0.79) for sitting to 0.92 (0.89–0.94) for gait” (opens the source at this quote in a new tab)
“Regarding the intra-individual meaningful change thresholds for the f-SARA total score, findings reported herein, and as triangulated with natural history data reports by Moulaire et al., support a 1-point annual worsening as clinically meaningful” (opens the source at this quote in a new tab)
“In conclusion, the psychometric data reported herein support the use of the f-SARA as a reliable COA to measure disease progression over a 1-year period or longer, noting that the sitting item appeared as the least responsive of the 4 f-SARA items.” (opens the source at this quote in a new tab)

SARA and fSARA treatment differences in the Niemann-Pick disease type C trial of levacetylleucine

“The primary end point was the total score on the Scale for the Assessment and Rating of Ataxia (SARA; range, 0 to 40, with lower scores indicating better neurologic status).” (opens the source at this quote in a new tab)
“The mean (±SD) change from baseline in the SARA total score was -1.97±2.43 points after 12 weeks of receiving NALL and -0.60±2.39 points after 12 weeks of receiving placebo (least-squares mean difference, -1.28 points; 95% confidence interval, -1.91 to -0.65; P<0.001).” (opens the source at this quote in a new tab)

“The estimated treatment difference for the fSARA total score was -0.4 (95% CI: -0.7, -0.2) (Table 4).” (opens the prescribing information at this quote)

Interpretability of the SARA in young children: FDA position and protocol subgroup analysis

“Ataxia and related domains are difficult to measure in young children with a progressive condition, a measurement challenge that is not specific to the SARA. SARA scores can have low reliability in developing young children with progressive conditions, which may interfere with interpretability (Brandsma et al. 2014) (Lawerman et al. 2017).” (opens the source at this quote in a new tab)

“At the request of the US Food and Drug Administration, a subgroup analysis of patients 4 – 9 years old versus ≥10 years is planned to ensure the results of the SARA can be interpreted consistently in each age group” (opens the source at this quote in a new tab)

Secondary and exploratory endpoints listed in the trial protocol

“Spinocerebellar Ataxia Functional Index (SCAFI)” (opens the source at this quote in a new tab)
“International Cooperative Ataxia Rating Scale (ICARS) [US only, key secondary endpoint in US]” (opens the source at this quote in a new tab)
“Functional Scale for the Assessment and Rating of Ataxia (f-SARA) [US only, key secondary endpoint in US]” (opens the source at this quote in a new tab)
“Quality of Life EQ-5D-5L for patients aged ≥18; EQ-5D-Y for children aged <18 years” (opens the source at this quote in a new tab)
“Investigator, Caregiver (if applicable), and Patient (if able) Clinical Global Impression of Improvement (CGI-I) comparing end of Treatment Period I (Visit 4) to baseline (Visit 2)” (opens the source at this quote in a new tab)
“Exit Interviews” (opens the source at this quote in a new tab)

ICARS and NeuroQOL-UEF designations changed in the statistical analysis plan

“appearing next to the ICARS and NeuroQOL-UEF endpoints in study protocol is not reflected in this SAP, as these endpoints are not limited to the US.” (opens the source at this quote in a new tab)
“is not applicable to ICARS endpoint.” (opens the source at this quote in a new tab)

International Cooperative Ataxia Rating Scale

“The International Cooperative Ataxia Rating Scale (ICARS; a 19-domain scale with symptoms grouped by postural and gait disturbances, limb ataxia, dysarthria, and oculomotor disorders, ranging from 0 to 100, in which 0 is the best neurological status and 100 the worst) was also used to quantify the level of neurological impairment and changes in overall” (opens the source at this quote in a new tab)
“neurological symptoms and status.” (opens the source at this quote in a new tab)

“With the long-term goal of double-blind controlled trials-multicentric and international-an ad hoc Committee of the World Federation of Neurology has worked to propose a one-hundred-point semi-quantitative International Cooperative Ataxia Rating Scale (ICARS).” (opens the source at this quote in a new tab)
“The validation of this scale is in progress.” (opens the source at this quote in a new tab)

“We recruited 63 patients with ataxia, aged 10.76 ± 3.2 years, followed at 6 international AT centers, 49 of them (77.8%) with classical AT.” (opens the source at this quote in a new tab)
“In addition we showed that ataxia can be reliably measured in children with AT by using ICARS.” (opens the source at this quote in a new tab)

Spinocerebellar Ataxia Functional Index

“Cerebellar function was assessed using the Spinocerebellar Ataxia Functional Index (SCAFI), comprising the timed 8-Meter Walk Test (8MWT), the timed 9-Hole Peg Test (9HPT) with the dominant and non-dominant hand, and the number of spoken PATA repetitions within 10 seconds; each test was done twice.” (opens the source at this quote in a new tab)

“A Z-score of 0 equates to the population mean at baseline. For all 3, higher Z-scores (above mean) mean better performance. The SCAFI total score was calculated as the arithmetic mean of the non-missing Z-scores for the 3. A higher total score means better performance.” (opens the source at this quote in a new tab)

“The Z-scores of each subtest correlated well with the Scale for the Assessment and Rating of Ataxia (SARA), the Unified Huntington's disease Rating Scale functional assessment, and disease duration.” (opens the source at this quote in a new tab)
“The proposed functional measures and their composite SCAFI have favorable properties to assess patients with spinocerebellar ataxia.” (opens the source at this quote in a new tab)

Clinical Global Impression scales

“The Clinical Global Impression of Improvement assessed by the investigator/caregiver/patient is evaluated on a 7 point Likert scale ranging from 1='very much improved' to 7='very much worse'” (opens the source at this quote in a new tab)

“It is important to realize that the CGI-I scores per visit for each patient as provided by the caregiver may be based on varying caregivers and hence additional variation is introduced.” (opens the source at this quote in a new tab)

Quality-of-life instruments and exit interviews

“Subjective impairment and quality of life were evaluated by use of the Clinical Global Impression of Severity (CGI-S) and Improvement Scale (completed by the investigators, caregivers, and patients)” (opens the source at this quote in a new tab)

“EQ-5D VAS is a 0-100 scale where patients are asked to indicate their overall health, with a score of 0 indicating worst health and a score of 100 indicating best health.” (opens the source at this quote in a new tab)

“In addition, as recommended by the US FDA, the Adult and Pediatric NeuroQOL Scales of Upper Extremity Function (NeuroQOL-UEF) will be performed to provide additional supportive evidence that the changes captured on the SARA are relevant to patient’s function. Given the NeuroQOL-UEF scale has not been validated in or known to be used in any clinical trials for patients with cerebellar ataxia, and the adult and pediatric patient questionnaires are different, this is a secondary endpoint that will be reported descriptively.” (opens the source at this quote in a new tab)
“Semi-structured interviews conducted with the patient (if able) or the caregiver (if applicable) at Visit 6 to better inform and evaluate the meaningfulness of the within-patient changes on the outcome assessments.” (opens the source at this quote in a new tab)

Safety assessments

“Safety assessments included adverse event monitoring, clinical laboratory testing and sparse pharmacokinetic sampling, physical examinations, and collecting vital signs and electrocardiograms.” (opens the source at this quote in a new tab)

Sample size calculation in the trial protocol

“In a one-sided test at the 0.05 level a total sample size of 46 in a two-treatment, two-period placebo-controlled cross-over trial, achieves approximately 80% power for treatment comparisons of the SARA total score. Based on the inclusion criteria (SARA total between 7 and 34) and recruitment in previous trials, the standard deviation of SARA was assumed to be between 7.5 and 8.5. A test-retest correlation of ρ = 0.95 was applied.” (opens the source at this quote in a new tab)
“Assuming a true mean difference between SARA scores of 1.0 and a standard deviation of difference of 2.69 a total of 46 patients provides 80% power to detect a treatment effect at a 1-sided 0.05 level.” (opens the source at this quote in a new tab)

Target numbers in the trial protocol

“To be screened: Approximately 70 patients” (opens the source at this quote in a new tab)
“To be analyzed according to the Intention to Treat (ITT): Approximately 46 patients” (opens the source at this quote in a new tab)

Estimated enrollment in the registry record

Field	Registry value
Enrollment (estimated)	“60”

Participants screened, randomized, and analyzed

Population	Participants
Screened	“77”
Excluded for not meeting inclusion criteria	“Four”
Enrolled and randomly assigned	“73”
Assigned to levacetylleucine followed by placebo	“36”
Assigned to placebo followed by levacetylleucine	“37”
Included in the primary analysis and safety sets	“73”

Analysis populations

“Safety and efficacy analyses were done in all randomly assigned patients who received at least one dose of study medication, and a linear mixed-effects model was used to account for data missing at random.” (opens the source at this quote in a new tab)

“The ITT population will consist of all randomized patients who receive at least one dose of IMP (IB1001 or placebo). This analysis set will be used for the efficacy analyses according to the sequence/treatment to which the patients were randomised.” (opens the source at this quote in a new tab)
“The Safety Analysis Set (SAF) will consist of all patients who receive at least one dose of IMP (IB1001 or placebo). This analysis set will be used for the safety and tolerability analyses, according to the actual treatment received.” (opens the source at this quote in a new tab)
“Protocol deviations will not be used in assigning patients to the analysis sets for this study, but will be listed.” (opens the source at this quote in a new tab)

Primary analysis model as reported in the publication

“The primary endpoint of the treatment was evaluated using a linear mixed-effects model with the SARA score at the end of each period as the independent variable. The model included baseline (visit 2 SARA score), sequence, period, treatment, and the interaction between baseline and period as fixed effects. Two-sided p values of the null hypothesis were calculated and a significance level of 0·05 was used to judge statistical significance. This method of analysis accounts for any crossover period effects, allows for data missing at random, and evaluates the within-patient differences.” (opens the source at this quote in a new tab)

Primary analysis model in the statistical analysis plan

“Statistical analysis will be performed using SAS PROC MIXED and results (LSMeans with 90% CI and 95% CI, and p-values) of the statistical analyses will be presented.” (opens the source at this quote in a new tab)
“The model will include baseline, sequence, period, treatment and the interaction between baseline and period as fixed effects. Additionally, it will include a random effect for subjects nested within sequence, and an unstructured covariance structure (TYPE=UN).” (opens the source at this quote in a new tab)

Primary estimand and intercurrent events

“ICE1: Withdrawal from study medication due to adverse events” (opens the source at this quote in a new tab)
“ICE2: Taking of prohibited medications: Sulfasalazine or Rosuvastatin” (opens the source at this quote in a new tab)
“A Treatment Policy strategy will be considered for these intercurrent events.” (opens the source at this quote in a new tab)
“For the primary estimand, the treatment policy strategy will be considered for all intercurrent events, e.g. all data as collected will be used, regardless of whether the ICE occurred or not.” (opens the source at this quote in a new tab)

Handling of missing data

“Should these events occur, a last observation carried forward approach (LOCF) on a per-period basis will be adopted based on Visits 2/3 for Treatment Period I and Visits 4/5 for Treatment Period 2. Consequently, patients who do not provide sufficient data for a LOCF approach will be omitted from analysis.” (opens the source at this quote in a new tab)

“For the SARA/functional SARA, last observation carried forward is applied for one patient to handle missing data at visit 6.” (opens the source at this quote in a new tab)
“Only reported data were included in the secondary endpoint analyses.” (opens the source at this quote in a new tab)

Significance level and multiplicity

“For the endpoints analyzed with statistical inferential methods, analysis will be conducted using 90% confidence intervals and one-sided tests with a significance level of 0.05 to guide evidence of activity. Additionally, two-sided test p-values and 95% confidence intervals will be presented, unless otherwise specified.” (opens the source at this quote in a new tab)
“One-sided p-values smaller than 0.05 will be considered statistically significant for the primary endpoint and indicative for other endpoints. No adjustment for multiple comparisons will be applied.” (opens the source at this quote in a new tab)
“All evaluations other than the primary endpoint will be considered exploratory in nature.” (opens the source at this quote in a new tab)

“Because there was no prespecified plan for adjustment of the widths of CIs for multiple comparisons, results for secondary endpoints are presented as point estimates and 95% CIs without p values and no definite conclusions can be drawn from these data.” (opens the source at this quote in a new tab)

Analysis of secondary endpoints

“The SCAFI and ICARS secondary endpoints were evaluated as per the primary endpoint. The change from baseline to the end of period 1 for the two treatment groups was assessed for the Clinical Global Impression of Improvement (CGI-I).” (opens the source at this quote in a new tab)

“f-SARA will be also analyzed using the same approach as per the Estimand 1 of the primary endpoint SARA.” (opens the source at this quote in a new tab)
“The 4 subscales and the total score will be summarized with descriptive statistics by treatment and analysis visit.” (opens the source at this quote in a new tab)
“The CGI-I scores at Visit 4 will be evaluated statistically between the two treatment arms using a two-sample t-test or Wilcoxon rank-sum test depending on the underlying distribution.” (opens the source at this quote in a new tab)
“For the exploratory endpoints as described in section 4.1.3, descriptive statistics by treatment and analysis visit will be made by pooled treatment, except for the Exit Interview results which will only be listed. No plots will be created, and no statistical analysis will be done.” (opens the source at this quote in a new tab)

Prespecified subgroups and interim analysis

“Naïve versus non-naïve as determined at screening” (opens the source at this quote in a new tab)
“Age (pediatric versus adult)” (opens the source at this quote in a new tab)
“Disease severity based on SARA below/ above the median SARA score at Visit 1” (opens the source at this quote in a new tab)
“Gender (male versus female)” (opens the source at this quote in a new tab)
“Region (US versus rest of world)” (opens the source at this quote in a new tab)
“A-T type (classical versus variant, based on medical history phenotype data, if available)” (opens the source at this quote in a new tab)
“There is no interim analysis planned.” (opens the source at this quote in a new tab)

“For the primary and each secondary endpoint, there were separate evaluations within key subgroups predefined in the statistical analysis plan (the trial was not powered for conclusions in these subgroups).” (opens the source at this quote in a new tab)

Screening, randomization, and inclusion in the analysis

“Four patients were excluded (not meeting inclusion criteria) and 73 were enrolled and randomly assigned (36 to levacetylleucine followed by placebo and 37 to placebo followed by levacetylleucine. 73 patients were included in the primary analysis and safety sets.” (opens the source at this quote in a new tab)

Withdrawals and their reasons

“One patient in the levacetylleucine followed by placebo group withdrew in period 1 between visit 2 and visit 3 due to a physician's decision after confirmation of an unrelated serious adverse event which emerged during the baseline period, but was not formally diagnosed until shortly after the patient began study drug (T-cell type acute leukaemia). Two patients in the placebo to levacetylleucine group withdrew (one in period 2 between visit 5 and visit 6 due to an unrelated serious adverse event [lower respiratory tract chest infection] and one in period 2 between visit 4 and visit 5 due to an unrelated serious adverse event [diffuse large B-cell lymphoma]). 70 patients completed the study and 73 were included in analyses.” (opens the source at this quote in a new tab)

Prescribing information: completion and missing assessments

“Seventy patients (96%) completed the study and received both placebo and AQNEURSA.” (opens the prescribing information at this quote)
“Two patients did not have an assessment at the end of Period I (week 12).” (opens the prescribing information at this quote)
“One patient did not have an assessment at the end of Period II (week 24).” (opens the prescribing information at this quote)
“Two patients did not have an assessment at the end of Period II (week 24).” (opens the prescribing information at this quote)

Congress abstract submitted before data availability: number randomized

“Seventy-four participants aged 5-50 years were randomized. Topline results including baseline demographics, primary efficacy and safety data will be presented pending data availability.” (opens the source at this quote in a new tab)

Congress results abstract: number enrolled

“Seventy-three participants aged 4 to 50 were enrolled.” (opens the source at this quote in a new tab)

Prescribing information: age, sex, and race

“Of the 73 randomized patients (26 adults and 47 pediatric patients), 38 were female and 35 were male. The median age at treatment initiation was 13 years (range: 4 to 50 years). 75% of the patients were White, 6% Asian, 1% Native Hawaiian or other Pacific Islander, 12% Not Reported, and 6% Other.” (opens the prescribing information at this quote)

Demographics and baseline characteristics by treatment sequence

Characteristic	Total, n = 73	Levacetylleucine to placebo, n = 36	Placebo to levacetylleucine, n = 37
Pediatric, younger than 18 years	“47 (64%)”	“23 (64%)”	“24 (65%)”
Adult, 18 years or older	“26 (36%)”	“13 (36%)”	“13 (35%)”
Female	“38 (52%)”	“17 (47%)”	“21 (57%)”
Male	“35 (48%)”	“19 (53%)”	“16 (43%)”
Hispanic or Latino	“4 (5%)”	“2 (6%)”	“2 (5%)”
Not Hispanic or Latino	“51 (70%)”	“26 (72%)”	“25 (68%)”
Ethnicity not reported	“3 (4%)”	“2 (6%)”	“1 (3%)”
Ethnicity unknown	“15 (21%)”	“6 (17%)”	“9 (24%)”
Asian	“4 (5%)”	“2 (6%)”	“2 (5%)”
Black or African American	“0”	“0”	“0”
Native Hawaiian or other Pacific Islander	“1 (1%)”	“1 (3%)”	“0”
White	“55 (75%)”	“28 (78%)”	“27 (73%)”
Race not reported	“9 (12%)”	“3 (8%)”	“6 (16%)”
Other race	“4 (5%)”	“2 (6%)”	“2 (5%)”
Age at diagnosis: early-infantile, younger than 2 years	“51 (70%)”	“24 (67%)”	“27 (73%)”
Age at diagnosis: late-infantile, 2 to younger than 6 years	“16 (22%)”	“8 (22%)”	“8 (22%)”
Age at diagnosis: juvenile, 6 to younger than 15 years	“3 (4%)”	“2 (6%)”	“1 (3%)”
Age at diagnosis: adolescent or adult, 15 years or older	“3 (4%)”	“2 (6%)”	“1 (3%)”
Weight 15 to less than 25 kg, 2 g per day	“18 (25%)”	“8 (22%)”	“10 (27%)”
Weight 25 to less than 35 kg, 3 g per day	“17 (23%)”	“9 (25%)”	“8 (22%)”
Weight 35 kg or more, 4 g per day	“38 (52%)”	“19 (53%)”	“19 (51%)”

“Reported other races were Hispanic, American Hispanic, Mixed (White and Asian), and Pakistani.” (opens the source at this quote in a new tab)

Baseline scores on the efficacy and quality-of-life measures

Measure	Baseline before levacetylleucine, mean (SD); n	Baseline before placebo, mean (SD); n
SARA	“19·81 (6·43); n=71”	“19·87 (6·41); n=72”
FDA functional SARA	“7·83 (2·60); n=71”	“7·86 (2·60); n=72”
SCAFI	“−0·50 (0·99); n=71”	“−0·50 (0·98); n=72”
ICARS	“51·20 (17·05); n=70”	“51·54 (16·97); n=72”
EQ-Visual Analogue Scale	“74·2 (21·3); n=71”	“74·5 (21·4); n=72”
Pediatric NeuroQuality of Life Upper Extremity Function	“60·5 (28·0); n=25”	“59·7 (27·8); n=26”
Adult NeuroQuality of Life Upper Extremity Function	“57·1 (20·4); n=15”	“57·1 (20·4); n=15”

Representativeness of the trial population

“Infantile or juvenile A-T patients are typically severely impacted by the disease and unable to complete functional assessments. Therefore, the age distribution in the study population is different from that encountered in the population as more adult patients were included.” (opens the source at this quote in a new tab)
“The study was conducted at centres in the US and Europe, thus the majority of patients in this trial were of North American/ European descent. No patients from Africa or South America were enrolled.” (opens the source at this quote in a new tab)

Primary endpoint: fSARA total score, prescribing information

“The Least Squares Mean fSARA total score was 7.2 when patients were treated with AQNEURSA and 7.8 when patients were treated with placebo. The Least Squares treatment effect for the fSARA total score was -0.6 (95% CI: -0.9, -0.2) (Table 5).” (opens the prescribing information at this quote)
“Two-sided p-value = 0.0013” (opens the prescribing information at this quote)

fSARA total score by period and treatment sequence, prescribing information

Variable	Treatment Sequence 1: AQNEURSA then placebo	Treatment Sequence 2: placebo then AQNEURSA
Baseline, participants	“N=36”	“N=37”
Baseline, mean (SD)	“7.3 (2.6)”	“8.5 (2.5)”
Period I, participants	“N=34”	“N=37”
Period I, mean (SD)	“6.6 (2.8)”	“8.5 (2.6)”
Period II, participants	“N=35”	“N=35”
Period II, mean (SD)	“7.0 (3.1)”	“7.8 (2.7)”

Least squares mean fSARA score by treatment, prescribing information

Treatment	Least squares mean fSARA score (SE)
AQNEURSA	“7.2 (0.1)”
Placebo	“7.8 (0.1)”
Treatment difference (95% CI)	“-0.6 (-0.9, -0.2)”

Change in fSARA score by period within each treatment sequence, prescribing information

“Patients who received AQNEURSA in Period I followed by placebo in Period II (Treatment Sequence 1) showed a greater improvement in the fSARA score while receiving AQNEURSA in Period I with a mean change from baseline of -0.7 (SD 1.0), compared to Period II with a mean change from baseline of -0.2 (1.1). Patients who received placebo in Period I followed by AQNEURSA in Period II (Treatment Sequence 2) had a mean change of 0.0 (0.9) in Period I but experienced greater improvement in the fSARA score while receiving AQNEURSA in Period II with a mean change of -0.6 (1.3).” (opens the prescribing information at this quote)
“Results on the fSARA were supported by consistent results demonstrated on the original SARA.” (opens the prescribing information at this quote)

FDA summary of the efficacy finding

“When patients were taking Aqneursa, they scored better on the fSARA compared to when these patients were taking placebo and showed significant improvement in neurological function.” (opens the source at this quote in a new tab)

Primary endpoint: SARA total score, peer-reviewed publication

“The mean change in the SARA total score with levacetylleucine was -1·92 (SD 2·81) versus -0·14 (2·38) with placebo (linear mixed model treatment effect -1·88 [SD 0·41], 95% CI -2·70 to -1·06; p<0·0001).” (opens the source at this quote in a new tab)

Primary and secondary efficacy endpoints at end of treatment, peer-reviewed publication

Endpoint	End of treatment, levacetylleucine, mean (SD); n	End of treatment, placebo, mean (SD); n	Mean change from baseline, levacetylleucine (SD)	Mean change from baseline, placebo (SD)	Linear mixed model treatment effect (95% CI)
SARA (primary)	“17·96 (7·30); n=69”	“19·73 (7·39); n=72”	“−1·92 (2·81)”	“−0·14 (2·38)”	“−1·88 (−2·70 to −1·06)”
FDA functional SARA	“7·20 (2·83); n=69”	“7·76 (2·96); n=72”	“−0·65 (1·16)”	“−0·10 (1·02)”	“−0·57 (−0·92 to −0·23)”
SCAFI	“−0·41 (1·06); n=70”	“−0·45 (1·05); n=72”	“0·06 (0·28)”	“0·04 (0·24)”	“0·01 (−0·06 to 0·07)”
ICARS	“47·30 (18·67); n=69”	“49·85 (19·10); n=72”	“−4·22 (7·77)”	“−1·69 (6·09)”	“−2·84 (−4·87 to −0·81)”
Investigator's Clinical Global Impression of Improvement	“3·4 (0·8); n=35”	“3·8 (0·6); n=37”	“−0·6 (0·8)”	“−0·2 (0·6)”	“−0·4 (−0·7 to −0·02)”

“Linear mixed model treatment effect was computed for the SARA primary endpoint and the functional SARA, SCAFI, and ICARS secondary endpoints (but not other secondary endpoints).” (opens the source at this quote in a new tab)
“The change from baseline is the reported change from a score of 4 (no change).” (opens the source at this quote in a new tab)

SARA change by period: placebo in period 1 and placebo after levacetylleucine in period 2

“Patients who received placebo in period 1 experienced no significant change at 12 weeks, with a mean change in SARA score of –0·14 points (SD 1·92). By contrast, patients who received levacetylleucine followed by placebo (n=35) had an increase in SARA score of 1·81 (SD 3·12) during period 2 on placebo, which effectively served as a washout from levacetylleucine, reflecting a deterioration in neurological signs and symptoms when treatment with levacetylleucine was stopped.” (opens the source at this quote in a new tab)

Secondary endpoints: fSARA, investigator CGI-I, ICARS, and SCAFI, peer-reviewed publication

“The mean change on the FDA f-SARA was –0·65 (SD 1·16) with levacetylleucine versus –0·10 (1·02) with placebo (least square mean difference of –0·57 (0·17, 95% CI –0·92 to –0·23; p=0·001; table 2). Relative to placebo, levacetylleucine demonstrated significant improvements on the CGI-I investigators’ scale (mean change –0·4, 95% CI –0·7 to –0·02; p=0·02) and ICARS (mean difference –2·84, 95% CI –4·87 to –0·81; p=0·003; table 2). The patients’ CGI-I scale and the SCAFI, including 8MWT, 9HPT-D (dominant hand), 9HPT-ND (non-dominant hand), and PATA domains, numerically favoured the levacetylleucine group (table 2).” (opens the source at this quote in a new tab)

Subgroup analyses of the SARA total score

“Figure 3B displays results for the primary SARA endpoint in the predefined subgroups showing 95% CIs. There is no evidence of heterogeneity in treatment effect across subgroups that would suggest a differential treatment effect across the population. Instead, across all subgroups, there were consistent improvements with levacetylleucine versus placebo.” (opens the source at this quote in a new tab)

Comparison of the observed effect with reported thresholds, as stated by the investigators

“the mean change on levacetylleucine and the treatment effect with levacetylleucine versus placebo are larger than all reported thresholds.” (opens the source at this quote in a new tab)
“For patients randomly assigned to sequence 1 (levacetylleucine to placebo), the improvements of levacetylleucine treatment observed in period 1 were lost in period 2 (consistent with the drug's pharmacological and pharmacokinetic action), as patients worsened and returned to their baseline status.” (opens the source at this quote in a new tab)

Primary endpoint: SARA total score, company-reported topline results

“Treatment with levacetylleucine demonstrated a statistically significant and clinically meaningful -1.88 point improvement of the SARA score compared to placebo (-1.92 on levacetylleucine vs -0.14 on placebo, p<0.001).” (opens the source at this quote in a new tab)

Secondary endpoints: ICARS and investigator CGI-I, company-reported topline results

“The trial also met secondary endpoints, demonstrating statistically significant and clinically meaningful improvement on the International Cooperative Ataxia Rating Scale (ICARS) (-4.22 on levacetylleucine vs. -1.69 on placebo; p=0.003) and the Investigator’s Clinical Global Impression of Improvement (CGI-I) (-0.6 on levacetylleucine vs. -0.2 on placebo; p=0.02).” (opens the source at this quote in a new tab)

Subgroup consistency, company-reported full data set

“Subgroup analysis of the primary and secondary endpoints demonstrated consistent clinical effects across all demographics (age, gender, disease severity, age of symptom onset, etc.).” (opens the source at this quote in a new tab)

SARA and fSARA treatment differences, company-reported at FDA approval

“AQNEURSA demonstrated statistically significant improvement compared to placebo on the primary efficacy endpoint, the Scale for the Assessment and Rating of Ataxia (SARA) with a treatment difference of -1.9 points (95% CI: –2.7, –1.1; two-sided p<0.001).” (opens the source at this quote in a new tab)
“The primary outcome assessed by the FDA was the functional SARA (fSARA), a modified version comprising the gait, sitting, stance, and speech disturbance domains. Patients who received AQNEURSA showed a greater improvement in fSARA score, with a mean treatment difference of −0.6 (95% CI: −0.9, −0.2; two-sided p<0.001).” (opens the source at this quote in a new tab)

Primary and secondary endpoints, congress results abstract

“The primary endpoint was met; mean change in the SARA total score with levacetylleucine was -1.92 (SD=2.81) and -0.14 (SD=2.38) with placebo; Linear Mixed Model (LMM) treatment effect -1.88 (SD=0.41) [95% confidence interval [CI] -2.70, -1.06; P<0.0001]. The trial met key secondary endpoints, including ICARS (95% CI: -4.87, -0.81; P=0.003) and Investigators’ CGI-I (95% CI -0.7, -0.01; P=0.02).” (opens the source at this quote in a new tab)

Patient-reported, caregiver-reported, and quality-of-life endpoints at end of treatment

Endpoint	End of treatment, levacetylleucine, mean (SD); n	End of treatment, placebo, mean (SD); n	Mean change from baseline, levacetylleucine (SD)	Mean change from baseline, placebo (SD)
Caregiver Clinical Global Impression of Improvement	“3·8 (0·8); n=30”	“3·8 (0·8); n=36”	“−0·2 (0·8)”	“−0·2 (0·8)”
Patient Clinical Global Impression of Improvement	“3·5 (1·0); n=31”	“3·6 (0·9); n=33”	“−0·5 (1·0)”	“−0·4 (0·9)”
EQ-Visual Analogue Scale	“75·8 (20·5); n=70”	“74·0 (22·5); n=71”	“1·3 (15·5)”	“−0·3 (19·2)”
Pediatric NeuroQuality of Life Upper Extremity Function	“52·6 (27·2); n=25”	“54·9 (25·3); n=25”	“−4·9 (11·9)”	“−6·2 (14·6)”
Adult NeuroQuality of Life Upper Extremity Function	“57·4 (18·2); n=15”	“57·2 (19·5); n=15”	“−0·4 (10·8)”	“−0·9 (9·4)”

EQ-5D-5L in adults and EQ-5D-Y in participants younger than 18 years

“Quality of life improvements with levacetylleucine versus placebo were captured for adult patients by the EQ-5D-5L assessment, which demonstrated a decrease” (opens the source at this quote in a new tab)
“in patient-reported rates of moderate to severe problems with mobility, a decrease in their pain and discomfort, and an increase in patient-reported ability to do usual activities.” (opens the source at this quote in a new tab)
“For paediatric patients, the EQ-5D-Y (used for patients aged <18 years) showed improvements in mobility and self-care with levacetylleucine. On the EQ-VAS, there was improvement with levacetylleucine, compared with a worsening on placebo (table 2).” (opens the source at this quote in a new tab)

Exit interviews: proportions reporting improvement and meaningful change

“57 (81%) of 70 exit interviews completed by participants or caregivers reported improvement in patients’ neurological signs and symptoms during the study while on levacetylleucine. 46 (66%) of 70 responders reported that the changes during the IB1001-303 parent study were relevant or meaningful to the patient's everyday life and highlighted how these functional improvements not only resulted in meaningful changes for the patients but also provided adjunct benefits to the caregivers, families, coworkers, or classmates. 29 (41%) of 70 exit interviews specifically noted how the improvements during the trial were relevant for their safety and everyday activities.” (opens the source at this quote in a new tab)

Exit interviews: improvements reported by participants and caregivers

“Improved ability to perform everyday tasks including: feeding, holding a glass and cutlery, autonomous eating, dressing, doing buttons, playing, work, doing schoolwork/homework, writing, coloring, drawing painting, playing on the playground, putting a key in a lock, cycling, carrying objects, using a tablet, dropping less items, training at the gym, using normal chairs, participating in leisure activities, better transfers (getting up/ onto couch or chair, getting in and out of bed, getting on/off toilet, going up and downstairs).” (opens the source at this quote in a new tab)
“Improvement in gait and balance: improved ambulation (including gain of independent ambulation, ability to climb stairs, move faster and a more stable gait), postural stability (fewer falls, less truncal sway, smoother movement), improved balance while sitting, standing, and walking, coordination.” (opens the source at this quote in a new tab)
“Improvements in communicating with others: speech more easily understood and fluent, faster (more normally paced speech), fewer delays in speech, easier to join into a conversation, and easier to communicate with.” (opens the source at this quote in a new tab)

Prescribing information: adverse reactions in Treatment Period I of Trial 2 at an incidence of 5% or more

Adverse reaction	AQNEURSA, N = 36, n (%)	Placebo, N = 37, n (%)
Fall	“2 (6)”	“1 (3)”
Skin laceration	“2 (6)”	“0 (0)”
Urinary tract infection	“2 (6)”	“1(3)”

Prescribing information: thrombocytopenia in one participant during Trial 2

“was observed in one patient during Trial 2. The patient had thrombocytopenia at baseline, which decreased further during the trial while the patient was receiving placebo.” (opens the prescribing information at this quote)

Treatment-emergent adverse events, serious adverse events, and deaths

“54 adverse events occurred in 29 patients receiving levacetylleucine versus 75 events in 25 patients receiving placebo. No treatment-related serious adverse events or deaths occurred.” (opens the source at this quote in a new tab)

Discontinuations and events assessed as related to levacetylleucine

“No treatment-emergent adverse events led to premature discontinuation of the study drug. No treatment-emergent adverse events occurred in more than 10% of patients on levacetylleucine. Two patients had 3 treatment-emergent adverse events that were assessed as related to levacetylleucine (diarrhoea [mild], eczema [mild], and insomnia [moderate]). These events were all transient.” (opens the source at this quote in a new tab)

Treatment-emergent adverse events by system organ class

System organ class	Levacetylleucine, n = 73, n (%)	Levacetylleucine, events	Placebo, n = 72, n (%)	Placebo, events	Total, n = 73, n (%)	Total, events
Any treatment emergent adverse event	“29 (40%)”	“54”	“25 (35%)”	“75”	“37 (51%)”	“129”
Infections and infestations	“15 (21%)”	“17”	“13 (18%)”	“15”	“22 (30%)”	“32”
Gastrointestinal disorders	“5 (7%)”	“6”	“10 (14%)”	“21”	“12 (16%)”	“27”
Injury, poisoning, and procedural complications	“7 (10%)”	“9”	“5 (7%)”	“7”	“10 (14%)”	“16”
Respiratory, thoracic, and mediastinal disorders	“6 (8%)”	“7”	“5 (7%)”	“8”	“8 (11%)”	“15”
General disorders and administration site conditions	“3 (4%)”	“4”	“3 (4%)”	“3”	“5 (7%)”	“7”
Nervous system disorders	“2 (3%)”	“2”	“3 (4%)”	“4”	“5 (7%)”	“6”
Skin and subcutaneous tissue disorders	“3 (4%)”	“3”	“2 (3%)”	“3”	“5 (7%)”	“6”
Psychiatric disorders	“1 (1%)”	“1”	“2 (3%)”	“3”	“3 (4%)”	“4”
Renal and urinary disorders	“0”	“0”	“3 (4%)”	“3”	“3 (4%)”	“3”
Eye disorders	“2 (3%)”	“2”	“1 (1%)”	“1”	“2 (3%)”	“3”
Blood and lymphatic system disorders	“1 (1%)”	“1”	“1 (1%)”	“1”	“2 (3%)”	“2”
Investigations	“0”	“0”	“2 (3%)”	“2”	“2 (3%)”	“2”
Metabolism and nutrition disorders	“1 (1%)”	“1”	“1 (1%)”	“1”	“2 (3%)”	“2”
Musculoskeletal and connective tissue disorders	“0”	“0”	“2 (3%)”	“2”	“2 (3%)”	“2”
Hepatobiliary disorders	“0”	“0”	“1 (1%)”	“1”	“1 (1%)”	“1”
Neoplasms benign, malignant and unspecified (including cysts and polyps)	“1 (1%)”	“1”	“0”	“0”	“1 (1%)”	“1”

“Data are included for all patients who were enrolled and received at least one dose of treatment. Data are reported by what product was being received at the time of event. Adverse events are coded according to MedDRA, version 27.1.” (opens the source at this quote in a new tab)

Treatment-emergent adverse events reported in two or more participants during either treatment

Preferred term	Levacetylleucine, n = 73, n (%)	Levacetylleucine, events	Placebo, n = 72, n (%)	Placebo, events	Total, n = 73, n (%)	Total, events
Cough	“6 (8%)”	“7”	“2 (3%)”	“3”	“6 (8%)”	“10”
Upper respiratory tract infection	“3 (4%)”	“3”	“3 (4%)”	“3”	“6 (8%)”	“6”
Fall	“3 (4%)”	“3”	“2 (3%)”	“2”	“5 (7%)”	“5”
Pyrexia	“3 (4%)”	“4”	“2 (3%)”	“2”	“5 (7%)”	“6”
Diarrhoea	“2 (3%)”	“2”	“4 (6%)”	“4”	“5 (7%)”	“6”
Vomiting	“1 (1%)”	“1”	“4 (6%)”	“7”	“5 (7%)”	“8”
Urinary tract infection	“2 (3%)”	“2”	“2 (3%)”	“2”	“3 (4%)”	“4”
Abdominal pain	“1 (1%)”	“1”	“3 (4%)”	“3”	“3 (4%)”	“4”
Lower respiratory tract infection	“2 (3%)”	“3”	“0”	“0”	“2 (3%)”	“3”
Respiratory tract infection	“2 (3%)”	“2”	“0”	“0”	“2 (3%)”	“2”
Skin laceration	“2 (3%)”	“2”	“1 (1%)”	“1”	“2 (3%)”	“3”
Thermal burn	“2 (3%)”	“2”	“0”	“0”	“2 (3%)”	“2”
Headache	“0”	“0”	“2 (3%)”	“2”	“2 (3%)”	“2”

Laboratory tests, vital signs, and electrocardiograms

“No study drug-related serious adverse events or deaths occurred in either group. Results of plasma and urine tests, vital signs, and ECG recordings were normal or rated as clinically non-significant.” (opens the source at this quote in a new tab)

FDA summary of adverse reactions in ataxia-telangiectasia

“The most common adverse reactions in patients with ataxia-telangiectasia were fall, skin laceration, and urinary tract infection.” (opens the source at this quote in a new tab)

Safety, company-reported at FDA approval

“AQNEURSA was well tolerated. No treatment-related serious adverse events and no deaths occurred, and no patients discontinued because of a treatment-related adverse event. The most common adverse reactions (incidence ≥5% and greater than placebo) were fall and skin laceration.” (opens the source at this quote in a new tab)

Safety, congress results abstract

“No treatment emergent adverse events occurred in more than 10% of participants on levacetylleucine and no serious adverse events or deaths occurred in either group.” (opens the source at this quote in a new tab)

Summary

IB1001-303 randomized 73 participants at ten centers to a two-period crossover with 12 weeks of each treatment and an immediate crossover, with no washout between periods. The protocol chose an analysis that does not require a washout, and the publication describes the placebo period that followed levacetylleucine as having effectively served as a washout. The publication and the prescribing information report no result of a test for carryover or sequence effects. In the prescribing information, mean baseline fSARA was 7.3 in the sequence that started with levacetylleucine and 8.5 in the sequence that started with placebo.

The endpoint reported differs by source. The protocol names the 40-point SARA as the primary endpoint in all jurisdictions besides the United States and the 16-point functional SARA (fSARA) as a key secondary endpoint for the United States. The publication reports a SARA treatment effect of -1.88 points (95% CI -2.70 to -1.06), with mean changes of -1.92 on levacetylleucine and -0.14 on placebo. The prescribing information reports an fSARA treatment difference of -0.6 (95% CI -0.9 to -0.2; two-sided p = 0.0013) and gives no numerical SARA result. The fSARA p value is 0.001 in the publication, and the company's approval release gives a two-sided p value below 0.001.

The sample size calculation used a one-sided significance level of 5% and assumed a 1.0-point SARA difference, a threshold taken from an analysis of the sponsor's trials in lysosomal storage disorders; an independent estimate of the SARA minimal clinically important difference is 1.5 points. No adjustment for multiple comparisons was applied, and the statistical analysis plan classes every evaluation other than the primary endpoint as exploratory. The statistical analysis plan specifies descriptive summaries for the ICARS, and the publication reports a model-based ICARS treatment effect with a p value. Success of masking was not assessed. The SARA has not been validated specifically in ataxia-telangiectasia, and pediatric SARA scores are age-dependent; 47 of 73 participants (64%) were younger than 18 years.

The controlled comparison lasted 12 weeks per treatment, 55 of 73 participants (75%) were White, and eligibility required an age of 4 years or older and a SARA score of 7 to 34. Long-term efficacy and safety data depend on the open-label extension phase, which was ongoing at publication. The results were published in a peer-reviewed journal in July 2026; the trial was funded by IntraBio, and the publication acknowledges an IntraBio employee for writing and editorial assistance. The ClinicalTrials.gov record lists an estimated enrollment of 60, was last updated in July 2025, and carries no posted results. One congress abstract, submitted before data were available, states that 74 participants were randomized, and the congress results abstract states that no serious adverse events occurred, whereas the publication reports 73 randomized participants and three withdrawals associated with serious adverse events judged unrelated to treatment.

Limitations stated by the investigators

“This study has several limitations. First, the study was designed to investigate the symptomatic effects of levacetylleucine; data from the ongoing extension phase will provide further insights into its impact on ataxia-telangiectasia disease progression and continued data on the long-term safety of levacetylleucine for ataxia-telangiectasia. Second, the focus on symptomatic endpoints excluded patients younger than 4 years, asymptomatic patients, or patients with advanced disease states who would not be reliably able to complete functional assessments. Third, the study included paediatric patients; although all study assessments have been used previously in paediatric populations, not all study assessments are formally validated for use in paediatric populations. Fourth, most patients in this trial were White and of North American or European descent, and data on patients of other ethnicities were scarce or absent.” (opens the source at this quote in a new tab)
“Fifth, there is no validated biomarker for ataxia-telangiectasia or a surrogate endpoint which is indicative of clinical improvement. Sixth, as with all clinical trials implementing null hypothesis significance testing, the design and sample size cannot exclude the potential of type I error. Finally, the study duration was not long enough to investigate the effects of levacetylleucine on other key features of ataxia-telangiectasia, such as immunological defects and oncological risks.” (opens the source at this quote in a new tab)

Multiplicity and the exploratory status of secondary endpoints

“There will be no formal control of multiplicity outside of the designation of a primary estimand, and the efficacy, safety, and tolerability of IB1001 will be judged based on the totality of evidence across a range of endpoints.” (opens the source at this quote in a new tab)