GM2 Gangliosidosis, Sandhoff Disease, Tay-Sachs Disease
Conditions
Brief summary
This is a multinational, multicenter, open-label, rater-blinded prospective Phase II study which will assess the safety and efficacy of N-Acetyl-L-Leucine (IB1001) for the treatment of GM2 Gangliosidosis (Tay-Sachs and Sandhoff Disease). There are two phases to this study: the Parent Study, and the Extension Phase. The Parent Study evaluates the safety and efficacy of N-Acetyl-L-Leucine (IB1001) in the symptomatic treatment of GM2 Gangliosidosis (Tay-Sachs and Sandhoff Disease). The Extension Phase evaluates the long-term safety and efficacy of IB1001 for the neuroprotective, disease-modifying treatment of GM2 Gangliosidosis. The Extension Phase was considered exploratory.
Detailed description
In the Parent Study, Patients will be assessed during three study phases: a baseline period, a 6-week treatment period, and a 6-week post-treatment washout period. If within 6 weeks prior to the initial screening visit, a patient has received any of the prohibited medications defined in the eligibility criteria (irrespective of the preceding treatment duration) a wash-out study-run-in of 6 weeks is required prior to the first baseline assessment. All patients will receive the study drug during the treatment period. For each individual patient, the Parent Study lasts for approximately 3.5 - 4 months during which there are 6 visits to the study site. This Extension Phase allows patients who have completed the Parent Study to, at the discretion of the Principal Investigator (PI), continue treatment with N-Acetyl-L-Leucine (IB1001). Patients will receive treatment with IB1001 for two one-year treatment periods, separated by a 6-week washout. All patients will receive the study drug during these two one-year treatment periods. For each individual patient, the Extension Phase lasts for approximately 25.5 months, during which there are 6 visits to the study site.
Interventions
DRUGIB1001
IB1001 (N-Acetyl-L-Leucine) is a modified amino-acid ester that is orally administered.
Sponsors
IntraBio Inc
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
The primary evaluation of the Clinical Impression of Change in Severity (CI-CS; Primary Endpoint) will be performed by two independent neurologists whose assessments are based on videos of patient's performance on either the 9 Hole Peg Test of the Dominant Hand (9HPT-D) or the 8 Meter Walk Test (8MWT) taken at each visit.
Intervention model description
In both the Parent Study and Extension Phase, patients will be assessed during three study phases: a baseline period (with or without a study run-in), a treatment period, and a washout period.
Eligibility
Sex/Gender
ALL
Age
6 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Parent Study Inclusion Criteria Individuals who meet all of the following criteria are eligible to participate in the study: 1. Written informed consent signed by the patient and/or their legal representative/ parent 2. Male or female aged ≥6 years in Europe OR ≥18 years in the United States with a confirmed diagnosis of GM2 Gangliosidosis ( i.e., clinical features and positive genetic test GM2-gangliosidosis caused by β-hexosaminidase deficiency resulting from mutations in the HEXA or HEXB genes) at the time of signing informed consent. 3. 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 continuing through 28 days after the last dose) or using one of the following highly effective contraceptives (i.e. results in \<1% failure rate when used consistently and correctly) 14 days prior to the first dose continuing through 28 days after the last dose: 1. intrauterine device (IUD); 2. surgical sterilization of the partner (vasectomy for 6 months minimum); 3. combined (estrogen or progestogen containing) hormonal contraception associated with the inhibition of ovulation (either oral, intravaginal, or transdermal); 4. progestogen-only hormonal contraception associated with the inhibition of ovulation (either oral, injectable, or implantable); 5. intrauterine hormone-releasing system (IUS); 6. bilateral tubal occlusion. 4. Females of non-childbearing potential must have undergone one of the following sterilization procedures at least 6 months prior to the first dose: 1. hysteroscopic sterilization; 2. bilateral tubal ligation or bilateral salpingectomy; 3. hysterectomy; 4. bilateral oophorectomy; OR be postmenopausal with amenorrhea for at least 1 year prior to the first dose and follicle stimulating hormone (FSH) serum levels consistent with postmenopausal status. FSH analysis for postmenopausal women will be done at screening. FSH levels should be in the postmenopausal range as determined by the central laboratory. 5. Non-vasectomized male patient agrees to use a condom with spermicide or abstain from sexual intercourse 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. For a vasectomized male who has had his vasectomy 6 months or more prior to study start, it is required that they use a condom during sexual intercourse. A male who has been vasectomized less than 6 months prior to study start must follow the same restrictions as a non-vasectomized male. 6. If male, the patient agrees not to donate sperm from the first dose until 90 days after dosing. 7. Patients must fall within: a) A Scale for the Assessment and Rating of Ataxia (SARA) score of 5 ≤ X ≤ 33 points (out of 40) AND i. Within the 2-7 range (out of 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. 8. Weight ≥15 kg at screening. 9. Patients are willing to disclose their existing medications/therapies for (the symptoms) of GM2 Gangliosidosis, including those on the prohibited medication list. Non-prohibited medications/therapies (e.g. concomitant speech therapy, and physiotherapy) are permitted provided: 1. The Investigator does not believe the medication/therapy will interfere with the study protocol/results 2. Patients have been on a stable dose/duration and type of therapy for at least 6 weeks before Visit 1 (Baseline 1) 3. Patients are willing to maintain a stable dose/do not change their therapy throughout the duration of the study. 10. An understanding of the implications of study participation, provided in the written patient information and informed consent by patients or their legal representative/parent, and demonstrates a willingness to comply with instructions and attend required study visits (for children this criterion will also be assessed in parents or appointed guardians). Parent Study
Exclusion criteria
Individuals who meet any of the following criteria are not eligible to participate in the study: 1. Asymptomatic patients 2. Patient has clinical features of Tay-Sachs or Sandhoff disease, but a completely negative result on a previous genetic test for GM2 Gangliosidosis caused by β-hexosaminidase deficiency resulting from mutations in the HEXA or HEXB genes 3. Patients who have any of the following: 1. Chronic diarrhea; 2. Unexplained visual loss; 3. Malignancies; 4. Insulin-dependent diabetes mellitus. 5. Known history of hypersensitivity to the N-Acetyl-Leucine (DL-, L-, D-) or derivatives. 6. History of known hypersensitivity to excipients of Ora-Blend® (namely sucrose, sorbitol, cellulose, carboxymethylcellulose, xanthan gum, carrageenan, dimethicone, methylparaben, and potassium sorbate). 4. Simultaneous participation in another clinical study or participation in any clinical study involving administration of an investigational medicinal product (IMP; 'study drug') within 6 weeks prior to Visit 1. 5. Patients with a physical or psychiatric condition which, at the investigator's discretion, may put the patient at risk, may confound the study results, or may interfere with the patient's participation in the clinical study. 6. Known clinically-significant (at the discretion of the investigator) laboratories in hematology, coagulation, clinical chemistry, or urinalysis, including, but not limited to: 1. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>5x upper limit of normal (ULN); 2. Total bilirubin \>1.5x ULN, unless Gilbert's syndrome is present in which case total bilirubin \>2x ULN. 7. Known or persistent use, misuse, or dependency of medication, drugs, or alcohol. 8. Current or planned pregnancy or women who are breastfeeding. 9. 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. 10. 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. 11. Patients unwilling and/or not able to undergo a 6-week washout period from any of the following prohibited medication prior to Visit 1 (Baseline 1) and remain without prohibited medication through Visit 6. 1. Aminopyridines (including sustained-release form); 2. N-Acetyl-DL-Leucine (e.g. Tanganil®); 3. N-Acetyl-L-Leucine (prohibited if not provided as IMP); 4. Riluzole; 5. Gabapentin; 6. Varenicline; 7. Chlorzoxazone; 8. Sulfasalazine; 9. Rosuvastatin. Extension Phase Inclusion Criteria 1. Completed Visit 6 of the IB1001-202 Parent Study 2. The Principal Investigator determines further treatment with IB1001 to be in the patient's best interest 3. Written informed consent signed by the patient and/or their legal representative/parent/ impartial witness for participation in the Extension Phase 4. Patients are willing to continue to remain without the following prohibited medication from Visit 6 throughout the duration of the Extension Phase: Aminopyridines (including sustained-release form); b) N-Acetyl-DL-Leucine (e.g. Tanganil®); c) N-Acetyl-L-Leucine (prohibited if not provided as IMP); d) Riluzole; e) Gabapentin; f) Varenicline; g) Chlorzoxazone; h) Sulfasalazine; i) Rosuvastatin.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Impression of Change in Severity (CI-CS) [Fields et al 2021] | (CI-CS comparing Baseline [Day 1] with IB1001 versus the end of 6-weeks treatment with IB1001 [approximately Day 42]) MINUS (CI-CS comparing the end of 6-weeks treatment with IB1001 [approximately Day 42] versus end of 6-weeks post-treatment washout); | The Clinical Impression of Change in Severity assessment will instruct the blinded rater to consider: compared to the first video, how has the severity of their performance on the 9 Hole Peg Test of the Dominant Hand (9HPT-D) or 8 Meter Walk Test (8MWT) changed (improved or worsened) in 6-weeks as observed in the second video? The Clinical Impression of Change in Severity is evaluated on a 7 point Likert scale (+3=significantly improved to -3= significantly worse). Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4)). Then, the mean change obtained in the post-treatment period was subtracted from the mean change obtained for the treatment with IB1001 period, with a positive value indicating an improvement in the treatment period compared to the post-treatment washout period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Key Secondary Endpoint: Change in Severity Based on Average CI-S | (CI-S comparing baseline period [average for Visit 1 and 2] and end of treatment period [average for Visit 3 and 4]) minus (change in CI-S between end of treatment period [average for Visit 3 and 4] and end of washout period [average for Visit 5 and 6]). | The Change in Severity assessment will instruct the blinded rater to consider the severity of the patient at each visit. The Clinical Impression of Severity (CI-S)-assessment ranged from +3 =normal not ill at all to -3=among the most extremely ill patients . Change values were calculated for each period, i.e. treatment with IB1001 (change between the baseline period (average for Visit 1 and Visit 2) and end of treatment period (average for Visit 3 and Visit 4)) and post-treatment washout (between end of treatment period (average for Visit 3 and Visit 4) and end of washout period (average for Visit 5 and Visit 6). Then, the mean change in the post-treatment period was subtracted from the mean change in the treatment with IB1001 period. |
| Key Secondary Endpoint: CI-CS Score Reclassified on a 3-Point Scale | Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post 6-week treatment washout | The Clinical Impression of Change in Severity assessment will instruct the blinded rater to consider: compared to the first video, how has the severity of their performance on the 9 Hole Peg Test of the Dominant Hand (9HPT-D) or 8 Meter Walk Test (8MWT) changed (improved or worsened) in 6-weeks as observed in the second video? The Clinical Impression of Change in Severity is evaluated on a 7 point Likert scale (+3=significantly improved to -3= significantly worse). CI-CS scores \<0 were reclassified as worsened (-1), CI-CS scores 0 remained classified as not changed (0), and CI-CS scores \>0 were reclassified as improved (+1). When comparing Visit 4 versus Visit 2 and Visit 6 versus Visit 4, CI-CS scores \<0 were reclassified as worsened (-1), CI-CS scores 0 remained classified as not changed (0), and CI-CS scores \>0 were reclassified as improved (+1). |
| Key Secondary Endpoint: CI-CS Score for the Non-Primary Anchor Test | CI-CS of the non-primary anchor test was evaluated, comparing the CI-CS of Visit 4 (end of treatment) versus Visit 2 (baseline) and of Visit 6 (end of washout) versus Visit 4 (end of treatment) as done for the primary anchor test. | The Clinical Impression of Change in Severity assessment will instruct the blinded rater to consider: compared to the first video, how has the severity of their performance on the 9 Hole Peg Test of the Dominant Hand (9HPT-D) or 8 Meter Walk Test (8MWT) changed (improved or worsened) in 6-weeks as observed in the second video? The Clinical Impression of Change in Severity is evaluated on a 7 point Likert scale (+3=significantly improved to -3= significantly worse). Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4)). |
| Spinocerebellar Ataxia Functional Index (SCAFI) [Schmitz-Hübsch et al, 2008] | Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4)). | Spinocerebellar Ataxia Functional Index (SCAFI) is composed of 8 Meter Walk Test, 9-Hole Peg Test of Dominant and Non-Dominant Hand (9HPT-D/9HPT-ND) (the 3 tests are timed assessments; each is done twice and values are averaged; the 8MWT and 9HPT-D and 9HPT-ND values are converted from times to rates, and the results expressed as a composite Z-score of each test relative to baseline) and the PATA rate (counted number how often a patient can repeat the syllables PATA within 10 seconds), a measure of speech performance. The scores of these 3 were transformed to Z-scores (=individual's average of both trials to perform the respective task -mean of study population at baseline) / SD of study population at baseline). 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. |
| Scale for Assessment and Rating of Ataxia (SARA) Score [Schmitz-Hübsch Etal, 2006; Subramony, 2007] | Baseline to end of treatment with IB1001 (Parent Study Day 42); End of treatment with IB1001 to the end of post treatment washout | 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. Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4)). |
| Key Secondary Endpoint: Individual Components of the CI-CS | Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post 6-week treatment washout. | The Clinical Impression of Change in Severity assessment will instruct the blinded rater to consider: compared to the first video, how has the severity of their performance on the 9 Hole Peg Test of the Dominant Hand (9HPT-D) or 8 Meter Walk Test (8MWT) changed (improved or worsened) in 6-weeks as observed in the second video? The Clinical Impression of Change in Severity is evaluated on a 7 point Likert scale (+3=significantly improved to -3= significantly worse). Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4)). |
| Modified Disability Rating Scale (mDRS) [Iturriaga et al. 2006] | Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post treatment washout. | Overall neurological status based on six domains (ambulation, manipulation,language, swallowing, seizures and ocular movements). The Modified Disability Rating Scale (mDRS) ranges from 0-24, where 0 is the best neurological status and 24 is the worst. Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4)) |
| Investigator's Clinical Global Impressions of Change (CGI-c) | Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post treatment washout. | The Clinical Global Impression of Change assessed by the investigator is evaluated on a 7 point Likert scale ranging from 1='very much improved' to 7='very much worse' Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4)). |
| Parent/Caregiver's Clinical Global Impression of Change (CGI-C) | Baseline to end of treatment with IB1001 (Parent Study 6-week treatment); End of treatment with IB1001 to the end of post treatment washout | The Clinical Global Impression of Change assessed by the parent/caregiver is evaluated on a 7 point Likert scale ranging from 1='very much improved' to 7='very much worse'. Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4)). |
| Patient's Clinical Global Impressions (CGI) if Able | Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post treatment washout. | The Clinical Global Impression of Change assessed by the patient (if able) is evaluated on a 7 point Likert scale ranging from 1='very much improved' to 7='very much worse'. Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4)). |
| EuroQuol- 5 Dimension (EQ-5D) Quality of Life Scale: Visual Analogue Scale (VAS) | Baseline to end of treatment with IB1001 (Parent Study 6-week treatment): observed VAS values at visit 4; End of treatment with IB1001 to the end of post treatment washout: observed VAS values at visit 6. | For posting, health-related quality of life based on the EQ-5D visual analogue scale (VAS) was presented as a secondary endpoint. 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 100indicating best health. |
Countries
Germany, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Parent Study All patients were first dosed with IB1001.Therefore, the baseline characteristics of patients dosed in the first IB1001treatment period in the parent study constitute the baseline characteristics for the entire study. | 30 |
| Total | 30 |
Baseline characteristics
| Characteristic | Parent Study |
|---|---|
| Age, Continuous | 27 years STANDARD_DEVIATION 15.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 8 Participants |
| Region of Enrollment Germany | 18 participants |
| Region of Enrollment Spain | 1 participants |
| Region of Enrollment United Kingdom | 1 participants |
| Region of Enrollment United States | 10 participants |
| Sex: Female, Male Female | 19 Participants |
| Sex: Female, Male Male | 11 Participants |
| Tay-Sachs vs. Sandhoff Patients Sandhoff | 3 participants |
| Tay-Sachs vs. Sandhoff Patients Tay-Sachs | 27 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 30 |
| other Total, other adverse events | 17 / 30 | 15 / 30 |
| serious Total, serious adverse events | 2 / 30 | 0 / 30 |
Outcome results
Primary
Clinical Impression of Change in Severity (CI-CS) [Fields et al 2021]
The Clinical Impression of Change in Severity assessment will instruct the blinded rater to consider: compared to the first video, how has the severity of their performance on the 9 Hole Peg Test of the Dominant Hand (9HPT-D) or 8 Meter Walk Test (8MWT) changed (improved or worsened) in 6-weeks as observed in the second video? The Clinical Impression of Change in Severity is evaluated on a 7 point Likert scale (+3=significantly improved to -3= significantly worse). Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4)). Then, the mean change obtained in the post-treatment period was subtracted from the mean change obtained for the treatment with IB1001 period, with a positive value indicating an improvement in the treatment period compared to the post-treatment washout period.
Time frame: (CI-CS comparing Baseline [Day 1] with IB1001 versus the end of 6-weeks treatment with IB1001 [approximately Day 42]) MINUS (CI-CS comparing the end of 6-weeks treatment with IB1001 [approximately Day 42] versus end of 6-weeks post-treatment washout);
Population: Modified Intention to Treat (mITT) Analysis Set is defined as all patients who receive at least one dose of the study drug and with one video recording during the baseline period (Visit 1 or 2, or both) and treatment period (Visit 3 or Visit 4, or both).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Parent Study | Clinical Impression of Change in Severity (CI-CS) [Fields et al 2021] | 0.71 score on a scale | Standard Deviation 2.09 |
p-value: 0.04490% CI: [0, 1.5]1-sided Wilcoxon signed-rank test
Secondary
EuroQuol- 5 Dimension (EQ-5D) Quality of Life Scale: Visual Analogue Scale (VAS)
For posting, health-related quality of life based on the EQ-5D visual analogue scale (VAS) was presented as a secondary endpoint. 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 100indicating best health.
Time frame: Baseline to end of treatment with IB1001 (Parent Study 6-week treatment): observed VAS values at visit 4; End of treatment with IB1001 to the end of post treatment washout: observed VAS values at visit 6.
Population: The Modified Intention to Treat (mITT) analysis set was defined as all patients who receive at least one dose of the study drug and with one video recording during the baseline period (Visit 1 or 2, or both) and treatment period (Visit 3 or Visit 4, or both). The overall mITT comprised 29 participants. Of these, 28 participants had values for the EQ-5D VAS analysis in the Treatment with IB1001 period and 27 participants in the Post-Treatment washout period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Parent Study | EuroQuol- 5 Dimension (EQ-5D) Quality of Life Scale: Visual Analogue Scale (VAS) | Treatment with IB1001 | 71.3 score on a scale | Standard Deviation 23.2 |
| Parent Study | EuroQuol- 5 Dimension (EQ-5D) Quality of Life Scale: Visual Analogue Scale (VAS) | Post-Treatment Washout | 71.1 score on a scale | Standard Deviation 21.2 |
Secondary
Investigator's Clinical Global Impressions of Change (CGI-c)
The Clinical Global Impression of Change assessed by the investigator is evaluated on a 7 point Likert scale ranging from 1='very much improved' to 7='very much worse' Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4)).
Time frame: Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post treatment washout.
Population: The Modified Intention to Treat (mITT) analysis set was defined as all patients who receive at least one dose of the study drug and with one video recording during the baseline period (Visit 1 or 2, or both) and treatment period (Visit 3 or Visit 4, or both). The overall mITT comprised 29 participants. Of these, 28 participants had values for theInvestigator's CGI-C analysis in the Treatment with IB1001 period and 27 participants in the Post-Treatment washout period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Parent Study | Investigator's Clinical Global Impressions of Change (CGI-c) | Treatment with IB1001 | 3.2 score on a scale | Standard Deviation 1 |
| Parent Study | Investigator's Clinical Global Impressions of Change (CGI-c) | Post-Treatment Washout | 4.9 score on a scale | Standard Deviation 0.8 |
Comparison: Treatment With IB1001p-value: <0.00190% CI: [3, 3.5]1-sided Wilcoxon signed-rank test
Comparison: Post-Treatment Washoutp-value: <0.00190% CI: [4.5, 5]1-sided Wilcoxon signed-rank test
Secondary
Key Secondary Endpoint: Change in Severity Based on Average CI-S
The Change in Severity assessment will instruct the blinded rater to consider the severity of the patient at each visit. The Clinical Impression of Severity (CI-S)-assessment ranged from +3 =normal not ill at all to -3=among the most extremely ill patients . Change values were calculated for each period, i.e. treatment with IB1001 (change between the baseline period (average for Visit 1 and Visit 2) and end of treatment period (average for Visit 3 and Visit 4)) and post-treatment washout (between end of treatment period (average for Visit 3 and Visit 4) and end of washout period (average for Visit 5 and Visit 6). Then, the mean change in the post-treatment period was subtracted from the mean change in the treatment with IB1001 period.
Time frame: (CI-S comparing baseline period [average for Visit 1 and 2] and end of treatment period [average for Visit 3 and 4]) minus (change in CI-S between end of treatment period [average for Visit 3 and 4] and end of washout period [average for Visit 5 and 6]).
Population: Modified Intention to Treat (mITT) Analysis Set is defined as all patients who receive at least one dose of the study drug and with one video recording during the baseline period (Visit 1 or 2, or both) and treatment period (Visit 3 or Visit 4, or both).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Parent Study | Key Secondary Endpoint: Change in Severity Based on Average CI-S | 0.09 score on a scale | Standard Deviation 0.71 |
p-value: 0.20690% CI: [-0.13, 0.25]1-sided Wilcoxon signed-rank test
Secondary
Key Secondary Endpoint: CI-CS Score for the Non-Primary Anchor Test
The Clinical Impression of Change in Severity assessment will instruct the blinded rater to consider: compared to the first video, how has the severity of their performance on the 9 Hole Peg Test of the Dominant Hand (9HPT-D) or 8 Meter Walk Test (8MWT) changed (improved or worsened) in 6-weeks as observed in the second video? The Clinical Impression of Change in Severity is evaluated on a 7 point Likert scale (+3=significantly improved to -3= significantly worse). Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4)).
Time frame: CI-CS of the non-primary anchor test was evaluated, comparing the CI-CS of Visit 4 (end of treatment) versus Visit 2 (baseline) and of Visit 6 (end of washout) versus Visit 4 (end of treatment) as done for the primary anchor test.
Population: Modified Intention to Treat (mITT) Analysis Set is defined as all patients who receive at least one dose of the study drug and with one video recording during the baseline period (Visit 1 or 2, or both) and treatment period (Visit 3 or Visit 4, or both). The overall mITT comprised 29 participants. Of these, 22 participants had values for the CI-CS Score for the Non-Primary Anchor Test analysis in the Treatment with IB1001 period and 20 participants in the Post-Treatment washout period
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Parent Study | Key Secondary Endpoint: CI-CS Score for the Non-Primary Anchor Test | Treatment with IB1001 | -0.30 score on a scale | Standard Deviation 1.33 |
| Parent Study | Key Secondary Endpoint: CI-CS Score for the Non-Primary Anchor Test | Post-treatment washout | 0.23 score on a scale | Standard Deviation 1.43 |
Secondary
Key Secondary Endpoint: CI-CS Score Reclassified on a 3-Point Scale
The Clinical Impression of Change in Severity assessment will instruct the blinded rater to consider: compared to the first video, how has the severity of their performance on the 9 Hole Peg Test of the Dominant Hand (9HPT-D) or 8 Meter Walk Test (8MWT) changed (improved or worsened) in 6-weeks as observed in the second video? The Clinical Impression of Change in Severity is evaluated on a 7 point Likert scale (+3=significantly improved to -3= significantly worse). CI-CS scores \<0 were reclassified as worsened (-1), CI-CS scores 0 remained classified as not changed (0), and CI-CS scores \>0 were reclassified as improved (+1). When comparing Visit 4 versus Visit 2 and Visit 6 versus Visit 4, CI-CS scores \<0 were reclassified as worsened (-1), CI-CS scores 0 remained classified as not changed (0), and CI-CS scores \>0 were reclassified as improved (+1).
Time frame: Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post 6-week treatment washout
Population: The Modified Intention to Treat (mITT) analysis set was defined as all patients who receive at least one dose of the study drug and with one video recording during the baseline period (Visit 1 or 2, or both) and treatment period (Visit 3 or Visit 4, or both). The overall mITT comprised 29 participants. Of these, 29 participants had values for the CI-CS analysis in the Treatment with IB1001 period and 27 participants in the Post-Treatment washout period.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Parent Study | Key Secondary Endpoint: CI-CS Score Reclassified on a 3-Point Scale | Treatment with IB1001 | -1 (Worsened) | 12 Participants |
| Parent Study | Key Secondary Endpoint: CI-CS Score Reclassified on a 3-Point Scale | Treatment with IB1001 | 0 (No observable change) | 1 Participants |
| Parent Study | Key Secondary Endpoint: CI-CS Score Reclassified on a 3-Point Scale | Treatment with IB1001 | +1 (Improved) | 16 Participants |
| Parent Study | Key Secondary Endpoint: CI-CS Score Reclassified on a 3-Point Scale | Post-treatment washout | -1 (Worsened) | 16 Participants |
| Parent Study | Key Secondary Endpoint: CI-CS Score Reclassified on a 3-Point Scale | Post-treatment washout | 0 (No observable change) | 3 Participants |
| Parent Study | Key Secondary Endpoint: CI-CS Score Reclassified on a 3-Point Scale | Post-treatment washout | +1 (Improved) | 8 Participants |
Secondary
Key Secondary Endpoint: Individual Components of the CI-CS
The Clinical Impression of Change in Severity assessment will instruct the blinded rater to consider: compared to the first video, how has the severity of their performance on the 9 Hole Peg Test of the Dominant Hand (9HPT-D) or 8 Meter Walk Test (8MWT) changed (improved or worsened) in 6-weeks as observed in the second video? The Clinical Impression of Change in Severity is evaluated on a 7 point Likert scale (+3=significantly improved to -3= significantly worse). Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4)).
Time frame: Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post 6-week treatment washout.
Population: Modified Intention to Treat (mITT) Analysis Set is defined as all patients who receive at least one dose of the study drug and with one video recording during the baseline period (Visit 1 or 2, or both) and treatment period (Visit 3 or Visit 4, or both). The overall mITT comprised 29 participants. Of these, 29 participants had values for the CI-CS analysis in the Treatment with IB1001 period and 27 participants in the Post-Treatment washout period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Parent Study | Key Secondary Endpoint: Individual Components of the CI-CS | Treatment with IB1001 | 0.34 score on a scale | Standard Deviation 1.59 |
| Parent Study | Key Secondary Endpoint: Individual Components of the CI-CS | Post-TreatmentWashout | -0.36 score on a scale | Standard Deviation 1.33 |
Secondary
Modified Disability Rating Scale (mDRS) [Iturriaga et al. 2006]
Overall neurological status based on six domains (ambulation, manipulation,language, swallowing, seizures and ocular movements). The Modified Disability Rating Scale (mDRS) ranges from 0-24, where 0 is the best neurological status and 24 is the worst. Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4))
Time frame: Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post treatment washout.
Population: The Modified Intention to Treat (mITT) analysis set was defined as all patients who receive at least one dose of the study drug and with one video recording during the baseline period (Visit 1 or 2, or both) and treatment period (Visit 3 or Visit 4, or both). The overall mITT comprised 29 participants. Of these, 28 participants had values for the mDRS analysis in the Treatment with IB1001 period and 27 participants in the Post-Treatment washout period
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Parent Study | Modified Disability Rating Scale (mDRS) [Iturriaga et al. 2006] | Treatment with IB1001 | -0.030 score on a scale | Standard Deviation 0.075 |
| Parent Study | Modified Disability Rating Scale (mDRS) [Iturriaga et al. 2006] | Post-Treatment Washout | 0.042 score on a scale | Standard Deviation 0.058 |
Comparison: Treatment with IB1001p-value: 0.0290% CI: [-0.063, 0]1-sided Wilcoxon signed-rank test
Comparison: Post-Treatment Washoutp-value: <0.00190% CI: [0.021, 0.063]1-sided Wilcoxon signed-rank test
Secondary
Parent/Caregiver's Clinical Global Impression of Change (CGI-C)
The Clinical Global Impression of Change assessed by the parent/caregiver is evaluated on a 7 point Likert scale ranging from 1='very much improved' to 7='very much worse'. Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4)).
Time frame: Baseline to end of treatment with IB1001 (Parent Study 6-week treatment); End of treatment with IB1001 to the end of post treatment washout
Population: The Modified Intention to Treat (mITT) analysis set was defined as all patients who receive at least one dose of the study drug and with one video recording during the baseline period (Visit 1 or 2, or both) and treatment period (Visit 3 or Visit 4, or both). The overall mITT comprised 29 participants. Of these, 26 participants had values for the Parent/Caregiver's CGI-C analysis in the Treatment with IB1001 period and 25 participants in the Post-Treatment washout period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Parent Study | Parent/Caregiver's Clinical Global Impression of Change (CGI-C) | Treatment With IB1001 | 3.2 score on a scale | Standard Deviation 1.2 |
| Parent Study | Parent/Caregiver's Clinical Global Impression of Change (CGI-C) | Post-Treatment Washout | 4.8 score on a scale | Standard Deviation 1 |
Secondary
Patient's Clinical Global Impressions (CGI) if Able
The Clinical Global Impression of Change assessed by the patient (if able) is evaluated on a 7 point Likert scale ranging from 1='very much improved' to 7='very much worse'. Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4)).
Time frame: Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post treatment washout.
Population: The Modified Intention to Treat (mITT) analysis set was defined as all patients who receive at least one dose of the study drug and with one video recording during the baseline period (Visit 1 or 2, or both) and treatment period (Visit 3 or Visit 4, or both). The overall mITT comprised 29 participants. Of these, 28 participants had values for the Patient's CGI if Able analysis in the Treatment with IB1001 period and 27 participants in the Post-Treatment washout period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Parent Study | Patient's Clinical Global Impressions (CGI) if Able | Treatment With IB1001 | 3.0 score on a scale | Standard Deviation 1.1 |
| Parent Study | Patient's Clinical Global Impressions (CGI) if Able | Post-Treatment Washout | 4.6 score on a scale | Standard Deviation 1.2 |
Secondary
Scale for Assessment and Rating of Ataxia (SARA) Score [Schmitz-Hübsch Etal, 2006; Subramony, 2007]
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. Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4)).
Time frame: Baseline to end of treatment with IB1001 (Parent Study Day 42); End of treatment with IB1001 to the end of post treatment washout
Population: The Modified Intention to Treat (mITT) analysis set was defined as all patients who receive at least one dose of the study drug and with one video recording during the baseline period (Visit 1 or 2, or both) and treatment period (Visit 3 or Visit 4, or both). The overall mITT comprised 29 participants. Of these, 28 participants had values for the SARA analysis in the Treatment with IB1001 period and 27 participants in the Post-Treatment washout period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Parent Study | Scale for Assessment and Rating of Ataxia (SARA) Score [Schmitz-Hübsch Etal, 2006; Subramony, 2007] | Treatment with IB1001 | -1.41 score on a scale | Standard Deviation 1.67 |
| Parent Study | Scale for Assessment and Rating of Ataxia (SARA) Score [Schmitz-Hübsch Etal, 2006; Subramony, 2007] | Post-treatment washout | 1.43 score on a scale | Standard Deviation 2.08 |
Comparison: Treatment With IB1001p-value: <0.00190% CI: [-1.75, -0.75]1-sided Wilcoxon signed-rank test
Comparison: Post-Treatment Washoutp-value: 0.00190% CI: [0.5, 2]1-sided Wilcoxon signed-rank test
Secondary
Spinocerebellar Ataxia Functional Index (SCAFI) [Schmitz-Hübsch et al, 2008]
Spinocerebellar Ataxia Functional Index (SCAFI) is composed of 8 Meter Walk Test, 9-Hole Peg Test of Dominant and Non-Dominant Hand (9HPT-D/9HPT-ND) (the 3 tests are timed assessments; each is done twice and values are averaged; the 8MWT and 9HPT-D and 9HPT-ND values are converted from times to rates, and the results expressed as a composite Z-score of each test relative to baseline) and the PATA rate (counted number how often a patient can repeat the syllables PATA within 10 seconds), a measure of speech performance. The scores of these 3 were transformed to Z-scores (=individual's average of both trials to perform the respective task -mean of study population at baseline) / SD of study population at baseline). 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.
Time frame: Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4)).
Population: Modified Intention to Treat (mITT) Analysis Set is defined as all patients who receive at least one dose of the study drug and with one video recording during the baseline period (Visit 1 or 2, or both) and treatment period (Visit 3 or Visit 4, or both). The overall mITT comprised 29 participants. Of these, 26 participants had values for the SCAFI Total score analysis in the Treatment with IB1001 period and 25 participants in the Post-Treatment washout period
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Parent Study | Spinocerebellar Ataxia Functional Index (SCAFI) [Schmitz-Hübsch et al, 2008] | Treatment with IB1001 | 0.0163 Z-scores | Standard Deviation 0.2749 |
| Parent Study | Spinocerebellar Ataxia Functional Index (SCAFI) [Schmitz-Hübsch et al, 2008] | Post-treatment washout | -0.0080 Z-scores | Standard Deviation 0.242 |
Comparison: Treatment With IB1001p-value: 0.2190% CI: [-0.0327, 0.104]1-sided Wilcoxon signed-rank test
Comparison: Post-Treatment Washoutp-value: 0.21290% CI: [-0.0863, 0.0262]1-sided Wilcoxon signed-rank test