. 2021 Jan 22;22:84. doi: 10.1186/s13063-020-05009-3

Table 1.

Inclusion and exclusion criteria for patient selection in the Parent Study

Inclusion Criteria	Exclusion 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/ impartial witness 2. *IB1001-201 (NPC) EU:* Male or female aged ≥6 years in Europe OR ≥18 years in the United States with a confirmed diagnosis of NPC at the time of signing informed consent. Confirmed diagnosis includes [Patterson et al, 2017]: a) Clinical features and positive biomarker screen and/or filipin test without genetic tests results (has not been performed) b) Clinical features and positive genetic test c) Clinical features and positive biomarker screen and/or filipin test but only one NPC mutation identified on genetic test d) Clinical features with positive biomarker screen and/or filipin test and positive genetic test *IB1001-201 (NPC) US:* Male or female aged ≥6 years in Europe OR ≥18 years in the United States with a confirmed diagnosis of NPC at the time of signing informed consent. Patients must have clinical features of NPC and a positive genetic test for mutations in both copies of NPC1 or in both copies of NPC2. *IB1001-202 (GM2):* Male or female aged ≥6 years in Europe OR ≥18 years in the United States with a confirmed diagnosis of GM2 Gangliosidosis at the time of signing informed consent. Confirmed diagnosis, i.e., clinical features and positive genetic test GM2-gangliosidosis caused by β-hexosaminidase deficiency resulting from mutations in the HEXA or HEXB genes *IB1001-203 (A-T):* Male or female aged ≥6 years in Europe OR ≥18 years in the United States with a confirmed genetic diagnosis of A-T 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^a 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 (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: a) intrauterine device (IUD); b) surgical sterilization of the partner (vasectomy for 6 months minimum); c) combined (estrogen or progestogen containing) hormonal contraception associated with the inhibition of ovulation (either oral, intravaginal, or transdermal); d) progestogen only hormonal contraception associated with the inhibition of ovulation (either oral, injectable, or implantable); e) intrauterine hormone releasing system (IUS); f) 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: a) hysteroscopic sterilization; b) bilateral tubal ligation or bilateral salpingectomy; c) hysterectomy; d) 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, patient agrees not to donate sperm from the first dose until 90 days after their last dose. 7. Patients must fall within: a) A SARA score of 5 ≤ X ≤ 33 points (out of 40) AND b) Either: i. 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. 8. Weight ≥15 kg at screening. 9. Patients are willing to disclose their existing medications/therapies for (the symptoms) of NPC, including those on the prohibited medication list. Non-prohibited medications/therapies (e.g. miglustat, concomitant speech therapy, and physiotherapy) are permitted provided: a) The Investigator does not believe the medication/therapy will interfere with the study protocol/results b) Patients have been on a stable dose/duration and type of therapy for at least 42 days before Visit 1 (Baseline 1) c) 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).	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 NPC and a positive biomarker screen and/or filipin test, but a completely negative result on a previous genetic test for NPC 3. Patients who have any of the following: a) Chronic diarrhea; b) Unexplained visual loss; c) Malignancies; d) Insulin-dependent diabetes mellitus. e) Known history of hypersensitivity to the Acetyl-Leucine (DL-, L-, D-) or derivatives. f) 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: a. *IB1001-201/ IB1001-202:* Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5x upper limit of normal (ULN);*IB1001-203:* Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3x upper limit of normal (ULN); b. 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 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. a) 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.

Inclusion Criteria

Exclusion 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/ impartial witness

2. IB1001-201 (NPC) EU: Male or female aged ≥6 years in Europe OR ≥18 years in the United States with a confirmed diagnosis of NPC at the time of signing informed consent. Confirmed diagnosis includes [Patterson et al, 2017]:

a) Clinical features and positive biomarker screen and/or filipin test without genetic tests results (has not been performed)

b) Clinical features and positive genetic test

c) Clinical features and positive biomarker screen and/or filipin test but only one NPC mutation identified on genetic test

d) Clinical features with positive biomarker screen and/or filipin test and positive genetic test

IB1001-201 (NPC) US: Male or female aged ≥6 years in Europe OR ≥18 years in the United States with a confirmed diagnosis of NPC at the time of signing informed consent. Patients must have clinical features of NPC and a positive genetic test for mutations in both copies of NPC1 or in both copies of NPC2.

IB1001-202 (GM2): Male or female aged ≥6 years in Europe OR ≥18 years in the United States with a confirmed diagnosis of GM2 Gangliosidosis at the time of signing informed consent. Confirmed diagnosis, i.e., clinical features and positive genetic test GM2-gangliosidosis caused by β-hexosaminidase deficiency resulting from mutations in the HEXA or HEXB genes

IB1001-203 (A-T): Male or female aged ≥6 years in Europe OR ≥18 years in the United States with a confirmed genetic diagnosis of A-T 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^a 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 (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:

a) intrauterine device (IUD);

b) surgical sterilization of the partner (vasectomy for 6 months minimum);

c) combined (estrogen or progestogen containing) hormonal contraception associated with the inhibition of ovulation (either oral, intravaginal, or transdermal);

d) progestogen only hormonal contraception associated with the inhibition of ovulation (either oral, injectable, or implantable);

e) intrauterine hormone releasing system (IUS);

f) 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:

a) hysteroscopic sterilization;

b) bilateral tubal ligation or bilateral salpingectomy;

c) hysterectomy;

d) 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, patient agrees not to donate sperm from the first dose until 90 days after their last dose.

7. Patients must fall within:

a) A SARA score of 5 ≤ X ≤ 33 points (out of 40)

AND

b) Either:

i. Within the 2-7 range (0-8 range) of the Gait subtest of the SARA scale

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 NPC, including those on the prohibited medication list. Non-prohibited medications/therapies (e.g. miglustat, concomitant speech therapy, and physiotherapy) are permitted provided:

a) The Investigator does not believe the medication/therapy will interfere with the study protocol/results

b) Patients have been on a stable dose/duration and type of therapy for at least 42 days before Visit 1 (Baseline 1)

c) 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).

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 NPC and a positive biomarker screen and/or filipin test, but a completely negative result on a previous genetic test for NPC

3. Patients who have any of the following:

a) Chronic diarrhea;

b) Unexplained visual loss;

c) Malignancies;

d) Insulin-dependent diabetes mellitus.

e) Known history of hypersensitivity to the Acetyl-Leucine (DL-, L-, D-) or derivatives.

f) 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:

a. IB1001-201/ IB1001-202: Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5x upper limit of normal (ULN);IB1001-203: Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3x upper limit of normal (ULN);

b. 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 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.

a) 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.

^aSexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. In this trial abstinence is only acceptable if in line with the patient’s preferred and usual lifestyle

Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception. As well, female condom and male condom should not be used together