NIH Clinical Center Search the Studies: Study Number, Study Title

Protocol Details

A Phase 1/2a, Randomized, Double-Blind, Placebo-Controlled, First In-Patient Study of AJ201 to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics in Adults With Spinal and Bulbar Muscular Atrophy (SBMA)

This study is currently recruiting participants.

Summary | Eligibility | Citations | Contacts

Summary

Number

001505-N

Sponsoring Institute

National Institute of Neurological Disorders and Stroke (NINDS)

Recruitment Detail

Type: Participants currently recruited/enrolled
Gender: Male
Min Age: 18 Years
Max Age: 120 Years

Referral Letter Required

No

Population Exclusion(s)

Female;
Children

Keywords

Neuromuscular Manifestations;
Central Nervous System Diseases;
Genetic Diseases, X-linked;
Neurodegenerative Diseases;
Motor Neuron Disease;
Spinal Cord Diseases;
Nervous system diseases;
Atrophy;
bulbo-spinal atrophy, X-linked;
Muscular Atrophy

Recruitment Keyword(s)

None

Condition(s)

Spinal and Bulbar Muscular Atrophy;
Kennedy's Disease

Investigational Drug(s)

AJ201

Investigational Device(s)

None

Intervention(s)

Drug: Placebo
Drug: AJ201

Supporting Site

National Institute of Neurological Disorders and Stroke

Background:

Spinal and bulbar muscular atrophy (SBMA), also called Kennedy s disease, is a rare disease that leads to muscle weakness. Researchers think an abnormal protein may cause the breakdown of muscles and nerve cells in people with SBMA. A study drug called AJ201 targets the abnormal protein. This drug may be able to improve muscle and nerve function in people with SMBA.

Objective:

To test AJ201 in people with SBMA.

Eligibility:

Males aged 18 years and older with SBMA.

Design:

Participants will visit the clinic at least 6 times in about 5 months.

A screening period will be 4 weeks. Participants will have a physical exam. They will have blood and urine tests and tests of their heart function. They will have imaging scans of their thighs and lower legs. They will have a DEXA scan: This test uses X-rays to measure lean body mass. They will perform tasks, such as walking and writing, to assess their muscle strength. They will have a biopsy: A small amount of muscle tissue will be removed with a needle.

AJ201 is a liquid taken by mouth. Participants will take the study drug once a day at home for 12 weeks. Some of the participants will take a placebo instead of AJ201. The placebo is a liquid that looks just like the AJ201 but contains no medicine. Participants will not know which they are taking.

Participants will record their doses in a diary.

The scans, biopsy, and other tests will be repeated after they finish taking the drug or placebo.

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Eligibility

INCLUSION CRITERIA:

Subjects must meet all the inclusion criteria below to be eligible:

-Able to give informed consent before any assessment is performed.

-Adult males aged 18 or greater with a confirmed genetic diagnosis (confirmed CAG repeat expansion in the AR gene of at least 36 repeat) of SBMA and clinical diagnosis of symptomatic muscle weakness.

-Able to complete 2MWT with or without the aid of an assisted device at screening.

-SBMAFRS score >=26 (subjects with moderate to high physical performance) at screening.

-Willing to participate in all aspects of study design and assessments, including blood draw and muscle biopsies.

-Male subjects and their female spouses/partners who are of childbearing potential must agree to use highly effective contraception consisting of 2 forms of birth control (at least 1 of which must be a barrier method) starting from the first dose of the study drug and continuing throughout the study period and for 90 days after the last dose of the study drug. Male subjects should also not donate sperm during the study and for 90 days after the final administration of the study drug.

-Able to communicate well with the Investigator, to understand, and comply with the requirements of the study.

EXCLUSION CRITERIA:

Subjects who meet any of the following exclusion criteria will be excluded from the study:

-Nonambulatory.

-Contraindications to MRI such as a contraindicated nonremovable metal device (ie, pacemaker, defibrillator, insulin pump, metal clips, nonremovable jewelry) or claustrophobia.

-Use of other investigational products within 30 days, or within 5 half-lives, whichever is longer, prior to the first dosing, or until the expected PD effect has returned to baseline, whichever is longer. Approved COVID-19 vaccines are not considered investigational treatments and are allowed prior to, during, and after the study.

-Use of drugs known to affect muscle metabolism within the previous 1 month prior to the first dosing, including (but not limited to) systemic corticosteroids (>10 mg/day prednisone or equivalent), androgens, or androgen reducing agents, systemic beta agonists or beta blockers, and relevant herbal, or nutraceutical products. For subjects using systemic corticosteroids (<=10 mg/day or equivalent), they should be on stable dose for the previous 3 months prior to first dosing.

-Known history of allergic reactions to curcumin analogs or excipients in the study drug formulation.

-Known history of clinically significant cardiovascular disease (including uncontrolled hypertension, ischemic heart disease [eg, myocardial infarction, angina, abnormal coronary arteriography or cardiac stress testing/imaging]), heart failure or left ventricle dysfunction of New York Heart Association Classification III-IV, or clinically significant cerebrovascular disease (stroke or transient ischemic attacks).

-An abnormal ECG at screening visit which is judged to be clinically relevant and represents an unacceptable risk for study participation by the Investigator. An example is Brugada-like ECG changes which have been reported in SBMA patients in Italy and Japan.

-Any surgical or medical condition which may jeopardize the subject in case of participation in the study. The Investigator should make this determination in consideration of the subject s medical history and/or clinical or laboratory evidence of any of the following during screening:

--Liver disease or liver injury as indicated by abnormal liver function tests such as AST, ALT, gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), or serum bilirubin in the presence of normal serum creatine kinase (CK).

--Significant swallowing dysfunction, which may increase the risk of accidental choking and aspiration pneumonia

-Subjects with renal impairment defined as a creatinine clearance of <90 mL/min at screening. (Creatinine Clearance = [140 age in years] *weight in kg]/[72*serum Cr(mg/dL)])

-History of active tuberculosis or exposure to endemic areas within 8 weeks prior to QuantiFERON (R) -TB testing performed at screening.

-Positive QuantiFERON (R) -TB indicating possible tuberculosis infection.

-History of immunodeficiency diseases, including a positive HIV test result at screening.

-A positive hepatitis B surface antigen or hepatitis C test result at screening.

-Subjects with known bleeding disorders, or who are under treatment with anticoagulants or with a platelet count <50,000 (due to the increased risk of bleeding during muscle biopsy procedure).

-History of drug or alcohol abuse within the 12 months prior to the first dosing, or evidence of such abuse as indicated by the laboratory assays conducted during screening.

-The Investigator should be guided by the following criteria during screening:

--Any single laboratory parameter may not exceed 3 times the upper limit of normal (ULN). A single parameter elevated up to and including 3 times the ULN should be re-checked once more as soon as possible, and in all cases, at least prior to enrollment/randomization, to rule out lab error. For abnormal liver function tests, in the presence of elevated serum CK levels, ALT, or AST, up to 5 times the ULN are acceptable if other liver tests are normal.

--If the total bilirubin concentration is increased above 1.5 times the ULN, total bilirubin should be differentiated into the direct and indirect reacting bilirubin. In any case, serum indirect bilirubin should not exceed the value of 1.6 mg/dL (27 mol/L).

-Use of drugs that are inhibitors of CYP3A4, 2B6, or 2C19 within 2 weeks prior to the first dosing and during the study.

-Use of drugs that are substrates of MATE1 or MATE2-K transporters within 2 weeks prior to the first dosing and during the study.

-Use of turmeric or products containing curcumin within 2 weeks prior to the first dosing and during the study.

-Use of aspirin or nonsteroidal anti-inflammatory agents within 3 days prior to the baseline visit (due to the increased risk of bleeding during muscle biopsy procedure).

-Any reason that, in the opinion of the Investigator, would prevent the subject from

participating in the study.


--Back to Top--

Citations:

Bott LC, Badders NM, Chen KL, Harmison GG, Bautista E, Shih CC, Katsuno M, Sobue G, Taylor JP, Dantuma NP, Fischbeck KH, Rinaldi C. A small-molecule Nrf1 and Nrf2 activator mitigates polyglutamine toxicity in spinal and bulbar muscular atrophy. Hum Mol Genet. 2016 May 15;25(10):1979-1989. doi: 10.1093/hmg/ddw073. Epub 2016 Mar 8. PMID: 26962150; PMCID: PMC5062587.

--Back to Top--

Contacts:

Principal Investigator

Referral Contact

For more information:

Christopher Grunseich, M.D.
National Institute of Neurological Disorders and Stroke (NINDS)
NIHBC 35 - PNRC I BG RM 2A-1010
35 CONVENT DR
BETHESDA MD 20892
(301) 402-5423
grunseichc@mail.nih.gov

Angela Kokkinis, R.N.
National Institute of Neurological Disorders and Stroke (NINDS)
National Institutes of Health
Building 10
Room 5S-219
10 Center Drive
Bethesda, Maryland 20892
(301) 451-8146
akokkinis@mail.cc.nih.gov

Office of Patient Recruitment
National Institutes of Health Clinical Center (CC)
Building 61, 10 Cloister Court
Bethesda, Maryland 20892
Toll Free: 1-800-411-1222
Local Phone: 301-451-4383
TTY: TTY Users Dial 7-1-1
ccopr@nih.gov

Clinical Trials Number:

NCT05517603

--Back to Top--

NIH Clinical Center Search the Studies: Study Number, Study Title

Protocol Details

A Phase 1/2a, Randomized, Double-Blind, Placebo-Controlled, First In-Patient Study of AJ201 to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics in Adults With Spinal and Bulbar Muscular Atrophy (SBMA)

This study is currently recruiting participants.

Summary | Eligibility | Citations | Contacts

Summary

Number

001505-N

Sponsoring Institute

National Institute of Neurological Disorders and Stroke (NINDS)

Recruitment Detail

Type: Participants currently recruited/enrolled
Gender: Male
Min Age: 18 Years
Max Age: 120 Years

Referral Letter Required

No

Population Exclusion(s)

Female;
Children

Keywords

Neuromuscular Manifestations;
Central Nervous System Diseases;
Genetic Diseases, X-linked;
Neurodegenerative Diseases;
Motor Neuron Disease;
Spinal Cord Diseases;
Nervous system diseases;
Atrophy;
bulbo-spinal atrophy, X-linked;
Muscular Atrophy

Recruitment Keyword(s)

None

Condition(s)

Spinal and Bulbar Muscular Atrophy;
Kennedy's Disease

Investigational Drug(s)

AJ201

Investigational Device(s)

None

Intervention(s)

Drug: Placebo
Drug: AJ201

Supporting Site

National Institute of Neurological Disorders and Stroke

Background:

Spinal and bulbar muscular atrophy (SBMA), also called Kennedy s disease, is a rare disease that leads to muscle weakness. Researchers think an abnormal protein may cause the breakdown of muscles and nerve cells in people with SBMA. A study drug called AJ201 targets the abnormal protein. This drug may be able to improve muscle and nerve function in people with SMBA.

Objective:

To test AJ201 in people with SBMA.

Eligibility:

Males aged 18 years and older with SBMA.

Design:

Participants will visit the clinic at least 6 times in about 5 months.

A screening period will be 4 weeks. Participants will have a physical exam. They will have blood and urine tests and tests of their heart function. They will have imaging scans of their thighs and lower legs. They will have a DEXA scan: This test uses X-rays to measure lean body mass. They will perform tasks, such as walking and writing, to assess their muscle strength. They will have a biopsy: A small amount of muscle tissue will be removed with a needle.

AJ201 is a liquid taken by mouth. Participants will take the study drug once a day at home for 12 weeks. Some of the participants will take a placebo instead of AJ201. The placebo is a liquid that looks just like the AJ201 but contains no medicine. Participants will not know which they are taking.

Participants will record their doses in a diary.

The scans, biopsy, and other tests will be repeated after they finish taking the drug or placebo.

--Back to Top--

Eligibility

INCLUSION CRITERIA:

Subjects must meet all the inclusion criteria below to be eligible:

-Able to give informed consent before any assessment is performed.

-Adult males aged 18 or greater with a confirmed genetic diagnosis (confirmed CAG repeat expansion in the AR gene of at least 36 repeat) of SBMA and clinical diagnosis of symptomatic muscle weakness.

-Able to complete 2MWT with or without the aid of an assisted device at screening.

-SBMAFRS score >=26 (subjects with moderate to high physical performance) at screening.

-Willing to participate in all aspects of study design and assessments, including blood draw and muscle biopsies.

-Male subjects and their female spouses/partners who are of childbearing potential must agree to use highly effective contraception consisting of 2 forms of birth control (at least 1 of which must be a barrier method) starting from the first dose of the study drug and continuing throughout the study period and for 90 days after the last dose of the study drug. Male subjects should also not donate sperm during the study and for 90 days after the final administration of the study drug.

-Able to communicate well with the Investigator, to understand, and comply with the requirements of the study.

EXCLUSION CRITERIA:

Subjects who meet any of the following exclusion criteria will be excluded from the study:

-Nonambulatory.

-Contraindications to MRI such as a contraindicated nonremovable metal device (ie, pacemaker, defibrillator, insulin pump, metal clips, nonremovable jewelry) or claustrophobia.

-Use of other investigational products within 30 days, or within 5 half-lives, whichever is longer, prior to the first dosing, or until the expected PD effect has returned to baseline, whichever is longer. Approved COVID-19 vaccines are not considered investigational treatments and are allowed prior to, during, and after the study.

-Use of drugs known to affect muscle metabolism within the previous 1 month prior to the first dosing, including (but not limited to) systemic corticosteroids (>10 mg/day prednisone or equivalent), androgens, or androgen reducing agents, systemic beta agonists or beta blockers, and relevant herbal, or nutraceutical products. For subjects using systemic corticosteroids (<=10 mg/day or equivalent), they should be on stable dose for the previous 3 months prior to first dosing.

-Known history of allergic reactions to curcumin analogs or excipients in the study drug formulation.

-Known history of clinically significant cardiovascular disease (including uncontrolled hypertension, ischemic heart disease [eg, myocardial infarction, angina, abnormal coronary arteriography or cardiac stress testing/imaging]), heart failure or left ventricle dysfunction of New York Heart Association Classification III-IV, or clinically significant cerebrovascular disease (stroke or transient ischemic attacks).

-An abnormal ECG at screening visit which is judged to be clinically relevant and represents an unacceptable risk for study participation by the Investigator. An example is Brugada-like ECG changes which have been reported in SBMA patients in Italy and Japan.

-Any surgical or medical condition which may jeopardize the subject in case of participation in the study. The Investigator should make this determination in consideration of the subject s medical history and/or clinical or laboratory evidence of any of the following during screening:

--Liver disease or liver injury as indicated by abnormal liver function tests such as AST, ALT, gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), or serum bilirubin in the presence of normal serum creatine kinase (CK).

--Significant swallowing dysfunction, which may increase the risk of accidental choking and aspiration pneumonia

-Subjects with renal impairment defined as a creatinine clearance of <90 mL/min at screening. (Creatinine Clearance = [140 age in years] *weight in kg]/[72*serum Cr(mg/dL)])

-History of active tuberculosis or exposure to endemic areas within 8 weeks prior to QuantiFERON (R) -TB testing performed at screening.

-Positive QuantiFERON (R) -TB indicating possible tuberculosis infection.

-History of immunodeficiency diseases, including a positive HIV test result at screening.

-A positive hepatitis B surface antigen or hepatitis C test result at screening.

-Subjects with known bleeding disorders, or who are under treatment with anticoagulants or with a platelet count <50,000 (due to the increased risk of bleeding during muscle biopsy procedure).

-History of drug or alcohol abuse within the 12 months prior to the first dosing, or evidence of such abuse as indicated by the laboratory assays conducted during screening.

-The Investigator should be guided by the following criteria during screening:

--Any single laboratory parameter may not exceed 3 times the upper limit of normal (ULN). A single parameter elevated up to and including 3 times the ULN should be re-checked once more as soon as possible, and in all cases, at least prior to enrollment/randomization, to rule out lab error. For abnormal liver function tests, in the presence of elevated serum CK levels, ALT, or AST, up to 5 times the ULN are acceptable if other liver tests are normal.

--If the total bilirubin concentration is increased above 1.5 times the ULN, total bilirubin should be differentiated into the direct and indirect reacting bilirubin. In any case, serum indirect bilirubin should not exceed the value of 1.6 mg/dL (27 mol/L).

-Use of drugs that are inhibitors of CYP3A4, 2B6, or 2C19 within 2 weeks prior to the first dosing and during the study.

-Use of drugs that are substrates of MATE1 or MATE2-K transporters within 2 weeks prior to the first dosing and during the study.

-Use of turmeric or products containing curcumin within 2 weeks prior to the first dosing and during the study.

-Use of aspirin or nonsteroidal anti-inflammatory agents within 3 days prior to the baseline visit (due to the increased risk of bleeding during muscle biopsy procedure).

-Any reason that, in the opinion of the Investigator, would prevent the subject from

participating in the study.


--Back to Top--

Citations:

Bott LC, Badders NM, Chen KL, Harmison GG, Bautista E, Shih CC, Katsuno M, Sobue G, Taylor JP, Dantuma NP, Fischbeck KH, Rinaldi C. A small-molecule Nrf1 and Nrf2 activator mitigates polyglutamine toxicity in spinal and bulbar muscular atrophy. Hum Mol Genet. 2016 May 15;25(10):1979-1989. doi: 10.1093/hmg/ddw073. Epub 2016 Mar 8. PMID: 26962150; PMCID: PMC5062587.

--Back to Top--

Contacts:

Principal Investigator

Referral Contact

For more information:

Christopher Grunseich, M.D.
National Institute of Neurological Disorders and Stroke (NINDS)
NIHBC 35 - PNRC I BG RM 2A-1010
35 CONVENT DR
BETHESDA MD 20892
(301) 402-5423
grunseichc@mail.nih.gov

Angela Kokkinis, R.N.
National Institute of Neurological Disorders and Stroke (NINDS)
National Institutes of Health
Building 10
Room 5S-219
10 Center Drive
Bethesda, Maryland 20892
(301) 451-8146
akokkinis@mail.cc.nih.gov

Office of Patient Recruitment
National Institutes of Health Clinical Center (CC)
Building 61, 10 Cloister Court
Bethesda, Maryland 20892
Toll Free: 1-800-411-1222
Local Phone: 301-451-4383
TTY: TTY Users Dial 7-1-1
ccopr@nih.gov

Clinical Trials Number:

NCT05517603

--Back to Top--