Ignite Creation Date:
2024-05-05 @ 6:33 PM
Last Modification Date:
2024-10-26 @ 9:34 AM
Study NCT ID:
NCT00505765
Status:
COMPLETED
Last Update Posted:
2017-03-10
First Post:
2007-07-20
Brief Title:
A Multicenter Study of NAP AL-108 in Schizophrenia
Sponsor:
University of California Los Angeles
Organization:
University of California Los Angeles
Study Overview
Official Title:
A Multicenter Ascending Dose Double Blind Placebo-controlled Study of NAP AL-108 in Chronic Schizophrenia
Status:
COMPLETED
Status Verified Date:
2017-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
AL-108
Brief Summary:
The TURNS is a NIMH-funded contract for the evaluation of new compounds for the treatment of cognitive impairments in schizophrenia HHSN 27820044 1003C PI Steve Marder MD Despite advances in the safety tolerability and effectiveness of antipsychotic medications for the treatment of schizophrenia many patients continue to be plagued by impairments in social and work functioning Persons with schizophrenia commonly show deficits in a number of areas of cognition that include impairments in attention memory and executive functioning the ability and organize ones behavior Importantly a large body of literature now shows a link between cognition and community functioning in schizophrenia It is believed that treatments that improve cognitive deficits may lead to improvements in work and social functioning
One approach to improve the community functioning of patients with schizophrenia is to develop new agents that treat the cognitive deficits of the illness A promising agent is called AL-108 This drug is administered as a nasal spray Studies in animals suggest that this drug may protect neurons and may improve cognition in schizophrenia The current study is a twelve-week multicenter double-blind randomized clinical trial of two doses of AL-108 5 and 30 mgday intranasally versus placebo in the treatment of persistent cognitive dysfunction in schizophrenia The study medication will be added to patients current atypical antipsychotic medication or to their current injectable first-generation antipsychotic medication The primary outcome measure will consist of the composite score of the MATRICS neuropsychological battery Secondary outcome measures will include scores on symptoms functional outcome and safety measures Sixty clinically stable patients with schizophrenia drawn from eight sites will participate in the study Twenty-five patients will be enrolled at UCLA
One approach to improve the community functioning of patients with schizophrenia is to develop new agents that treat the cognitive deficits of the illness A promising agent is called AL-108 This drug is administered as a nasal spray Studies in animals suggest that this drug may protect neurons and may improve cognition in schizophrenia The current study is a twelve-week multicenter double-blind randomized clinical trial of two doses of AL-108 5 and 30 mgday intranasally versus placebo in the treatment of persistent cognitive dysfunction in schizophrenia The study medication will be added to patients current atypical antipsychotic medication or to their current injectable first-generation antipsychotic medication The primary outcome measure will consist of the composite score of the MATRICS neuropsychological battery Secondary outcome measures will include scores on symptoms functional outcome and safety measures Sixty clinically stable patients with schizophrenia drawn from eight sites will participate in the study Twenty-five patients will be enrolled at UCLA
Detailed Description:
Background
AL-108 is an intranasal drug product containing NAP an 8 amino-acid peptide Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln NAPVSIPQ MW8249 fragment of the much larger approx 124KD Activity-Dependent Neuroprotective Protein ADNP which participates in neurodevelopment and neuroprotection In mice ADNP knockouts are lethal exhibiting CNS dysgenesis ADNP mediates its effects in part through interaction with microtubules Because of its large size ADNP is assumed to not penetrate the BBB and thus cannot be used pharmacologically NAP was chosen because it represents the epitope most associated with microtubule interaction and neuroprotection NAP is absorbed following IV or intranasal administration and has been shown to cross the BBB
Rationale for NAP treatment tubulin function in brain function
The cytoskeleton plays a key role in maintaining the highly asymmetrical shape and structural polarity of neurons that are essential for neuronal physiology The cytoskeleton is made up of microfilaments intermediate filaments and microtubules Microfilaments 4-9 nm diameter are made up of actin monomers and they function mainly to provide mechanical support and locomotion to the cell Intermediate filaments are cytoplasmic fibers of 10nm diameter They provide supporting framework within the cell Microtubules 24nm diameter consist of tubulin and microtubule associate proteins They function to transport nutrients and chemical messengers along the cell Neurofibrillary tangles are twisted bundles of neurofibrils formed when the microtubule-associated protein tau dissociates from microtubules and clusters to form an insoluble mass Under normal conditions tau binds to microtubules stabilizing neuronal structure and integrity
Hyperphosphorylation of tau is assumed to be the cause for the formation of neurofibrillary tangles Although neurofibrillary tangles are most associated with cognitive dysfunction in Alzheimers disease some increase in neurofibrillary pathology has also been reported in schizophrenia potentially as consequence of antipsychotic medication 1 Thus mechanisms underlying microtubular function may be relevant to schizophrenia as well In association with tubulin polymerization into microtubules NAP influences tau dynamics by increasing the ratio of non-phosphorylated tau to phosphorylated tau implying a dynamic process of cellular maintenance of the microtubular network which is essential for the survival of the cell
In brain tubulin frameworks are stabilized by recently described STOP proteins 2 aka MAP6 Linkages to allelic variation in STOP genes has been reported in schizophrenia along with altered STOP protein expression in some brain regions 3 STOP knockdown mice show disturbances in dopaminergic neurotransmission 4 along with deficits in PPI and hypermotility that were partially reversed with clozapine 5 Thus neuropathological features of schizophrenia may be due in part to abnormal STOP-related stabilization of microtubular structure and NAP may stabilize STOP-related abnormal neurophysiological processes in schizophrenia
AL-108 is an intranasal drug product containing NAP an 8 amino-acid peptide Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln NAPVSIPQ MW8249 fragment of the much larger approx 124KD Activity-Dependent Neuroprotective Protein ADNP which participates in neurodevelopment and neuroprotection In mice ADNP knockouts are lethal exhibiting CNS dysgenesis ADNP mediates its effects in part through interaction with microtubules Because of its large size ADNP is assumed to not penetrate the BBB and thus cannot be used pharmacologically NAP was chosen because it represents the epitope most associated with microtubule interaction and neuroprotection NAP is absorbed following IV or intranasal administration and has been shown to cross the BBB
Rationale for NAP treatment tubulin function in brain function
The cytoskeleton plays a key role in maintaining the highly asymmetrical shape and structural polarity of neurons that are essential for neuronal physiology The cytoskeleton is made up of microfilaments intermediate filaments and microtubules Microfilaments 4-9 nm diameter are made up of actin monomers and they function mainly to provide mechanical support and locomotion to the cell Intermediate filaments are cytoplasmic fibers of 10nm diameter They provide supporting framework within the cell Microtubules 24nm diameter consist of tubulin and microtubule associate proteins They function to transport nutrients and chemical messengers along the cell Neurofibrillary tangles are twisted bundles of neurofibrils formed when the microtubule-associated protein tau dissociates from microtubules and clusters to form an insoluble mass Under normal conditions tau binds to microtubules stabilizing neuronal structure and integrity
Hyperphosphorylation of tau is assumed to be the cause for the formation of neurofibrillary tangles Although neurofibrillary tangles are most associated with cognitive dysfunction in Alzheimers disease some increase in neurofibrillary pathology has also been reported in schizophrenia potentially as consequence of antipsychotic medication 1 Thus mechanisms underlying microtubular function may be relevant to schizophrenia as well In association with tubulin polymerization into microtubules NAP influences tau dynamics by increasing the ratio of non-phosphorylated tau to phosphorylated tau implying a dynamic process of cellular maintenance of the microtubular network which is essential for the survival of the cell
In brain tubulin frameworks are stabilized by recently described STOP proteins 2 aka MAP6 Linkages to allelic variation in STOP genes has been reported in schizophrenia along with altered STOP protein expression in some brain regions 3 STOP knockdown mice show disturbances in dopaminergic neurotransmission 4 along with deficits in PPI and hypermotility that were partially reversed with clozapine 5 Thus neuropathological features of schizophrenia may be due in part to abnormal STOP-related stabilization of microtubular structure and NAP may stabilize STOP-related abnormal neurophysiological processes in schizophrenia
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| HHSN 278200441003C | OTHER_GRANT | NIMH | None |