Open-label Study to Compare Hospitalization Rates of Schi... | NCT01432444

Status Module

Description Module

Label	Type	Description	Intervention Names
OPC-14597	Experimental	Aripiprazole IM depot injection 300 mg or 400 mg.	Drug: Aripiprazole (Abilify®) IM Depot Injection

Name	Type	Description	Arm Group Labels	Other Names
Aripiprazole (Abilify®) IM Depot Injection	Drug	400 mg IM depot injection every 26-30 days. Dosage may be adjusted at the investigator's discretion to 300 mg. Number of injections: 6. Subjects have the option of entering the extension phase of the study and continuing with injections every 26-30 days until the drug is either commercially available, or December 2013.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Number of Inpatient Psychiatric Hospitalization for Retrospective Period (Months 4-6) and Prospective Period (Months 4-6).	The comparison of inpatient psychiatric hospitalization rates (proportion of patients with ≥ inpatient psychiatric hospitalizations) between the retrospective period months 4-6 (Weeks-12 to -24) while on oral standard of care antipsychotic treatment and the prospective period Phase B months 4-6 (Weeks 12 to 24) after the switch to aripiprazole IM depot. Open-label Aripiprazole IM Depot Treatment Phase 3-month Completer sample comprised of all participants who entered open-label aripiprazole IM depot treatment Phase and completed at least 3 months of treatment. This sample was used for the primary endpoint analysis (N=336).	Retrospective period Months 4-6; Prospective period Months 4-6

Secondary Outcomes

Measure	Description	Time Frame
Change From Baseline in PANSS (Positive and Negative Syndrome Scale) Total Score.	The PANSS consists of three subscales with a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 indicates (absence of symptoms) and a score of 7 indicates (extremely severe symptoms). The symptom constructs for each subscale are as follows: 7 Positive subscale symptom constructs, 7 Negative subscale symptom constructs and 16 General Psychopathology subscale symptom constructs. The PANSS total score ranges from 30 to 210.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Subjects who are able to provide written informed consent. If the IRB requires consent by a legally acceptable representative in addition to the subject, all required consents must be obtained prior to any protocol-required procedure.
Male and female subjects 18 to 65 years of age, inclusive.
Current diagnosis of schizophrenia as defined by DSM-IV-TR criteria and a history of the illness for at least 1 year (12 months).
Subjects who in the investigator's judgment would benefit from extended treatment with a long-acting injectable formulation.
Subjects who have at least 1 inpatient psychiatric hospitalization in the 4 years (48 months) prior to screening, but have been managed as outpatients for the 4 weeks prior entering the study.
Subjects must have been on oral antipsychotic treatment for the full 7 months prior to the screening phase.
Subjects who have shown response to previous antipsychotic treatment.
Subjects who understand the nature of the trial and are able to follow the protocol requirements.

Exclusion Criteria:

Prisoners or subjects who are compulsorily detained (involuntarily incarcerated), or have been incarcerated in the past 7 months for any reason must not be enrolled into this trial.
Subjects who may require potent CYP2D6 or CYP3A4 inhibitors or CYP3A4 inducers during the trial.
Any subject who requires or may need any other antipsychotic medications during the course of the trial, other than allowed rescue medication.
Subjects who are known to be allergic, intolerant, or unresponsive to prior treatment with aripiprazole or other quinolinones.
Subjects with a history of hypersensitivity to antipsychotic agents.
Subjects deemed intolerant of receiving injectable treatment.
Subjects who have received electroconvulsive therapy within the last 7 months prior to screening.
Subjects with a history of neuroleptic malignant syndrome or clinically significant tardive dyskinesia as assessed by the investigator.
Subjects with a current DSM-IV-TR diagnosis other than schizophrenia, including schizoaffective disorder, major depressive disorder, bipolar disorder, delirium, dementia, amnestic or other cognitive disorders. Also, subjects with borderline, paranoid, histrionic, schizotypal, schizoid, or antisocial personality disorder.
Subjects requiring hospitalization for any psychiatric reason during the 4 weeks prior to signing the ICF or during the screening period.
Subjects without at least 1 inpatient psychiatric hospitalization in the last 4 years (48 months) prior to screening.
Subjects who have met DSM-IV-TR criteria for any significant substance use disorder within 3 months prior to screening.
Subjects who are considered treatment-resistant to antipsychotic medication other than clozapine.
Treatment with long-acting injectable antipsychotics in which the last dose was within 7 months prior to screening.
Subjects who have not been treated with oral antipsychotics for 7 months prior to screening.
Subjects who have a significant risk of committing suicide
Subjects who have a history or evidence of a medical condition that would expose them to an undue risk of a significant adverse event or interfere with assessments of safety or efficacy during the course of the trial.
Females who are pregnant or lactating, sexually active males and females who will not commit to utilizing birth control during the trial and for up to 180 days following the trial.
Abnormal laboratory or physical examination results indicating a condition which may interfere with the results of the study or pose a safety risk to the subject.
Subjects who have previously enrolled in an aripiprazole IM depot clinical study, except for subjects entering this trial from the Canadian 31-11-284 trial.
Subjects who have participated in any clinical trial with an investigational agent within the past 30 days.

Name	Affiliation	Role
Kevin Cox, MD	Kevin.TC-Cox@otsuka-us.com	Study Director

PubMed Identifier	Type	Citation	Retractions
27531181	Derived	Peters-Strickland T, Zhao C, Perry PP, Eramo A, Salzman PM, McQuade RD, Johnson BR, Sanchez R. Effects of aripiprazole once-monthly on symptoms of schizophrenia in patients switched from oral antipsychotics. CNS Spectr. 2016 Dec;21(6):460-465. doi: 10.1017/S1092852916000365. Epub 2016 Aug 17.
25347448	Derived

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Tolerability/Cross-titration Phase (Phase A)	In Phase A, participants who had no history of tolerating oral aripiprazole entered a Tolerability Assessment/Cross-titration Phase in order to assess tolerability to oral aripiprazole. The recommended initial dose of oral aripiprazole in the Tolerability Assessment/Cross-titration Phase was 10 mg or 15 mg/day, depending on the participant's symptoms and the study physician's judgment. Participants were seen in the clinic at baseline and weekly thereafter for a minimum of 1 week and maximum of 4 weeks/28 days, until tolerability to oral aripiprazole had been determined, based on physician's discretion, or until the participant was terminated from the study.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Number of Inpatient Psychiatric Hospitalization for Retrospective Period (Months 4-6) and Prospective Period (Months 4-6).

The comparison of inpatient psychiatric hospitalization rates (proportion of patients with ≥ inpatient psychiatric hospitalizations) between the retrospective period months 4-6 (Weeks-12 to -24) while on oral standard of care antipsychotic treatment and the prospective period Phase B months 4-6 (Weeks 12 to 24) after the switch to aripiprazole IM depot. Open-label Aripiprazole IM Depot Treatment Phase 3-month Completer sample comprised of all participants who entered open-label aripiprazole IM depot treatment Phase and completed at least 3 months of treatment. This sample was used for the primary endpoint analysis (N=336).

The core dataset for all efficacy analyses is the Intent-to-Treat (ITT) dataset which consisted of data from all participants who entered Phase B regardless of receiving a dose in the Open-label Aripiprazole IM Depot Treatment Phase.

Posted

Number

participants

Retrospective period Months 4-6; Prospective period Months 4-6

ID	Title	Description
OG000	Open-label Aripiprazole IM Depot Treatment Phase (Phase B)	In Phase B, all participants received aripiprazole IM depot 400 mg and had received supplemental oral aripiprazole for the first 14 days of Phase B (open-label aripiprazole IM depot treatment phase) for more than or equal to 3 months. However, at the discretion of the study physician, the dose of aripiprazole IM depot was decreased to 300 mg only if needed for tolerability and subsequently increased the dose to 400 mg for efficacy as required. This dose adjustment was permitted as often as necessary to maintain symptomatic stability with acceptable tolerability. For purposes of this study, participants who completed Week 24 of Phase B were defined as trial completers.

Units	Counts
Participants	OG000336

Title

Denominators

Categories

Retrospective period

Title	Measurements
	OG00091± 0.6

Prospective period

Title	Measurements
	OG0009± 0.2

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000	Inpatient hospitalization for retrospective period (Months 4-6) and prospective period (Months 4-6) for closed or open unit.	McNemar		<.0001	P-value was derived from Exact McNemar test.												No	Superiority or Other

Secondary

Change From Baseline in PANSS (Positive and Negative Syndrome Scale) Total Score.

The core dataset for all efficacy analyses is the ITT dataset which consisted of data from all participants who entered Phase B regardless of receiving a dose in the Open-label Aripiprazole IM Depot Treatment Phase.

Posted

Mean

Standard Deviation

Units on a scale

Baseline to Week 24

ID	Title	Description
OG000	Open-label Aripiprazole IM Depot Treatment Phase (Phase B)	In Phase B, all participants received aripiprazole IM depot 400 mg and had received supplemental oral aripiprazole for the first 14 days of Phase B (open-label aripiprazole IM depot treatment phase) for more than or equal to 3 months. However, at the discretion of the study physician, the dose of aripiprazole IM depot was decreased to 300 mg only if needed for tolerability and subsequently increased the dose to 400 mg for efficacy as required. This dose adjustment was permitted as often as necessary to maintain symptomatic stability with acceptable tolerability. For purposes of this study, participants who completed Week 24 of Phase B were defined as trial completers.

Secondary

Change From Baseline in PANSS Positive Subscale Score.

The PANSS consists of three subscales with a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 indicates (absence of symptoms) and a score of 7 indicates (extremely severe symptoms). The symptom constructs for each subscale are as follows: 7 Positive subscale symptom constructs, 7 Negative subscale symptom constructs and 16 General Psychopathology subscale symptom constructs. The 7 positive symptom constructs are delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity suspiciousness/ persecution, and hostility. The PANSS Positive Subscale ranges from 7 (absence of symptoms) to 49 (extremely severe symptoms).

Posted

Mean

Standard Deviation

Units on a scale

Baseline to Week 24

ID	Title	Description
OG000	Open-label Aripiprazole IM Depot Treatment Phase (Phase B)	In Phase B, all participants received aripiprazole IM depot 400 mg and had received supplemental oral aripiprazole for the first 14 days of Phase B (open-label aripiprazole IM depot treatment phase) for more than or equal to 3 months. However, at the discretion of the study physician, the dose of aripiprazole IM depot was decreased to 300 mg only if needed for tolerability and subsequently increased the dose to 400 mg for efficacy as required. This dose adjustment was permitted as often as necessary to maintain symptomatic stability with acceptable tolerability. For purposes of this study, participants who completed Week 24 of Phase B were defined as trial completers.

Secondary

Change From Baseline in PANSS Negative Subscale Score.

The PANSS consists of three subscales with a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 indicates (absence of symptoms) and a score of 7 indicates (extremely severe symptoms). The symptom constructs for each subscale are as follows: 7 Positive subscale symptom constructs, 7 Negative subscale symptom constructs and 16 General Psychopathology subscale symptom constructs. The 7 negative symptom constructs are blunted affect, emotional withdrawal, poor rapport, passive pathetic withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking. The PANSS Negative Subscale ranges from 7 (absence of symptoms) to 49 (extremely severe symptoms).

Posted

Mean

Standard Deviation

Units on a scale

Baseline to Week 24

ID	Title	Description
OG000	Open-label Aripiprazole IM Depot Treatment Phase (Phase B)	In Phase B, all participants received aripiprazole IM depot 400 mg and had received supplemental oral aripiprazole for the first 14 days of Phase B (open-label aripiprazole IM depot treatment phase) for more than or equal to 3 months. However, at the discretion of the study physician, the dose of aripiprazole IM depot was decreased to 300 mg only if needed for tolerability and subsequently increased the dose to 400 mg for efficacy as required. This dose adjustment was permitted as often as necessary to maintain symptomatic stability with acceptable tolerability. For purposes of this study, participants who completed Week 24 of Phase B were defined as trial completers.

Secondary

Change From Baseline in Clinical Global Impression-Severity Score (CGI-S).

The severity of illness for each participant were rated using the CGI-S scale. To assess CGI-S, study physician were to answer the following question: "Considering your total clinical experience with this particular population, how mentally ill is the patient at this time?" Response choices included: 0 = not assessed; 1 = normal, not ill at all; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill patients.

Posted

Mean

Standard Deviation

Units on a scale

Baseline to Week 24

ID	Title	Description
OG000	Open-label Aripiprazole IM Depot Treatment Phase (Phase B)	In Phase B, all participants received aripiprazole IM depot 400 mg and had received supplemental oral aripiprazole for the first 14 days of Phase B (open-label aripiprazole IM depot treatment phase) for more than or equal to 3 months. However, at the discretion of the study physician, the dose of aripiprazole IM depot was decreased to 300 mg only if needed for tolerability and subsequently increased the dose to 400 mg for efficacy as required. This dose adjustment was permitted as often as necessary to maintain symptomatic stability with acceptable tolerability. For purposes of this study, participants who completed Week 24 of Phase B were defined as trial completers.

Secondary

Mean Clinical Global Impression-Improvement Score (CGI-I) by Week.

The efficacy of trial medication was rated for each participant using the CGI-I scale. The study physician would rate the participants total improvement whether or not it was entirely due to drug treatment. All responses were compared to the participants condition at Baseline of the appropriate phase. The CGI-I during Phase B were assessed relative to the participants condition at the Phase B Baseline visit. Response choices included: 0 = not assessed; 1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; and 7 = very much worse.

Posted

Mean

Standard Deviation

Units on a scale

Week 4, 12 and 24

ID	Title	Description
OG000	Open-label Aripiprazole IM Depot Treatment Phase (Phase B)	In Phase B, all participants received aripiprazole IM depot 400 mg and had received supplemental oral aripiprazole for the first 14 days of Phase B (open-label aripiprazole IM depot treatment phase) for more than or equal to 3 months. However, at the discretion of the study physician, the dose of aripiprazole IM depot was decreased to 300 mg only if needed for tolerability and subsequently increased the dose to 400 mg for efficacy as required. This dose adjustment was permitted as often as necessary to maintain symptomatic stability with acceptable tolerability. For purposes of this study, participants who completed Week 24 of Phase B were defined as trial completers.

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Open-label Aripiprazole IM Depot Treatment Phase (Phase B)	In Phase B, all participants received aripiprazole IM depot 400 mg and had received supplemental oral aripiprazole for the first 14 days of Phase B (open-label aripiprazole IM depot treatment phase) for more than or equal to 3 months. However, at the discretion of the study physician, the dose of aripiprazole IM depot was decreased to 300 mg only if needed for tolerability and subsequently increased the dose to 400 mg for efficacy as required. This dose adjustment was permitted as often as necessary to maintain symptomatic stability with acceptable tolerability. For purposes of this study, participants who completed Week 24 of Phase B were defined as trial completers.			61	431	60	431
EG001	Extension Phase (Phase C)	Participants who completed the 24-Week treatment period (Phase B), and whom the study physician believed would benefit from continued treatment with aripiprazole IM depot, were eligible to enter Phase C. During Phase C, participants were to continue treatment with aripiprazole IM depot until approximately 400 subjects have enrolled in Phase B (in order to achieve approximately 200 Phase B completers).			19	192	24	192

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Acute myocardial infarction	Cardiac disorders	MedDRA 16.0	Non-systematic Assessment	EG0001 affected431 at risk EG0010 affected192 at risk
Angina pectoris	Cardiac disorders	MedDRA 16.0	Non-systematic Assessment	EG0000 affected431 at risk EG0011 affected192 at risk
Cardio-respiratory arrest	Cardiac disorders	MedDRA 16.0	Non-systematic Assessment	EG0000 affected431 at risk EG0011 affected192 at risk
Myocardial infarction	Cardiac disorders	MedDRA 16.0	Non-systematic Assessment	EG0001 affected431 at risk EG0010 affected192 at risk
Sinus tachycardia	Cardiac disorders	MedDRA 16.0	Non-systematic Assessment	EG0001 affected431 at risk EG0010 affected192 at risk
Gastrointestinal haemorrhage	Gastrointestinal disorders	MedDRA 16.0	Non-systematic Assessment	EG0001 affected431 at risk EG0010 affected192 at risk
Asthenia	General disorders	MedDRA 16.0	Non-systematic Assessment	EG0001 affected431 at risk EG0010 affected192 at risk
Chest pain	General disorders	MedDRA 16.0	Non-systematic Assessment	EG0001 affected431 at risk EG0010 affected192 at risk
Non-cardiac chest pain	General disorders	MedDRA 16.0	Non-systematic Assessment	EG0001 affected431 at risk EG0010 affected192 at risk
Cholecystitis	Hepatobiliary disorders	MedDRA 16.0	Non-systematic Assessment	EG0001 affected431 at risk EG0010 affected192 at risk
Hepatitis acute	Hepatobiliary disorders	MedDRA 16.0	Non-systematic Assessment	EG0000 affected431 at risk EG0011 affected192 at risk
Lobar pneumonia	Infections and infestations	MedDRA 16.0	Non-systematic Assessment	EG0001 affected431 at risk EG0010 affected192 at risk
Pneumonia	Infections and infestations	MedDRA 16.0	Non-systematic Assessment	EG0001 affected431 at risk EG0010 affected192 at risk
Accidental overdose	Injury, poisoning and procedural complications	MedDRA 16.0	Non-systematic Assessment	EG0002 affected431 at risk EG0010 affected192 at risk
Craniocerebral injury	Injury, poisoning and procedural complications	MedDRA 16.0	Non-systematic Assessment	EG0001 affected431 at risk EG0010 affected192 at risk
Blood glucose increased	Investigations	MedDRA 16.0	Non-systematic Assessment	EG0001 affected431 at risk EG0010 affected192 at risk
Dehydration	Metabolism and nutrition disorders	MedDRA 16.0	Non-systematic Assessment	EG0001 affected431 at risk EG0010 affected192 at risk
Hyperglycaemia	Metabolism and nutrition disorders	MedDRA 16.0	Non-systematic Assessment	EG0001 affected431 at risk EG0010 affected192 at risk
Hypoglycaemia	Metabolism and nutrition disorders	MedDRA 16.0	Non-systematic Assessment	EG0001 affected431 at risk EG0010 affected192 at risk
Hyponatraemia	Metabolism and nutrition disorders	MedDRA 16.0	Non-systematic Assessment	EG0001 affected431 at risk EG0010 affected192 at risk
Hypovolaemia	Metabolism and nutrition disorders	MedDRA 16.0	Non-systematic Assessment	EG0001 affected431 at risk EG0010 affected192 at risk
Type 2 diabetis mellitus	Metabolism and nutrition disorders	MedDRA 16.0	Non-systematic Assessment	EG0001 affected431 at risk EG0011 affected192 at risk
Rhabdomyolysis	Musculoskeletal and connective tissue disorders	MedDRA 16.0	Non-systematic Assessment	EG0002 affected431 at risk EG0010 affected192 at risk
Renal cell carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 16.0	Non-systematic Assessment	EG0001 affected431 at risk EG0010 affected192 at risk
Akathisia	Nervous system disorders	MedDRA 16.0	Non-systematic Assessment	EG0001 affected431 at risk EG0010 affected192 at risk
Convulsion	Nervous system disorders	MedDRA 16.0	Non-systematic Assessment	EG0004 affected431 at risk EG0011 affected192 at risk
Hypoxic-ischaemic encephalopathy	Nervous system disorders	MedDRA 16.0	Non-systematic Assessment	EG0000 affected431 at risk EG0011 affected192 at risk
Sedation	Nervous system disorders	MedDRA 16.0	Non-systematic Assessment	EG0001 affected431 at risk EG0010 affected192 at risk
Abortion spontaneous	Pregnancy, puerperium and perinatal conditions	MedDRA 16.0	Non-systematic Assessment	EG0002 affected431 at risk EG0010 affected192 at risk
Acute psychosis	Psychiatric disorders	MedDRA 16.0	Non-systematic Assessment	EG0001 affected431 at risk EG0010 affected192 at risk
Anxiety	Psychiatric disorders	MedDRA 16.0	Non-systematic Assessment	EG0001 affected431 at risk EG0010 affected192 at risk
Depression	Psychiatric disorders	MedDRA 16.0	Non-systematic Assessment	EG0002 affected431 at risk EG0011 affected192 at risk
Psychotic disorder	Psychiatric disorders	MedDRA 16.0	Non-systematic Assessment	EG0008 affected431 at risk EG0013 affected192 at risk
Schizophrenia	Psychiatric disorders	MedDRA 16.0	Non-systematic Assessment	EG00011 affected431 at risk EG0016 affected192 at risk
Schizophrenia, paranoid type	Psychiatric disorders	MedDRA 16.0	Non-systematic Assessment	EG00014 affected431 at risk EG0013 affected192 at risk
Schizophrenia, undifferentiated type	Psychiatric disorders	MedDRA 16.0	Non-systematic Assessment	EG0000 affected431 at risk EG0011 affected192 at risk
Suicidal ideation	Psychiatric disorders	MedDRA 16.0	Non-systematic Assessment	EG0006 affected431 at risk EG0011 affected192 at risk
Suicide attempt	Psychiatric disorders	MedDRA 16.0	Non-systematic Assessment	EG0003 affected431 at risk EG0011 affected192 at risk
Penile oedema	Reproductive system and breast disorders	MedDRA 16.0	Non-systematic Assessment	EG0001 affected431 at risk EG0010 affected192 at risk
Scrotal oedema	Reproductive system and breast disorders	MedDRA 16.0	Non-systematic Assessment	EG0001 affected431 at risk EG0010 affected192 at risk
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	MedDRA 16.0	Non-systematic Assessment	EG0001 affected431 at risk EG0010 affected192 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA 16.0	Non-systematic Assessment	EG0000 affected431 at risk EG0011 affected192 at risk
Respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA 16.0	Non-systematic Assessment	EG0001 affected431 at risk EG0010 affected192 at risk
Hypertension	Vascular disorders	MedDRA 16.0	Non-systematic Assessment	EG0002 affected431 at risk EG0010 affected192 at risk

Facility	Status	City	State	ZIP	Country	Contacts
		Dothan	Alabama	36305	United States

ID	Term
D019967	Schizophrenia Spectrum and Other Psychotic Disorders
D001523	Mental Disorders

ID	Term
D010879	Piperazines
D006573	Heterocyclic Compounds, 1-Ring
D006571	Heterocyclic Compounds
D015363	Quinolones
D011804	Quinolines
D006574	Heterocyclic Compounds, 2-Ring
D000072471	Heterocyclic Compounds, Fused-Ring