| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | |
| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10039626 |
| E.1.2 | Term | Schizophrenia |
| E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
1. To compare the efficacy of MK-8189 at 16 and 24 mg to placebo in reducing the Positive and Negative Syndrome Scale (PANSS) total score at Week 6
2. To evaluate the safety and tolerability of MK-8189
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| E.2.2 | Secondary objectives of the trial |
1. To compare the efficacy of MK-8189 at 16 and 24 mg to placebo in reducing the PANSS positive subscale (PSS) at Week 6
2. To evaluate the efficacy of MK-8189 at 16 and 24 mg in reducing the Clinical Global Impression-Severity of Illness (CGI-S) score at Week 6, as compared to placebo
3. To evaluate the impact of MK-8189 on weight at Week 12, as compared to risperidone
4. To evaluate the impact of MK-8189 on weight at Week 6, as compared to placebo
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Meet the diagnostic criteria for schizophrenia according to the DSM-5 ™.
2. Be currently experiencing active phase symptoms of schizophrenia (DSM-5 ™ Criterion A).
3. Have an illness duration for schizophrenia of at least 1 year.
4. Be confirmed to be experiencing an acute episode of schizophrenia, as evidenced by ALL of the following:
a. Onset of the current acute episode is ≤6 weeks before screening
b. Current symptoms represent a marked and substantial worsening compared with the participant’s usual symptomatic state prior to the current acute episode, and are associated with diminished functional ability
c. In need of increased psychiatric attention to treat worsening acute episode symptoms
5. Have a minimum PANSS total score of ≥80 at screening.
6. Have a score of ≥4 (moderate) in 2 or more of the following items in the positive subscale of the PANSS at screening: delusions, hallucinations, conceptual disorganization, suspiciousness; at least 1 must be hallucinations or delusions.
7. Have a CGI-S score of ≥4 (moderately ill) at screening and baseline.
8. Be able to taper off psychotropic medications (including antipsychotics, antidepressants and mood stabilizers) without significant destabilization or increased suicidality in the opinion of the investigator with the last dose taken no later than the evening before the baseline visit (Visit 2/Day 1; the dosing cycle of depot neuroleptics must end no later than the day before baseline), with the exception that the last dose of past MAO
inhibitors cannot be within 30 days of the screening visit.
9. Have had a positive response to antipsychotic medication (other than clozapine) during at least 1 period of treatment for a prior psychotic episode.
10. Be male or female from 18 years to 56 years of age inclusive, at the time of signing the informed consent.
11. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
- Not a WOCBP
OR
- A WOCBP and:
* uses a contraceptive method that is highly effective, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle during the intervention period and for at least 14 days after the last dose of study intervention.
* Has a negative highly sensitive pregnancy test ([urine or serum] as required by local regulations) before the first dose of study intervention. If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
* Abstains from breastfeeding during the study intervention period and for at least 7 days after study intervention.
* Medical history, menstrual history, and recent sexual activity has been reviewed by the investigator to decrease the risk for inclusion of a woman with an early undetected pregnancy.
12. Provide documented informed consent for the study. The participant may also provide consent for future biomedical research. However, the participant may participate in the main study without participating in future biomedical research.
13. Have a level of decision-making capacity needed to make a meaningful choice about whether to participate in the study.
14. Be willing and considered able by the investigator to participate in protocol assessments, including recordings of interviews, adhere to dose and visit schedules, study procedures and restrictions; this includes the ability to participate in all study procedures without the use of a language interpreter.
15. Have an identified responsible person (eg, family member, social worker, case worker, case manager, or nurse), referred to as the “external contact person” in the protocol, who has agreed to provide information about the participant’s location if needed during outpatient portion of the study. The site personnel must consider this identified responsible person a reliable contact person, and the contact person must have regular contact with the participant (defined at screening as direct contact no fewer than 3 times per week with the participant, and with the expectation that this frequency of contact would continue (either in person or via other contact method) throughout duration of study, including the follow-up period).
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| E.4 | Principal exclusion criteria |
1. Has a primary current diagnosis other than schizophrenia or a comorbid diagnosis (for example, major depression) that is primarily responsible for the current symptoms and functional impairment.
2. Meets criteria for moderate to severe substance use disorder currently or within past 6 months prior to screening.
3. Has a known history of the following:
a. Borderline personality disorder, antisocial personality disorder, or bipolar disorder
b. Traumatic brain injury causing ongoing cognitive difficulties, Alzheimer’s disease or another form of dementia, or any chronic organic disease of the central nervous system
c. Intellectual disability of a severity that would impact the ability of the participant to participate in the study
4. Has a current diagnosis of a psychotic disorder (other than schizophrenia), or a behavioral disturbance thought to be substance-induced or due to substance abuse.
5. Has moderate or severe tardive dyskinesia according to the investigator.
6. Is or was under involuntary commitment for the current acute episode, because the participant is considered a danger to themselves or others.
7. Has committed an act of violence (assaultive behavior) ≤ 2 years prior to the screening visit.
8. Has a BMI <18.5 kg/m2.
9. Has a risk factor for QTc prolongation as defined by:
a. A known history or current evidence of QTc interval > 450 msec (for both men and women)
b. A known history of risk factors for Torsades de Pointes
10. Has known renal disease or is experiencing renal insufficiency as defined by:
eGFR of <50 mL/min/1.73m2 (as measured by CKD-EPI formula)
11. Has known history of chronic convulsive disorder (eg, epilepsy or seizure disorder) except febrile seizures of childhood.
12. Has a history of neuroleptic malignant syndrome.
13. Has a history of malignancy ≤3 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer.
14. Is at imminent risk of self-harm or harm to others.
15. Has a history of 3 or more significant allergies (including latex allergy) to prescription or nonprescription drugs or food.
16. Has a known allergy or intolerance to risperidone or any of its active or inert ingredients.
17. Has hypothyroidism, diabetes, high blood pressure, cardiovascular condition, respiratory condition or other chronic medical conditions unless the condition is stable; the prescribed dose and regimen of medication are stable for ≥ 3 months prior to screening; and there are no expected changes in comedication during the study.
18. Has a history of treatment resistance exhibited by any of the following:
a. No or minimal response to at least 2 periods of treatment lasting 6 weeks or longer, with antipsychotic agents (from at least 2 different chemical classes) at the maximally tolerated dose.
b. History of ECT treatment for treatment resistant schizophrenia within the past 6 months.
c. Past or current use of clozapine as single or adjunctive therapy for schizophrenia within the past 5 years
19. Is currently taking and benefiting from a moderate or strong CYP3A and/or CYP2C9 inhibitors and inducers and/or CYP2B6 sensitive substrates.
20. Is currently taking and benefiting from strong CYP2D6 inhibitors.
21. Is currently participating in or has participated in another clinical study and received an experimental or investigational drug agent within 3 months prior to screening visit of this current study and no more than 2 studies in the past 2 years.
22. Has been previously participated in the MK-8189 program according to the following: previous screen failure in this study; was previously randomized (regardless of treatment) in any MK-8189 study.
23. Is unwilling to allow the recording of the MINI and PANSS interview at screening and baseline.
24. Has laboratory or clinical evidence of clinically significant hepatic conditions such as one or more of the following:
a. ALT or AST > 2X ULN and total bilirubin > 1.5X ULN
b. ALT or AST > 3X ULN
c. A history of hepatitis or liver disease that has been active within the 6 months prior to screening
25. Has a prolactin laboratory value of ≥ 5X ULN at screening
26. Has a positive urine alcohol/drug screen at the screening visit
27. Is unwilling or unable to remain hospitalized for the duration of screening and at least the first 28 days of treatment period.
28. Has a severe, acute or chronic medical condition or laboratory abnormality.
29. Has adverse events or clinically significant abnormal laboratory, vital sign, or physical examination, or ECG finding during screening period
30. Is known to be repeatedly medically noncompliant in the management of their schizophrenia as assessed by the investigator.
31. Is known to be noncompliant or who is assessed by the investigator to be potentially noncompliant with the management of a current severe, acute or chronic medical
condition
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Change from baseline in Positive and Negative Syndrome Scale (PANSS) total score at Week 6: MK-8189 24 mg, MK-8189 16 mg, or placebo
2. Number of participants who experience one or more adverse events (AEs)
3. Number of participants who discontinue study treatment due to an AE
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Baseline, Week 6
2. ~ Up to Week 14
3. ~ Up to Week 12
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| E.5.2 | Secondary end point(s) |
1. Change from baseline in PANSS positive subscale (PSS) score at Week 6: MK-8189 24 mg, MK-8189 16 mg, or placebo
2. Change from baseline in Clinical Global Impression-Severity of Illness (CGI-S) score at Week 6: MK-8189 24 mg, MK-8189 16 mg, or placebo
3. Change from baseline in weight at Week 12: MK-8189 24 mg, MK-8189 16 mg or risperidone
4. Change from baseline in weight at Week 6: MK-8189 24 mg, MK-8189 16 mg or placebo
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Baseline, Week 6
2. Baseline, Week 6
3. Baseline, Week 12
4. Baseline, Week 6
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 27 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Japan |
| Korea, Republic of |
| Taiwan |
| United States |
| Russian Federation |
| Ukraine |
| Serbia |
| Bulgaria |
| Croatia |
| Latvia |
| Poland |
| Romania |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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