Schizophrenia
Conditions
Keywords
risperidone, schizophrenia, implant
Brief summary
This is an Open-Label Study in Stable Schizophrenia Patients to Evaluate the Safety, Tolerability, and Pharmacokinetics of Switching from Oral Risperidone to Risperidone Implant (DLP-114).
Detailed description
Phase 1 open-label study in stable schizophrenia patients designed to evaluate the safety, tolerability, and Pharmacokinetics of switching from 2 mg/day or 3 mg/day oral risperidone to two DLP-114 devices for a six or twelve-month dosing period.
Interventions
COMBINATION_PRODUCTRisperidone
Risperidone Implant
Sponsors
National Institute of Mental Health (NIMH)
Delpor, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Adult patients 18-70 years of age of both sexes diagnosed with schizophrenia or schizoaffective disorder according to Diagnostic and Statistical Manual (DSM)-V who have been stable on oral risperidone (2mg-3mg) for at least 2 weeks. 2. Patient (and/or a patient's authorized legal representative) has provided written informed consent 3. Patient meets the following criteria: 1. Outpatient status 2. PANSS Total Score ≤ 80 at screening. 3. A score of ≤ 4 on the following PANSS items: i. Conceptual disorganization ii. Suspiciousness iii. Hallucinatory behavior iv. Unusual thought content v. Hostility d. Clinical Global Impression Scale (CGI-S) ≤ 4 (moderately ill)\\Lack of clinically significant suicidal ideation or behavior; Columbia Suicide Severity Rating Scale (C-SSRS) score type of 4-5 require evaluation by mental health professional to ensure patient safety in study 4. Body Mass Index (BMI) within the range of 18.5 to 40.0 kg/m2 (inclusive); 5. Ability to understand the nature and objectives of the trial, including risks and adverse events, and be able to read, review and sign the informed consent document prior to conduct of any study procedures; 6. Willing and able to comply with the requirements of the study protocol; including willingness to visit the clinical facility for all outpatient visits and confinement periods; 7. Have suitable venous access for blood sampling. 8. Patient is assessed by the Investigator to be symptomatically stable with regard to pre-existing medical conditions as evidenced by medical history, non-clinically significant findings on physical examination, vital signs, clinical laboratory evaluations (hematology, serum chemistries, and urinalysis) or 12-lead electrocardiogram (ECG). Subjects may continue on their current prescribed medication regimens to control pre-existing medical and psychiatric conditions (other than schizophrenia) including the use of prescribed PRN medications.
Exclusion criteria
1. PANSS score at baseline is ≥ 20% change from screening. 2. Hospitalized or required acute crisis intervention for symptom exacerbation in the 60 days prior to admission as determined by the Investigator 3. Patient has a history of suicide attempt in the last year, or in the opinion of the investigator is currently at imminent risk of suicide. 4. Patient experiencing acute depressive symptoms within the past 30 days, according to the Investigator's opinion, that required treatment with an antidepressant 5. Has a current or recent (within 12 months) DSM-V diagnosis of moderate or severe substance use disorder (except for tobacco use disorder) or has a positive urine drug screen for prohibited substances at screening. 6. Have impaired hepatic (Alanine transaminase (ALT) /aspartate aminotransferase (AST) \>1.5 times higher than the upper limit of normal) or renal function (eGFR\<50 mL/min) 7. Previously defined hypersensitivity to Risperidone 8. History of neuroleptic malignant syndrome (NMS) 9. Electroconvulsive therapy within 6 months of admission 10. Requires current use of agents that are strong inhibitors and inducers of cytochrome P450; 11. Known hypersensitivity or allergy to lidocaine or any local anesthetic agent of the amide type (local anesthetic used during implant and explant procedures); 12. Presence of clinically significant skin disorders (such as, but not limited to, skin cancer, psoriasis, eczema, or atopic dermatitis), evidence of recent sunburn, scar tissue, tattoo, open sore, body piercing or branding at the intended implantation site that would interfere with the implantation procedure or interfere with implant site assessments as determined by the investigator; 13. History of clinically significant hypersensitivity or allergic reactions; 14. Known allergy or hypersensitivity to para-aminobenzoic acid (PABA); 15. Known allergy or hypersensitivity to parabens, local anesthetics of the ester type, and sulfa drugs including antibiotics and thiazide diuretics; 16. Known hypersensitivity to titanium, implant materials or procedure; 17. Administration of an investigational drug or device within 1 month prior to first dosing; 18. Positive result for hepatitis B surface antigen (HBsAg), hepatitis C (HCV) antibody, or HIV antibody; 19. Pregnant or lactating patients. Positive pregnancy test; 20. Positive drug test for Methamphetamines, Opiates, Cocaine, Phencyclidine, Benzodiazepines, Barbiturates, Methadone, Antidepressants and Amphetamines or positive alcohol test at screening or prior to first dose; 21. Poor CYP2D6 metabolizer; 22. History of skin picking or delusional parasitosis; 23. Known history of abnormal scar formation or family history of keloid formation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events | Up to 8 months and up to 15 months for groups 1 and 2 respectively. | Number of Participants with Treatment-Emergent Adverse Events. |
| Percentage of Implant Site Assessments With a Dermal Irritation Scale Rating Greater Than Zero | 6 months and 12 months for groups 1 and 2 respectively. | Evaluate the incidence of local site reactions. Percentage of implant site assessments with a dermal irritation scale rating greater than zero (rating scale is 0 to 4, where 0 indicates no erythema or edema, and 4 indicates erythema or slight eschar). |
| Number of Participants Who Experienced an AE Related to Implantation or Explantation Procedures | 6 months and 12 months for groups 1 and 2 respectively. | Number of participants who experienced an Adverse Events related to Implantation or Explantation Procedures |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Average Clinical Global Impression-Improvement (CGI-I) Scale During the Implant Phase | CGI-I assessments were conducted over the course of the study per the protocol schedule of assessments. For Group 1: day 7, 14, 28, 42, 70, 112,140, 68, 183 and for Group 2: day 7, 14, 28, 56, 84, 112,140, 168,182, 210, 238, 252, 280, 308, 336, 350, 364. | Average Clinical Global Impression-Improvement (CGI-I) Scale during the Implant Phase. The average CGI-I score was calculated for each participant during the Implant Phase. The CGI-I score reported is the average of all participants who completed the study in each group. The CGI-I is a 7-point scale that requires the clinician to assess how much the participant's illness has improved or worsened relative to a baseline state at the beginning of the intervention and rated as: 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; 7=very much worse. |
| Average Daily Risperidone Implant Output During the Implant Phase | 6-months and 12-months for groups 1 and 2 respectively. Remaining Risperidone measurements taken at the end of the Implant Phase. | Average daily Risperidone Implant output during the Implant Phase. Average daily output is calculated by using the amount of Risperidone drug substance remaining in the DLP-114 reservoir following removal. The average daily output is calculated for each participant by using the two devices that each participant received. Risperidone output reported as the average for each group. |
| Oral Phase Cave: Average Plasma Concentration of Active Moiety (Risperidone + 9 OH Risperidone) During 24 Hours After 3 Days of Repeated 3mg QD Oral Administrations | t=0, 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours following oral administration. | Oral Phase Cave: Average plasma concentration of active moiety (risperidone + 9 OH risperidone) during 24 hours after 3 days of repeated 3mg QD oral administrations |
| Number of Participants Who Experienced Implant Migration in at Least One of the Implanted Devices | Group 1 (6-month): Assessments performed day 1 and day 183. Group 2 (12-month): Assessments performed day 1 and 364. | Implant migration is defined as a distance of greater than 3cm between the initial incision and the proximal end of the implant device prior to removal. |
| Implant Device Placement Depth | Group 1 (6-month): Ultrasound on days 14 and 183. Group 2 (12-month): Ultrasound on days 14 and 364. | Average depth of implant device placement measured by ultrasound in mm. The average depth was calculated for each participant. The implant device depth reported is the average of all participants who completed the study in each group. |
| Implant Cave: Average Plasma Concentration of Active Moiety (Risperidone + 9 OH Risperidone) During the Implant Phase | PK blood draw & analysis were performed per protocol time intervals; 0, 1, 2, 3, 4, 6, 8, 12, 24, 28, 32, 36, 48, and 52 hours post-placement of implants; 1x/day for 4 additional days, 1x/week during days 5-28; biweekly until day of device removal. | Average plasma concentration of active moiety (risperidone + 9 OH risperidone) following switch from oral risperidone to subcutaneous implantation of two DLP-114 devices at specific time intervals per protocol for 6 months or 12 months (groups 1 and 2 respectively). |
| Average Positive and Negative Syndrome Scale (PANSS) During the Study (Oral & Implant Phases) | For group 1: Screening period, day -1, day 84, day 183; and for Group 2: Screening period, day -1, day 84, day 182, day 280, day 364. | Average Positive and Negative Syndrome Scale (PANSS) during the study (Oral & Implant Phases). The average PANSS score was calculated for each participant during the study. The PANSS score reported is the average of all participants who completed the study in each group. The PANSS provides a total score (sum of the scores of all 30 items) ranging from 30 to 210, higher scores indicate more severe neuropsychiatric symptoms of schizophrenia. Scores for 3 subscales, that is, for positive subscale (sum of the scores of all 7 items) and negative subscale (sum of the scores of all 7 items) ranges from 7 (absent) to 49 (extreme psychopathology), and for the general psychopathology subscale (sum of the scores of all 16 items) score ranges from 16 (absent) to 112 (extreme psychopathology) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| DLP-114 Alpha-4 (6-months) Group 1: 6-month implant arm
Oral Phase: 3 mg of Risperidone for 2 weeks
Implant Phase: 2 implants (360 mg of Risperidone per implant) for 6 months | 14 |
| DLP-114 Alpha-7 (12-months) Group 2: 12-month implant arm
Oral Phase: 3 mg of Risperidone for 2 weeks
Implant Phase: 2 implants (435 mg of Risperidone per implant) for 12 months | 14 |
| Total | 28 |
Baseline characteristics
| Characteristic | DLP-114 Alpha-4 (6-months) | DLP-114 Alpha-7 (12-months) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 14 Participants | 28 Participants |
| Age, Continuous | 54.5 Years | 54.5 Years | 54.5 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 13 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants | 13 Participants | 22 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 1 Participants | 6 Participants |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 7 Participants |
| Sex: Female, Male Male | 11 Participants | 10 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 14 |
| other Total, other adverse events | 10 / 14 | 12 / 14 |
| serious Total, serious adverse events | 0 / 14 | 1 / 14 |
Outcome results
Primary
Adverse Events
Number of Participants with Treatment-Emergent Adverse Events.
Time frame: Up to 8 months and up to 15 months for groups 1 and 2 respectively.
Population: All patients participating in both phases of the study (Oral and implant).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| DLP-114 Alpha-4 (6-months) | Adverse Events | 10 Participants |
| DLP-114 Alpha-7 (12-months) | Adverse Events | 13 Participants |
Primary
Number of Participants Who Experienced an AE Related to Implantation or Explantation Procedures
Number of participants who experienced an Adverse Events related to Implantation or Explantation Procedures
Time frame: 6 months and 12 months for groups 1 and 2 respectively.
Population: Patients who started the implant phase
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| DLP-114 Alpha-4 (6-months) | Number of Participants Who Experienced an AE Related to Implantation or Explantation Procedures | 7 Participants |
| DLP-114 Alpha-7 (12-months) | Number of Participants Who Experienced an AE Related to Implantation or Explantation Procedures | 2 Participants |
Primary
Percentage of Implant Site Assessments With a Dermal Irritation Scale Rating Greater Than Zero
Evaluate the incidence of local site reactions. Percentage of implant site assessments with a dermal irritation scale rating greater than zero (rating scale is 0 to 4, where 0 indicates no erythema or edema, and 4 indicates erythema or slight eschar).
Time frame: 6 months and 12 months for groups 1 and 2 respectively.
Population: Participants who enrolled in the implant phase of the study,
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DLP-114 Alpha-4 (6-months) | Percentage of Implant Site Assessments With a Dermal Irritation Scale Rating Greater Than Zero | 10.1 percentage of site assessments rated >0 |
| DLP-114 Alpha-7 (12-months) | Percentage of Implant Site Assessments With a Dermal Irritation Scale Rating Greater Than Zero | 5.1 percentage of site assessments rated >0 |
Secondary
Average Clinical Global Impression-Improvement (CGI-I) Scale During the Implant Phase
Average Clinical Global Impression-Improvement (CGI-I) Scale during the Implant Phase. The average CGI-I score was calculated for each participant during the Implant Phase. The CGI-I score reported is the average of all participants who completed the study in each group. The CGI-I is a 7-point scale that requires the clinician to assess how much the participant's illness has improved or worsened relative to a baseline state at the beginning of the intervention and rated as: 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; 7=very much worse.
Time frame: CGI-I assessments were conducted over the course of the study per the protocol schedule of assessments. For Group 1: day 7, 14, 28, 42, 70, 112,140, 68, 183 and for Group 2: day 7, 14, 28, 56, 84, 112,140, 168,182, 210, 238, 252, 280, 308, 336, 350, 364.
Population: Participants who completed the study
| Arm | Measure | Value (MEAN) |
|---|---|---|
| DLP-114 Alpha-4 (6-months) | Average Clinical Global Impression-Improvement (CGI-I) Scale During the Implant Phase | 3.5 Score on CGI-I scale |
| DLP-114 Alpha-7 (12-months) | Average Clinical Global Impression-Improvement (CGI-I) Scale During the Implant Phase | 3.7 Score on CGI-I scale |
Secondary
Average Daily Risperidone Implant Output During the Implant Phase
Average daily Risperidone Implant output during the Implant Phase. Average daily output is calculated by using the amount of Risperidone drug substance remaining in the DLP-114 reservoir following removal. The average daily output is calculated for each participant by using the two devices that each participant received. Risperidone output reported as the average for each group.
Time frame: 6-months and 12-months for groups 1 and 2 respectively. Remaining Risperidone measurements taken at the end of the Implant Phase.
Population: Participants who completed the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DLP-114 Alpha-4 (6-months) | Average Daily Risperidone Implant Output During the Implant Phase | 0.676 mg/day | Standard Deviation 0.156 |
| DLP-114 Alpha-7 (12-months) | Average Daily Risperidone Implant Output During the Implant Phase | 0.531 mg/day | Standard Deviation 0.106 |
Secondary
Average Positive and Negative Syndrome Scale (PANSS) During the Study (Oral & Implant Phases)
Average Positive and Negative Syndrome Scale (PANSS) during the study (Oral & Implant Phases). The average PANSS score was calculated for each participant during the study. The PANSS score reported is the average of all participants who completed the study in each group. The PANSS provides a total score (sum of the scores of all 30 items) ranging from 30 to 210, higher scores indicate more severe neuropsychiatric symptoms of schizophrenia. Scores for 3 subscales, that is, for positive subscale (sum of the scores of all 7 items) and negative subscale (sum of the scores of all 7 items) ranges from 7 (absent) to 49 (extreme psychopathology), and for the general psychopathology subscale (sum of the scores of all 16 items) score ranges from 16 (absent) to 112 (extreme psychopathology)
Time frame: For group 1: Screening period, day -1, day 84, day 183; and for Group 2: Screening period, day -1, day 84, day 182, day 280, day 364.
Population: Participants who completed the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DLP-114 Alpha-4 (6-months) | Average Positive and Negative Syndrome Scale (PANSS) During the Study (Oral & Implant Phases) | 56.92 Total score on PANSS scale | Standard Deviation 7.55 |
| DLP-114 Alpha-7 (12-months) | Average Positive and Negative Syndrome Scale (PANSS) During the Study (Oral & Implant Phases) | 57.51 Total score on PANSS scale | Standard Deviation 8.43 |
Secondary
Implant Cave: Average Plasma Concentration of Active Moiety (Risperidone + 9 OH Risperidone) During the Implant Phase
Average plasma concentration of active moiety (risperidone + 9 OH risperidone) following switch from oral risperidone to subcutaneous implantation of two DLP-114 devices at specific time intervals per protocol for 6 months or 12 months (groups 1 and 2 respectively).
Time frame: PK blood draw & analysis were performed per protocol time intervals; 0, 1, 2, 3, 4, 6, 8, 12, 24, 28, 32, 36, 48, and 52 hours post-placement of implants; 1x/day for 4 additional days, 1x/week during days 5-28; biweekly until day of device removal.
Population: Participants who completed the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DLP-114 Alpha-4 (6-months) | Implant Cave: Average Plasma Concentration of Active Moiety (Risperidone + 9 OH Risperidone) During the Implant Phase | 11.54 ng/ML | Standard Deviation 3.99 |
| DLP-114 Alpha-7 (12-months) | Implant Cave: Average Plasma Concentration of Active Moiety (Risperidone + 9 OH Risperidone) During the Implant Phase | 14.41 ng/ML | Standard Deviation 6.76 |
Secondary
Implant Device Placement Depth
Average depth of implant device placement measured by ultrasound in mm. The average depth was calculated for each participant. The implant device depth reported is the average of all participants who completed the study in each group.
Time frame: Group 1 (6-month): Ultrasound on days 14 and 183. Group 2 (12-month): Ultrasound on days 14 and 364.
Population: Participants who completed the study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DLP-114 Alpha-4 (6-months) | Implant Device Placement Depth | 4.10 mm | Standard Deviation 1.84 |
| DLP-114 Alpha-7 (12-months) | Implant Device Placement Depth | 4.85 mm | Standard Deviation 1.4 |
Secondary
Number of Participants Who Experienced Implant Migration in at Least One of the Implanted Devices
Implant migration is defined as a distance of greater than 3cm between the initial incision and the proximal end of the implant device prior to removal.
Time frame: Group 1 (6-month): Assessments performed day 1 and day 183. Group 2 (12-month): Assessments performed day 1 and 364.
Population: Participants who completed the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DLP-114 Alpha-4 (6-months) | Number of Participants Who Experienced Implant Migration in at Least One of the Implanted Devices | 0 number of participants |
| DLP-114 Alpha-7 (12-months) | Number of Participants Who Experienced Implant Migration in at Least One of the Implanted Devices | 0 number of participants |
Secondary
Oral Phase Cave: Average Plasma Concentration of Active Moiety (Risperidone + 9 OH Risperidone) During 24 Hours After 3 Days of Repeated 3mg QD Oral Administrations
Oral Phase Cave: Average plasma concentration of active moiety (risperidone + 9 OH risperidone) during 24 hours after 3 days of repeated 3mg QD oral administrations
Time frame: t=0, 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours following oral administration.
Population: Participants who completed the Oral Dose Phase and began the Implant Phase.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DLP-114 Alpha-4 (6-months) | Oral Phase Cave: Average Plasma Concentration of Active Moiety (Risperidone + 9 OH Risperidone) During 24 Hours After 3 Days of Repeated 3mg QD Oral Administrations | 43.07 ng/mL | Standard Deviation 13.32 |
| DLP-114 Alpha-7 (12-months) | Oral Phase Cave: Average Plasma Concentration of Active Moiety (Risperidone + 9 OH Risperidone) During 24 Hours After 3 Days of Repeated 3mg QD Oral Administrations | 43.86 ng/mL | Standard Deviation 14.12 |