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Low recruitment rate
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A Phase II, multicenter, double blind, double dummy, randomized, 2 arms parallel study to evaluate the efficacy, safety and pharmacokinetics of CHF6563 in babies with Neonatal Opioid Withdrawal Syndrome
This was a randomised, multicentre, double-blind, double-dummy, parallel-group, controlled study of CHF6563 (non-ethanolic buprenorphine) sublingual solution.
For the enrolled subjects, withdrawal signs were assessed using a pre-defined Finnegan Neonatal Abstinence Scoring Tool (FNAST). FNAST assessments were made in neonates who showed signs of withdrawal despite appropriate non-pharmacological care and were recorded every 4 hours (±1 hour). Pharmacological treatment was to be started up to 7 days after birth in neonates who showed signs of neonatal opioid withdrawal syndrome (NOWS), defined as the sum of three consecutive FNAST scores ≥24 or a single score ≥12, and had failed to respond to non-pharmacological care. After FNAST assessment had started, it was continued for at least 24 hours, even if the baby was not randomised.
Sublingual administration of CHF6563 (non-ethanolic buprenorphine) solution (0.075 mg/mL) at a starting dose of 10 μg/kg every 8 hours (q8), using birth weight and oral administration of morphine-matched placebo (sterile water for injection USP), every 4 hours (q4). Thereafter, up-titrations of CHF6563 were possible to a maximum scheduled dose of 90 μg/kg/day. At the discretion of the physician, rescue doses of CHF6563 or morphine could have been given during the treatment to a neonate who had a single score of ≥12. Duration of treatment could last a maximum of 10 weeks. Adverse events (AEs) and serious adverse events (SAEs) were collected starting from the time of informed consent signature or from the neonate's birth (if the informed consent was signed before birth) through treatment and the follow-up period.
The study was terminated for non-safety reasons on 04 February 2022, due to low recruitment rate, after only 7 subjects out of a planned 57 subjects had been randomised. An Independent Safety Monitoring Board (ISMB) was in-place to review the safety profile of CHF6563/morphine treatment; the study was terminated before the ISMB reviewed any data.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| CHF6563 | Experimental | Sublingual dose of CHF6563 and the corresponding oral dose of morphine matched placebo |
|
| Morphine | Active Comparator | Oral dose of morphine and the corresponding sublingual dose of CHF6563 matched placebo. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| CHF6563 | Drug | Sublingual CHF6563 administration at starting dose of 10 µg/kg q8 |
| |
| Measure | Description | Time Frame |
|---|---|---|
| Duration of Treatment | Duration of treatment defined as the number of hours from first dose of study drug administration until the last dose of study drug. Shown are results for the duration of treatment in all treated patients, regardless of discontinuation status, as well as those patients who completed the study (with non missing data). The number of subjects randomised in the study was much lower than planned. Although data from 5 subjects were used in the CHF6563 treatment group, only 2 subjects completed the study as planned i.e. 1 subject in each study arm; no imputation of missing or incomplete data was possible according to the methods defined in the study protocol and the SAP. No statistical analysis was performed. | Up to 10 weeks after first dose |
| Measure | Description | Time Frame |
|---|---|---|
| Time to First Weaning | Record the time to first weaning, defined as the number of hours from first dose of study drug administration until the first dose reduction. The number of subjects randomised in the study was much lower than planned. Although data from 5 subjects were used in the CHF6563 treatment group, only 2 subjects completed the study as planned i.e. 1 subject in each study arm; no imputation of missing or incomplete data was possible according to the methods defined in the study protocol and the SAP. No statistical analysis was performed. |
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Inclusion Criteria:
Exclusion Criteria:
Familial history of prolonged QTc syndrome
Major congenital malformations or evidence of congenital infection
Signs of fetal alcohol spectrum disorders
Maternal alcohol abuse, defined as average of 3 or more drinks per week in the last 30 days
Medical illness at the time of randomization, including but not exclusively:
Unable to tolerate an oral or sublingual medication
Need for medications forbidden in this study protocol
Any condition that, in the opinion of the Investigator, would place the neonate at undue risk
Participation in another clinical trial of any medicinal product, placebo, experimental medical device or biological substance conducted under the provisions of a protocol on the same therapeutic target. The participation in studies involving diagnostic devices or treatments for conditions other than NOWS and Neonatal abstinence syndrome (NAS) may be permitted following an agreement with the Sponsor. Non-interventional observational studies are allowed
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| Name | Affiliation | Role |
|---|---|---|
| Walter Kraft | Thomas Jefferson University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Clinical site 015 | Las Vegas | Nevada | 89102 | United States | ||
| Thomas Jefferson University |
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| ID | Title | Description |
|---|---|---|
| FG000 | CHF6563 | Sublingual dose of CHF6563 and the corresponding oral dose of morphine matched placebo |
| FG001 | Morphine | Oral dose of morphine and the corresponding sublingual dose of CHF6563 matched placebo |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | CHF6563 | Sublingual dose of CHF6563 and the corresponding oral dose of morphine matched placebo CHF6563: Sublingual CHF6563 administration at starting dose of 10 µg/kg q8 Morphine matched placebo: Oral morphine matched placebo administration |
| BG001 | Morphine |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| 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 | Duration of Treatment | Duration of treatment defined as the number of hours from first dose of study drug administration until the last dose of study drug. Shown are results for the duration of treatment in all treated patients, regardless of discontinuation status, as well as those patients who completed the study (with non missing data). The number of subjects randomised in the study was much lower than planned. Although data from 5 subjects were used in the CHF6563 treatment group, only 2 subjects completed the study as planned i.e. 1 subject in each study arm; no imputation of missing or incomplete data was possible according to the methods defined in the study protocol and the SAP. No statistical analysis was performed. | Randomised Set: All randomised subjects. Only 7 subjects were randomised into the study; 2 subjects completed the study as planned; therefore, no statistical analysis was performed. Due to low recruitment rate, the study was terminated early for non-safety reasons. | Posted | Mean | Full Range | hours | Up to 10 weeks after first dose |
|
AEs and serious AEs (SAEs) were collected from the time of informed consent signature or from the neonate's birth through treatment and follow-up (FU) period (48 h after last treatment). Daily phone calls with the primary caregiver was for the first 7 d; weekly phone contact was up to 6 weeks after the final opioid treatment dose. NOWS treatment duration depends on Finnegan Neonatal Abstinence Scoring Tool (FNAST) scores and differs for each neonate; the maximum length of treatment was 10 weeks.
Pre-treatment AEs=From between informed consent and first study drug administration. Treatment-emergent adverse events (TEAE)=From on or after first administration of any study drug. Peri-dosing AEs=AEs occurring during or shortly after (i.e., within 10 minutes) administration of study drug. Post-treatment AEs=From on or after the start of the FU phase (i.e. >48h after end of treatment). Ongoing AEs/SAEs were followed until the event resolved/stabilized, as acceptable to the Investigator.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | CHF6563 | Sublingual dose of CHF6563 and the corresponding oral dose of morphine matched placebo CHF6563: Sublingual CHF6563 administration at starting dose of 10 µg/kg q8 Morphine matched-placebo: Oral morphine-matched placebo administration |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Vomiting | Gastrointestinal disorders | MedDRA (24.0) | Systematic Assessment |
The study objectives could not be addressed because the study was terminated due to a low recruitment; for non-safety reasons.
Despite concerted efforts by the Sponsor to improve the enrolment rate (e.g., through communications with the Investigators, changing the training modalities to meet nurses' requests, and decreasing the sample size), the projected time frame to complete the study was longer than 5 years; this was considered unacceptable for the clinical development programme.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Clinical Trial Transparency | Chiesi Farmaceutici S.p.A. | + 39 0521 2791 | clinicaltrials_info@chiesi.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Mar 18, 2021 | Dec 22, 2022 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jul 7, 2022 | Dec 22, 2022 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D009020 | Morphine |
| ID | Term |
|---|---|
| D009022 | Morphine Derivatives |
| D009019 | Morphinans |
| D053610 | Opiate Alkaloids |
| D000470 | Alkaloids |
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double blind, double-dummy
| Morphine |
| Drug |
Oral morphine administration at starting dose of 0.07 mg/kg q4 |
|
| CHF6563 matched placebo | Drug | Sublingual CHF6563 matched placebo administration |
|
| Morphine matched placebo | Drug | Oral morphine matched placebo administration |
|
| up to 10 weeks after first dose |
| Adjunctive Therapy | Record the requirement for adjunctive drug therapy (phenobarbital) for signs of NOWS, recorded as Yes/No. Overall, 1 subject in the CHF6563 group and zero subjects in the morphine were reported as having received adjunctive drug therapy with phenobarbital. The number of subjects randomised in the study was much lower than planned. No imputation of missing or incomplete data was made. No statistical analysis was performed. NOWS=Neonatal Opioid Withdrawal Syndrome | up to 10 weeks after first dose |
| Requirement for Rescue Doses (CHF6563 or Morphine) | Requirement for rescue doses and number of rescue doses administered (CHF6563 or morphine); (yes/no). The number of subjects randomised in the study was lower than planned. No imputation of missing or incomplete data was made. No statistical analysis was performed. | up to 10 weeks after first dose |
| Number of Rescue Doses Administered | Number of rescue doses administered. The number of subjects randomised in the study was much lower than planned. Although data from 5 subjects were used in the CHF6563 treatment group, only 2 subjects completed the study as planned i.e. 1 subject in each study arm; no imputation of missing or incomplete data was possible according to the methods defined in the study protocol and the SAP. No statistical analysis was performed. At the discretion of the physician, a rescue dose of CHF6563 or morphine could be given during the up-titration phase or during the weaning phases to a neonate who had a single FNAST score ≥12. A rescue dose was not to be administered within 1 hour of the previous dose or 1 hour before the next scheduled dose. Rescue doses were the same as the previous dose. | up to 10 weeks after first dose |
| Length of Opioid-related Hospital Stay | Length of opioid-related hospital stay was defined as number of days from day of birth until 48 hours after the final dose of drug treatment for NOWS. Reported data show the length of opioid-related hospital stay (defined as number of days from day of birth until 48 hours after the final dose of drug treatment for NOWS). The number of subjects randomised in the study was much lower than planned. Although data from 5 subjects were used in the CHF6563 treatment group, only 2 subjects completed the study as planned i.e. 1 subject in each study arm; no imputation of missing or incomplete data was possible according to the methods defined in the study protocol and the SAP. No statistical analysis was performed. | up to 10 weeks plus 48 hours |
| Relapse of NOWS | Relapse of NOWS, defined as experiencing recurrence of significant signs of withdrawal . Reported are subjects with experiencing a relapse. The number of subjects randomised in the study was much lower than planned. No imputation of missing or incomplete data was made. No statistical analysis was performed. NOWS=Neonatal Opioid Withdrawal Syndrome | up to 6 weeks after last dose |
| Philadelphia |
| Pennsylvania |
| 19144 |
| United States |
| Physician Decision |
|
Oral dose of morphine and the corresponding sublingual dose of CHF6563 matched placebo. Morphine: Oral morphine administration at starting dose of 0.07 mg/kg q4 CHF6563 matched placebo: Sublingual CHF6563 matched placebo administration |
| BG002 | Total | Total of all reporting groups |
| days |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Gestational age | Mean | Standard Deviation | weeks |
|
| Body length | Mean | Standard Deviation | cm |
|
| Weight | Mean | Standard Deviation | kg |
|
| Head circumference | Mean | Standard Deviation | cm |
|
| OG000 |
| CHF6563 |
Sublingual dose of CHF6563 and the corresponding oral dose of morphine matched placebo CHF6563 |
| OG001 | Morphine | Oral dose of morphine and the corresponding sublingual dose of CHF6563 matched placebo. |
|
|
| Secondary | Time to First Weaning | Record the time to first weaning, defined as the number of hours from first dose of study drug administration until the first dose reduction. The number of subjects randomised in the study was much lower than planned. Although data from 5 subjects were used in the CHF6563 treatment group, only 2 subjects completed the study as planned i.e. 1 subject in each study arm; no imputation of missing or incomplete data was possible according to the methods defined in the study protocol and the SAP. No statistical analysis was performed. | Randomised Set: All randomised subjects. Only 7 subjects were randomised into the study; 2 subjects completed the study as planned; therefore, no statistical analysis was performed. Due to low recruitment rate, the study was terminated early for non-safety reasons. | Posted | Mean | Full Range | hours | up to 10 weeks after first dose |
|
|
|
| Secondary | Adjunctive Therapy | Record the requirement for adjunctive drug therapy (phenobarbital) for signs of NOWS, recorded as Yes/No. Overall, 1 subject in the CHF6563 group and zero subjects in the morphine were reported as having received adjunctive drug therapy with phenobarbital. The number of subjects randomised in the study was much lower than planned. No imputation of missing or incomplete data was made. No statistical analysis was performed. NOWS=Neonatal Opioid Withdrawal Syndrome | Randomised Set: All randomised subjects. Only 7 subjects were randomised into the study; 2 subjects completed the study as planned; therefore, no statistical analysis was performed. Due to low recruitment rate, the study was terminated early for non-safety reasons. | Posted | Count of Participants | Participants | up to 10 weeks after first dose |
|
|
|
| Secondary | Requirement for Rescue Doses (CHF6563 or Morphine) | Requirement for rescue doses and number of rescue doses administered (CHF6563 or morphine); (yes/no). The number of subjects randomised in the study was lower than planned. No imputation of missing or incomplete data was made. No statistical analysis was performed. | Randomised Set: All randomised subjects. Only 7 subjects were randomised into the study; 2 subjects completed the study as planned; therefore, no statistical analysis was performed. Due to low recruitment rate, the study was terminated early for non-safety reasons. | Posted | Count of Participants | Participants | up to 10 weeks after first dose |
|
|
|
| Secondary | Number of Rescue Doses Administered | Number of rescue doses administered. The number of subjects randomised in the study was much lower than planned. Although data from 5 subjects were used in the CHF6563 treatment group, only 2 subjects completed the study as planned i.e. 1 subject in each study arm; no imputation of missing or incomplete data was possible according to the methods defined in the study protocol and the SAP. No statistical analysis was performed. At the discretion of the physician, a rescue dose of CHF6563 or morphine could be given during the up-titration phase or during the weaning phases to a neonate who had a single FNAST score ≥12. A rescue dose was not to be administered within 1 hour of the previous dose or 1 hour before the next scheduled dose. Rescue doses were the same as the previous dose. | Randomised Set: All randomised subjects. Only 7 subjects were randomised into the study; 2 subjects completed the study as planned; therefore, no statistical analysis was performed. Due to low recruitment rate, the study was terminated early for non-safety reasons. | Posted | Mean | Full Range | number of rescue doses | up to 10 weeks after first dose |
|
|
|
| Secondary | Length of Opioid-related Hospital Stay | Length of opioid-related hospital stay was defined as number of days from day of birth until 48 hours after the final dose of drug treatment for NOWS. Reported data show the length of opioid-related hospital stay (defined as number of days from day of birth until 48 hours after the final dose of drug treatment for NOWS). The number of subjects randomised in the study was much lower than planned. Although data from 5 subjects were used in the CHF6563 treatment group, only 2 subjects completed the study as planned i.e. 1 subject in each study arm; no imputation of missing or incomplete data was possible according to the methods defined in the study protocol and the SAP. No statistical analysis was performed. | Randomised Set: All randomised subjects. Only 7 subjects were randomised into the study; 2 subjects completed the study as planned; therefore, no statistical analysis was performed. Due to low recruitment rate, the study was terminated early for non-safety reasons. | Posted | Mean | Full Range | days | up to 10 weeks plus 48 hours |
|
|
|
| Secondary | Relapse of NOWS | Relapse of NOWS, defined as experiencing recurrence of significant signs of withdrawal . Reported are subjects with experiencing a relapse. The number of subjects randomised in the study was much lower than planned. No imputation of missing or incomplete data was made. No statistical analysis was performed. NOWS=Neonatal Opioid Withdrawal Syndrome | Randomised Set: All randomised subjects. Only 7 subjects were randomised into the study; 2 subjects completed the study as planned; therefore, no statistical analysis was performed. Due to low recruitment rate, the study was terminated early for non-safety reasons. | Posted | Count of Participants | Participants | up to 6 weeks after last dose |
|
|
|
| 0 |
| 5 |
| 0 |
| 5 |
| 2 |
| 5 |
| EG001 | Morphine | Oral dose of morphine and the corresponding sublingual dose of CHF6563 matched placebo. Morphine: Oral morphine administration at starting dose of 0.07 mg/kg q4 CHF6563 matched-placebo: Sublingual CHF6563 matched-placebo administration | 0 | 2 | 0 | 2 | 2 | 2 |
| Flatulence | Gastrointestinal disorders | MedDRA (24.0) | Systematic Assessment |
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| Fungal infection | Infections and infestations | MedDRA (24.0) | Systematic Assessment |
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| Skin candida | Infections and infestations | MedDRA (24.0) | Systematic Assessment |
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| Rash | Skin and subcutaneous tissue disorders | MedDRA (24.0) | Systematic Assessment |
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| Overdose | Injury, poisoning and procedural complications | MedDRA (24.0) | Systematic Assessment |
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| Poor feeding infant | Metabolism and nutrition disorders | MedDRA (24.0) | Systematic Assessment |
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| Somnolence | Nervous system disorders | MedDRA (24.0) | Systematic Assessment |
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| Hypotonia neonatal | Musculoskeletal and connective tissue disorders | MedDRA (24.0) | Systematic Assessment |
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| Infantile vomiting | Gastrointestinal disorders | MedDRA (24.0) | Systematic Assessment | Post-treatment AE |
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| Dry skin | Skin and subcutaneous tissue disorders | MedDRA (24.0) | Systematic Assessment | Post-treatment AE |
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Chiesi can publish and/or present any results of this study at scientific meetings, and to submit the clinical trial data to national and international Regulatory Authorities. Chiesi reserves the right to use such data for industrial purposes. Investigators will inform Chiesi before using the results of the study for publication or presentation, and agree to provide the Sponsor with a copy of the proposed presentation. Data from individual study sites must not be published separately.
| D006571 |
| Heterocyclic Compounds |
| D006572 | Heterocyclic Compounds, Bridged-Ring |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D010616 | Phenanthrenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D011083 | Polycyclic Compounds |
| Patients who completed the study (With Non Missing Data) |
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| Patients who completed the study (With Non Missing Data) |
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| Patients who completed the study (With Non Missing Data) |
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