Neonatal Opioid Withdrawal Syndrome
Conditions
Brief summary
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
Detailed description
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.
Interventions
DRUGCHF6563 matched placebo
Sublingual CHF6563 matched placebo administration
DRUGCHF6563
Sublingual CHF6563 administration at starting dose of 10 µg/kg q8
DRUGMorphine
Oral morphine administration at starting dose of 0.07 mg/kg q4
DRUGMorphine matched placebo
Oral morphine matched placebo administration
Sponsors
Chiesi Farmaceutici S.p.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
double blind, double-dummy
Eligibility
Sex/Gender
ALL
Age
No minimum to 7 Days
Healthy volunteers
No
Inclusion criteria
1. Written informed consent obtained by parents/legal representative(according to local regulation) prior to or after birth. 2. Birth weight ≥ 3rd centile for gestational age (GA), according to the Centers for Disease Control and Prevention (CDC) growth chart 3. Gestational age ≥ 36 weeks 4. Exposure to opioids during the last month of fetal life 5. Signs of neonatal opioid withdrawal syndrome requiring treatment, and the sum of 3 consecutive FNAST scores is ≥ 24 or a single score ≥ 12
Exclusion criteria
1. Familial history of prolonged QTc syndrome 2. Major congenital malformations or evidence of congenital infection 3. Signs of fetal alcohol spectrum disorders 4. Maternal alcohol abuse, defined as average of 3 or more drinks per week in the last 30 days 5. Medical illness at the time of randomization, including but not exclusively: 1. Neonatal hypoglycemia requiring intravenous glucose therapy 2. Neonatal respiratory illness requiring non-invasive or invasive respiratory support 3. Neonatal encephalopathy (including hypoxic ischemic encephalopathy or seizures 4. Severe hyperbilirubinemia-bilirubin at or above the exchange transfusion threshold as defined by the American Academy of Pediatrics (AAP) 5. Severe elevation of serum aminotransferases (more than twice the upper limit of the age appropriate aminotransferases reference range of the investigational site). 6. Proven or suspected early onset neonatal infection which will require more than 48 hours treatment with antibiotics 6. Unable to tolerate an oral or sublingual medication 7. Need for medications forbidden in this study protocol 8. Any condition that, in the opinion of the Investigator, would place the neonate at undue risk 9. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Treatment | Up to 10 weeks after first dose | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adjunctive Therapy | up to 10 weeks after first dose | 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 |
| Requirement for Rescue Doses (CHF6563 or Morphine) | up to 10 weeks after first dose | 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. |
| Time to First Weaning | up to 10 weeks after first dose | 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. |
| Length of Opioid-related Hospital Stay | up to 10 weeks plus 48 hours | 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. |
| Relapse of NOWS | up to 6 weeks after last dose | 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 |
| Number of Rescue Doses Administered | up to 10 weeks after first dose | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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 | 5 |
| 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 | 2 |
| Total | 7 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Physician Decision | 2 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Total | CHF6563 | Morphine |
|---|---|---|---|
| Age, Continuous | 0.9 days STANDARD_DEVIATION 0.7 | 1.0 days STANDARD_DEVIATION 0.7 | 0.5 days STANDARD_DEVIATION 0.7 |
| Body length | 49.66 cm STANDARD_DEVIATION 2.12 | 49.16 cm STANDARD_DEVIATION 2.37 | 50.90 cm STANDARD_DEVIATION 0.14 |
| Gestational age | 38.59 weeks STANDARD_DEVIATION 1.22 | 38.37 weeks STANDARD_DEVIATION 1.17 | 39.14 weeks STANDARD_DEVIATION 1.62 |
| Head circumference | 34.07 cm STANDARD_DEVIATION 1.59 | 33.50 cm STANDARD_DEVIATION 1.12 | 35.50 cm STANDARD_DEVIATION 2.12 |
| 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 | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 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 | 3 Participants | 2 Participants |
| Region of Enrollment United States | 7 participants | 5 participants | 2 participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 0 Participants |
| Sex: Female, Male Male | 5 Participants | 3 Participants | 2 Participants |
| Weight | 3.3507 kg STANDARD_DEVIATION 0.6382 | 3.1718 kg STANDARD_DEVIATION 0.5319 | 3.7980 kg STANDARD_DEVIATION 0.8669 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 2 |
| other Total, other adverse events | 2 / 5 | 2 / 2 |
| serious Total, serious adverse events | 0 / 5 | 0 / 2 |
Outcome results
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.
Time frame: Up to 10 weeks after first dose
Population: 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.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| CHF6563 | Duration of Treatment | All treated patients | 157.62 hours |
| CHF6563 | Duration of Treatment | Patients who completed the study (With Non Missing Data) | 547.7 hours |
| Morphine | Duration of Treatment | All treated patients | 570.85 hours |
| Morphine | Duration of Treatment | Patients who completed the study (With Non Missing Data) | 501.5 hours |
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
Time frame: up to 10 weeks after first dose
Population: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CHF6563 | Adjunctive Therapy | 1 Participants |
| Morphine | Adjunctive Therapy | 0 Participants |
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.
Time frame: up to 10 weeks plus 48 hours
Population: 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.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| CHF6563 | Length of Opioid-related Hospital Stay | All Treated Patients | 10.64 days |
| CHF6563 | Length of Opioid-related Hospital Stay | Patients who completed the study (With Non Missing Data) | 27.0 days |
| Morphine | Length of Opioid-related Hospital Stay | All Treated Patients | 29.5 days |
| Morphine | Length of Opioid-related Hospital Stay | Patients who completed the study (With Non Missing Data) | 26.2 days |
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.
Time frame: up to 10 weeks after first dose
Population: 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.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| CHF6563 | Number of Rescue Doses Administered | All Treated Patients | 1.6 number of rescue doses |
| CHF6563 | Number of Rescue Doses Administered | Patients who completed the study (With Non Missing Data) | 4 number of rescue doses |
| Morphine | Number of Rescue Doses Administered | All Treated Patients | 3 number of rescue doses |
| Morphine | Number of Rescue Doses Administered | Patients who completed the study (With Non Missing Data) | 1 number of rescue doses |
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
Time frame: up to 6 weeks after last dose
Population: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CHF6563 | Relapse of NOWS | 1 Participants |
| Morphine | Relapse of NOWS | 0 Participants |
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.
Time frame: up to 10 weeks after first dose
Population: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| CHF6563 | Requirement for Rescue Doses (CHF6563 or Morphine) | Requirement for rescue doses -- Yes | 4 Participants |
| CHF6563 | Requirement for Rescue Doses (CHF6563 or Morphine) | Requirement for rescue doses -- No | 1 Participants |
| Morphine | Requirement for Rescue Doses (CHF6563 or Morphine) | Requirement for rescue doses -- Yes | 2 Participants |
| Morphine | Requirement for Rescue Doses (CHF6563 or Morphine) | Requirement for rescue doses -- No | 0 Participants |
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.
Time frame: up to 10 weeks after first dose
Population: 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.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| CHF6563 | Time to First Weaning | Patients who completed the study (With Non Missing Data) | 120.3 hours |
| CHF6563 | Time to First Weaning | All Treated Patients | 120.3 hours |
| Morphine | Time to First Weaning | All Treated Patients | 56.2 hours |
| Morphine | Time to First Weaning | Patients who completed the study (With Non Missing Data) | 72 hours |