CHF6563 in Babies With Neonatal Opioid Withdrawal Syndrome

Study Overview
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Brief Summary
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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

Detailed Description
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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.

Official Title
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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

Conditions
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Neonatal Opioid Withdrawal Syndrome

Intervention / Treatment
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* Drug: CHF6563
* Drug: Morphine
* Drug: CHF6563 matched placebo
* Drug: Morphine matched placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent obtained by parents/legal representative(according to local regulation) prior to or after birth. Birth weight ≥ 3rd centile for gestational age (GA), according to the Centers for Disease Control and Prevention (CDC) growth chart Gestational age ≥ 36 weeks Exposure to opioids during the last month of fetal life 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: 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: Neonatal hypoglycemia requiring intravenous glucose therapy Neonatal respiratory illness requiring non-invasive or invasive respiratory support Neonatal encephalopathy (including hypoxic ischemic encephalopathy or seizures Severe hyperbilirubinemia-bilirubin at or above the exchange transfusion threshold as defined by the American Academy of Pediatrics (AAP) Severe elevation of serum aminotransferases (more than twice the upper limit of the age appropriate aminotransferases reference range of the investigational site). Proven or suspected early onset neonatal infection which will require more than 48 hours treatment with antibiotics 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

Ages Eligible for Study
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Maximum Age: 7 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CHF6563<br>Sublingual dose of CHF6563 and the corresponding oral dose of morphine matched placebo | Drug: CHF6563<br>* Sublingual CHF6563 administration at starting dose of 10 µg/kg q8<br>Drug: Morphine matched placebo<br>* Oral morphine matched placebo administration<br>|
| Active Comparator: Morphine<br>Oral dose of morphine and the corresponding sublingual dose of CHF6563 matched placebo. | Drug: Morphine<br>* Oral morphine administration at starting dose of 0.07 mg/kg q4<br>Drug: CHF6563 matched placebo<br>* Sublingual CHF6563 matched placebo administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 | 

Secondary Outcome Measures

| Outcome Measure | 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. | 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 |