Subcutaneous Rehydration Compared to Intravenous Rehydration

Study Overview
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Brief Summary
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Randomized (1:1 ratio) study of subcutaneous (SC) versus intravenous (IV) fluid rehydration in mildly to moderately dehydrated pediatric patients.

Detailed Description
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This is a prospective, randomized (1:1 ratio), open-label, parallel group, multicenter, multi-national, study of SC versus IV fluid rehydration in mildly to moderately dehydrated pediatric patients treated in the Emergency Department (ED), inpatient pediatric unit, and/or outpatient urgent care facility. It is expected that up to 186 patients, in order to achieve 148 evaluable patients, will be randomized in a 1:1 ratio to receive isotonic fluid rehydration by either SC administration with hylenex (150 Units) or IV without hylenex.

Official Title
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Subcutaneous Rehydration With Hylenex Compared to Intravenous Rehydration in Infants and Young Children With Mild to Moderate Dehydration

Conditions
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Dehydration

Intervention / Treatment
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* Drug: recombinant human hyaluronidase


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children of either gender from one month to ≤10 years of age. Patients with mild or moderate dehydration Healthy child except for the underlying etiology for dehydration Pre-dehydration body weight ≥ 5th percentile for age Parents or legal guardian(s) available to provide informed consent. Exclusion Criteria: Severe dehydration Shock or life-threatening situation (life expectancy < 10 days). Requirement for IV access for any indication other than for treatment of dehydration. Indwelling IV catheter, except for one intended only for collection of clinical laboratory specimens. Any condition precluding SC infusion or infusion site evaluation Any reason (prior to study enrollment) for a hospital admission or an extended stay in the ED for other than dehydration. Known hypersensitivity to hyaluronidase or hylenex. Known hyponatremia (< 130 milliequivalents per liter [mEq/L]) or hypernatremia (> 155 mEq/L). Known hypokalemia (< 3.0 mEq/L). Any medical condition likely to interfere with the patient's ability to fully complete all protocol-specified interventions, the ability to undergo all protocol-specified assessments, or likely to prolong the patient's need for medical attention beyond that required for treatment of dehydration. Participation in an investigational drug or device study within 30 days prior to enrollment in this study.

Ages Eligible for Study
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Minimum Age: 30 Days
Maximum Age: 10 Years

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Subcutaneous<br>Isotonic fluid rehydration by SC administration with hylenex (150 Units in 1 mL) | Drug: recombinant human hyaluronidase<br>* 150 Units in 1 mL<br>* Other names: Hylenex;|
| Active Comparator: Intravenous<br>Isotonic fluid rehydration by IV | Drug: recombinant human hyaluronidase<br>* 150 Units in 1 mL<br>* Other names: Hylenex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Total Volume of Fluid Administered at a Single Infusion Site, From the Start to the Cessation of Fluid Administration, for All Randomized Participants | It was anticipated that most participants in this study would be hydrated through only one infusion site. For participants who received fluid at more than one administration site, a single infusion site was defined as the anatomical site at which the majority of the total infusion volume was infused. The term anatomical site was designated as: 1) the back; 2) left thigh; 3) right thigh; 4) abdomen; or 5) chest. | During the infusion (single bolus dose of hylenex [1 hr], followed by subcutaneous fluid for 1 hour to 72 hours) | 
| Mean Total Volume of Fluid Administered at a Single Infusion Site, From the Start to the Cessation of Fluid Administration, for Non-rescued Participants | It was anticipated that most participants in this study would be hydrated through only one infusion site. For participants who received fluid at more than one administration site, a single infusion site was defined as the anatomical site at which the majority of the total infusion volume was infused. The term anatomical site was designated as: 1) the back; 2) left thigh; 3) right thigh; 4) abdomen; or 5) chest. Participants randomized to receive intravenous isotonic fluid were permitted to receive subcutaneous fluid administration by hylenex-facilitated infusion as rescue. | During the infusion (single bolus dose of hylenex [1 hr], followed by subcutaneous fluid for 1 hour to 72 hours) | 
| Mean Total Volume of Fluid Administered at a Single Infusion Site, From the Start to the Cessation of Fluid Administration, for All Rescued Participants | It was anticipated that most participants in this study would be hydrated through only one infusion site. For participants who received fluid at more than one administration site, a single infusion site was defined as the anatomical site at which the majority of the total infusion volume was infused. The term anatomical site was designated as: 1) the back; 2) left thigh; 3) right thigh; 4) abdomen; or 5) chest. Participants randomized to receive intravenous isotonic fluid were permitted to receive subcutaneous fluid administration by hylenex-facilitated infusion as rescue. | During the infusion (single bolus dose of hylenex [1 hr], followed by subcutaneous fluid for 1 hour to 72 hours) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Total Volume of Fluid Administered at All Infusion Sites, From the Start to the Cessation of Fluid Administration, for All Randomized Participants | It was anticipated that most participants in this study would be hydrated through only one infusion site. For participants who received fluid at more than one administration site, a single infusion site was defined as the anatomical site at which the majority of the total infusion volume was infused. The term anatomical site was designated as: 1) the back; 2) left thigh; 3) right thigh; 4) abdomen; or 5) chest. | During the infusion (single bolus dose of hylenex [1 hr], followed by subcutaneous fluid for 1 hour to 72 hours) | 
| Mean Total Volume of Fluid Administered at All Infusion Sites, From the Start to the Cessation of Fluid Administration, for All Randomized Participants Achieving > 200 mL | It was anticipated that most participants in this study would be hydrated through only one infusion site. For participants who received fluid at more than one administration site, a single infusion site was defined as the anatomical site at which the majority of the total infusion volume was infused. The term anatomical site was designated as: 1) the back; 2) left thigh; 3) right thigh; 4) abdomen; or 5) chest. The label for hylenex indicated precautionary wording recommending an upper limit on the volume of fluid (200 mL) administered subcutaneously to infants less than 3 years of age. In October 2008, the Food and Drug Administration (FDA) removed this wording from the label, thus negating the need for these data and associated analyses. The protocol was amended to reflect this label change; thus, this analysis was not conducted. | During the infusion (single bolus dose of hylenex [1 hr], followed by subcutaneous fluid for 1 hour to 72 hours) | 
| Mean Total Volume of Fluid Administered at All Infusion Sites, From the Start to the Cessation of Fluid Administration, for Non-rescued Participants Achieving > 200 mL | It was anticipated that most participants in this study would be hydrated through only one infusion site. For participants who received fluid at more than one administration site, a single infusion site was defined as the anatomical site at which the majority of the total infusion volume was infused. The term anatomical site was designated as: 1) the back; 2) left thigh; 3) right thigh; 4) abdomen; or 5) chest. Participants randomized to receive intravenous isotonic fluid were permitted to receive subcutaneous fluid administration by hylenex-facilitated infusion as rescue. The label for hylenex indicated precautionary wording recommending an upper limit on the volume of fluid (200 mL) administered subcutaneously to infants less than 3 years of age. In October 2008, the FDA removed this wording from the label, thus negating the need for these data and associated analyses. The protocol was amended to reflect this label change; thus, this analysis was not conducted. | During the infusion (single bolus dose of hylenex [1 hr], followed by subcutaneous fluid for 1 hour to 72 hours) | 
| Mean Total Volume of Fluid Administered at All Infusion Sites, From the Start to the Cessation of Fluid Administration, for All Rescued Participants Achieving > 200 mL | It was anticipated that most participants in this study would be hydrated through only one infusion site. For participants who received fluid at more than one administration site, a single infusion site was defined as the anatomical site at which the majority of the total infusion volume was infused. The term anatomical site was designated as: 1) the back; 2) left thigh; 3) right thigh; 4) abdomen; or 5) chest. Participants randomized to receive intravenous isotonic fluid were permitted to receive subcutaneous fluid administration by hylenex-facilitated infusion as rescue. The label for hylenex indicated precautionary wording recommending an upper limit on the volume of fluid (200 mL) administered subcutaneously to infants less than 3 years of age. In October 2008, the FDA removed this wording from the label, thus negating the need for these data and associated analyses. The protocol was amended to reflect this label change; thus, this analysis was not conducted. | During the infusion (single bolus dose of hylenex [1 hr], followed by subcutaneous fluid for 1 hour to 72 hours) | 
| Mean Flow Rate, Delivered Per Unit Time, for All Randomized Participants | The mean flow rate was averaged over any 60-minute period of time. | During the infusion (single bolus dose of hylenex [1 hr], followed by subcutaneous fluid for 1 hour to 72 hours) | 
| Mean Flow Rate, Delivered Per Unit Time, for All Non-rescued Participants | The mean flow rate was averaged over any 60-minute period of time. Participants randomized to receive intravenous isotonic fluid were permitted to receive subcutaneous fluid administration by hylenex-facilitated infusion as rescue. | During the infusion (single bolus dose of hylenex [1 hr], followed by subcutaneous fluid for 1 hour to 72 hours) | 
| Mean Flow Rate, Delivered Per Unit Time, for All Rescued Participants | The mean flow rate was averaged over any 60-minute period of time. Participants randomized to receive intravenous isotonic fluid were permitted to receive subcutaneous fluid administration by hylenex-facilitated infusion as rescue. | During the infusion (single bolus dose of hylenex [1 hr], followed by subcutaneous fluid for 1 hour to 72 hours) | 
| Mean Flow Rate, Delivered by Volume Per Unit Body Weight Per Unit Time, for All Randomized Participants | The mean flow rate was averaged over any 60-minute period of time. | During the infusion (single bolus dose of hylenex [1 hr], followed by subcutaneous fluid for 1 hour to 72 hours) | 
| Mean Flow Rate, Delivered by Volume Per Unit Body Weight Per Unit Time, for All Non-rescued Participants | The mean flow rate was averaged over any 60-minute period of time. Participants randomized to receive intravenous isotonic fluid were permitted to receive subcutaneous fluid administration by hylenex-facilitated infusion as rescue. | During the infusion (single bolus dose of hylenex [1 hr], followed by subcutaneous fluid for 1 hour to 72 hours) | 
| Mean Flow Rate, Delivered by Volume Per Unit Body Weight Per Unit Time, for All Rescued Participants | The mean flow rate was averaged over any 60-minute period of time. Participants randomized to receive intravenous isotonic fluid were permitted to receive subcutaneous fluid administration by hylenex-facilitated infusion as rescue. | During the infusion (single bolus dose of hylenex [1 hr], followed by subcutaneous fluid for 1 hour to 72 hours) | 
| Number of Participants Achieving a Maximum Flow Rate of > 2 Milliliters Per Minute (mL/Min), as an Indication of Successful Hydration | The maximum flow rate was averaged over any 60-minute period of time. | During the infusion (single bolus dose of hylenex [1 hr], followed by subcutaneous fluid for 1 hour to 72 hours) | 
| Number of Participants Administered at Least 200 Milliliter (mL) Total Volume at a Single Infusion Site, From the Start to the Cessation of Fluid Administration | The number of participants administered at least 20 mL total volume was assessed. | During the infusion (single bolus dose of hylenex [1 hr], followed by subcutaneous fluid for 1 hour to 72 hours) | 
| Number of Participants With the Indicated Type of Adverse Events | Adverse events (AEs) are defined as any untoward medical occurrence in a participant administered a product, which did not necessarily have a causal relationship with the treatment. Treatment-emergent adverse events (TEAEs) are defined as those events that occurred on or after the first injection device insertion attempt. | up to 7 days after hospital discharge | 
| Number of Participants With Normal Physical Examination Findings at Baseline That Shifted to Abnormal at the End of Fluid Administration | Baseline was defined as the time prior to the single site fluid infusion. End of infusion was defined as the end of infusion of the single site fluid infusion for participants who had more than one fluid infusion. Not Rel Dehy = Abnormal, Not Related to Dehydration; Rel Dehy = Abnormal, Related to Dehydration. The investigator assessed findings as abnormal. | Baseline; after infusion (single bolus dose of hylenex [1 hr], followed by subcutaneous fluid for 1 hour to 72 hours) | 
| Mean Change From Baseline in Heart Rate | Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Baseline was defined as the time prior to the single site fluid infusion. End of infusion was defined as the end of infusion of the single site fluid infusion for participants who had more than one fluid infusion. | Baseline; after infusion (single bolus dose of hylenex [1 hr], followed by subcutaneous fluid for 1 hour to 72 hours) | 
| Mean Change From Baseline in Respiratory Rate | Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Baseline was defined as the time prior to the single site fluid infusion. End of infusion was defined as the end of infusion of the single site fluid infusion for participants who had more than one fluid infusion. | Baseline; after infusion (single bolus dose of hylenex [1 hr], followed by subcutaneous fluid for 1 hour to 72 hours) | 
| Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure | Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Baseline was defined as the time prior to the single site fluid infusion. End of infusion was defined as the end of infusion of the single site fluid infusion for participants who had more than one fluid infusion. | Baseline; after infusion (single bolus dose of hylenex [1 hr], followed by subcutaneous fluid for 1 hour to 72 hours) | 
| Mean Change From Baseline in the Face, Legs, Activity, Cry, Consolability (FLACC) Pain Scale Score | The infusion site was assessed for pain at two time points: after placement of the infusion device but before fluid infusion and at the end of infusion. Pain was recorded using the FLACC pain scale for children less than 3 years of age. Scores on the scale ranged from 0 (no hurt) to 10 (hurt worst). | Before infusion (Baseline); after infusion (single bolus dose of hylenex [1 hr], followed by subcutaneous fluid for 1 hour to 72 hours) | 
| Number of Participants With the Indicated Type of Fluid Administered | Data are reported for the initial fluid administered. | During the infusion (single bolus dose of hylenex [1 hr], followed by subcutaneous fluid for 1 hour to 72 hours) | 
| Infusion Duration During the Initial Infusion | Infusion duration was assessed as a measure of the time required to complete the initial infusion of 20 mL/kg. | first hour of infusion | 
| Change From Baseline in Hydration Status According to the Gorelick Assessment at the End of Fluid Infusion | Hydration status was assessed clinically using the Gorelick 10-item scale: general condition, quality of radial pulse, quality of respiration, skin elasticity, eyes, tears, mucous membranes, urine output, heart rate, and capillary refill time at the fingertip. Scores ranged from 0 (less severe impairment) to 10 (more severe impairment). Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline; during the infusion (single bolus dose of hylenex [1 hr], followed by subcutaneous fluid for 1 hour to 72 hours) | 
| Percent Change From Baseline in Body Weight | Percent change from Baseline was calculated as the ([post-Baseline value minus the Baseline value] / Baseline value) * 100. | Baseline; during the infusion (single bolus dose of hylenex [1 hr], followed by subcutaneous fluid for 1 hour to 72 hours) | 
| Number of Participants With the Indicated Type of Rescue Route Therapy Administered | Participants for whom parenteral access by the randomized route of administration could not be achieved after a reasonable number of attempts and for whom the investigator had deemed the access by that route a failure were expected to receive fluid administration by other means, designated as rescue route for the purpose of this study. This rescue route may have included venous cut-down, central venous line, interosseous access, etc., and for those participants initially randomly assigned to IV fluid administration, SC fluid administration by hylenex-facilitated infusion. | During the infusion (single bolus dose of hylenex [1 hr], followed by subcutaneous fluid for 1 hour to 72 hours) | 
| Number of Participants Classified With the Indicated Healthcare Provider Responses to the Questions Comprising the Healthcare Provider Global Satisfaction Questionnaire | A global assessment of overall satisfaction with the rehydration therapy by healthcare provider was performed at the end of SC or IV fluid rehydration utilizing a simple questionnaire. There were separate questionnaires for the two types of rehydration (SC and IV). Question 1: Was the participant successfully hydrated using the randomized route of administration?; Question 2: Overall, was the procedure of fluid infusion easy to perform?; Question 3: Were there any unacceptable side effects from the therapy?; Question 4: Would you consider using this hydration therapy for this indication in the future? | During the infusion (single bolus dose of hylenex [1 hr], followed by subcutaneous fluid for 1 hour to 72 hours) | 
| Number of Participants Classified With the Indicated Healthcare Provider Responses to the Question: How Does This Therapy Compare to Your Experience With IV (for SC Group) / SC (for IV Group) Therapy? | A global assessment of overall satisfaction with the rehydration therapy by healthcare provider was performed at the end of SC or IV fluid rehydration utilizing a simple questionnaire. There were separate questionnaires for the two types of rehydration (SC and IV). | During the infusion (single bolus dose of hylenex [1 hr], followed by subcutaneous fluid for 1 hour to 72 hours) | 
| Number of Participants Classified With the Indicated Parent/Guardian Responses to the Questions Comprising the Parent / Guardian Global Satisfaction Questionnaire | A global assessment of overall satisfaction with the rehydration therapy by healthcare provider was performed at the end of SC or IV fluid rehydration utilizing a simple questionnaire. There were separate questionnaires for the two types of rehydration (SC and IV). Question 1: Do you believe the method of therapy was successful in your child's rehydration?; Question 2: Have you or your child ever previously had IV fluids (for SC Group) / SC fluids (for IV Group)?; Question 3: If the response to Question 2 was yes, how does this compare to prior experience with IV (for SC Group) / SC (for IV Group)?; Question 4: Should your child(ren) need rehydration treatment in the future, would you opt for this procedure?; Question 5: Should you need rehydration treatment in the future, would you opt for this procedure?; Question 6: What is your global satisfaction with the study procedure? | During the infusion (single bolus dose of hylenex [1 hr], followed by subcutaneous fluid for 1 hour to 72 hours) | 
| Number of Participants With the Indicated Number of Different Anatomical Administration Sites Needed After the Start of Fluid Administration | In the event that the degree of local infusion site swelling became unacceptable for any reason (e.g., a 30% or greater increase from the baseline circumference of the infused thigh or in the clinical judgment of the investigator), the infusion rate was decreased or the infusion site was changed. | During the infusion (single bolus dose of hylenex [1 hr], followed by subcutaneous fluid for 1 hour to 72 hours) | 
| Number of Participants Experiencing Reductions in Flow Rate | In the event that the degree of local infusion site swelling became unacceptable for any reason (e.g., a 30% or greater increase from the baseline circumference of the infused thigh or in the clinical judgment of the investigator), the infusion rate was decreased or the infusion site was changed. | During the infusion (single bolus dose of hylenex [1 hr], followed by subcutaneous fluid for 1 hour to 72 hours) | 
| Number of Participants Who Received Needle Placement by People With the Indicated Level of Staff Training | Data were collected for the level of staff training for the person who performed the needle placement. | average of approximately 3 minutes | 
| Number of Participants for Which the Indicated Number of Additional Personnel Was Involved in Needle Placement | Data were collected for the number of additional personnel involved in needle placement. | average of approximately 3 minutes | 
| Time From the Start of Infusion to the Time of Emergency Department (ED) Discharge | Data are reported from the start of infusion to the time of ED discharge. | up to approximately 26 hours | 
| Time From Randomization to the First Drop of Fluid Infusion | Data are reported for the time from randomization to the start of fluid infusion for all randomized participants. | up to approximately 110 and 220 minutes for the SC and IV arms, respectively | 
| Number of Participants With the Indicated Number of Needle Stick Attempts Needed to Initiate Fluid Administration | Data are reported for the number of needle stick attempts needed to initiate fluid administration. | average of approximately 3 minutes | 
| Number of Participants for Which the Indicated Type of Infusion Device Was Used | Data are reported for the type of infusion device used. | average of approximately 3 minutes | 
| Number of Participants for Which the Indicated Gauge for Infusion Device Was Used | Data are reported for the gauge of infusion device used. | average of approximately 3 minutes | 
| Number of Participants Discharged From the ED to Home or the Hospital | Participants were discharged from the ED to home or the hospital to continue hydration therapy. | up to approximately 26 hours | 
| Number of Participants With the Indicated Reason for Rehospitalization Within 48 and 72 Hours After Discharge | Participants were discharged from the ED to home or the hospital to continue hydration therapy. | from randomization up to approximately 98 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pediatric, hylenex, subcutaneous infusion, hyaluronidase, rHuPH20, recombinant human hyaluronidase