PERFORMUS

17 evidence topics · 1 source

Objective

Efficacy, safety, and delineation of treatment indications

“To assess the efficacy and safety of sirolimus for children with slow-flow vascular malformations to better delineate the indications for treatment.” (opens the source at this quote in a new tab)

Location and study date

Recruitment interval

Field	Quoted date
First recruitment date	“September 28, 2015”
Last recruitment date	“March 22, 2018”

Study design

Observational-phase randomized design with randomized switch time

“This multicenter, open-label, observational-phase randomized clinical trial included 59 children aged 6 to 18 years with a slow-flow vascular malformation who were recruited between September 28, 2015, and March 22, 2018, in 11 French tertiary hospital centers.” (opens the source at this quote in a new tab)
“Participants first underwent an observational period (OP) with no treatment and then switched to an interventional period (IP) when they received sirolimus. The switch time was randomized from month 4 to month 8, and the whole study period lasted 12 months for each patient” (opens the source at this quote in a new tab)
“The trial was an open-label trial. However, the primary outcome was based on an objective outcome (ie, MRI scans interpreted by a radiologist blinded to treatment periods).” (opens the source at this quote in a new tab)

Eligibility criteria

Age, malformation type, and exclusions

“Criteria for eligibility were pediatric patients, aged 6 to 18 years, with a complicated slow-flow vascular malformation (VM, LM apart from pure macrocystic LM, and combined venolymphatic malformations, including syndromic forms) extending to underlying tissues (subcutaneous tissue and muscles), confirmed by magnetic resonance imaging (MRI).” (opens the source at this quote in a new tab)
“We did not include children younger than 6 years of age because MRI requires sedation for children of this age.” (opens the source at this quote in a new tab)
“We excluded children with a vascular malformation that required immediate medical treatment or individuals who had contraindications to MRI or sirolimus (allergy, immunosuppression, chronic infectious disease or cancer, liver insufficiency, cytopenia, hypercholesterolemia, pregnancy, and women of childbearing age not using birth control).” (opens the source at this quote in a new tab)

Treatment

Systemic treatment exposure target

Field	Quoted value
Sirolimus target serum concentration, ng/mL	“4-12”

Study outcomes

Rationale for using change in malformation volume on magnetic resonance imaging as the primary endpoint

Centralized blinded imaging as the objective measure

“The primary outcome was change in the volume of vascular malformations detected on magnetic resonance imaging scan (with centralized interpretation) per unit of time (ie, between the interventional period and the observational period).” (opens the source at this quote in a new tab)
“The MRI scans were centralized and interpreted by the same radiologist (B.M.), with blinding to participants’ names and protocol sequence time.” (opens the source at this quote in a new tab)

Statistical analysis description

Number of participants (Planned and analyzed)

Enrollment and main analysis population

Population	Quoted count
Enrolled	“63”
Main analysis	“59”

Description of analysis sets

Missing-data handling for the primary analysis

“multiple imputations” (opens the source at this quote in a new tab)

Results

Participant disposition

Treatment discontinuation because of adverse events

Outcome	Quoted count
Participants discontinuing treatment	“5”

Baseline characteristics

Baseline malformation categories

Category	Quoted count
Pure venous malformations	“22”
Lymphatic malformations	“18”
Combined malformations	“19”

Efficacy results

Primary volumetric comparison: overall population

“not overall significantly different” (opens the source at this quote in a new tab)

Primary volumetric comparison: by malformation subtype

“Variations in the volume of vascular malformations detected on magnetic resonance imaging scans associated with the duration period were not overall significantly different between the interventional period and the observational period (all vascular malformations: mean [SD] difference, –0.001 [0.007]; venous malformations: mean [SD] difference, 0.001 [0.004]; combined malformations: mean [SD] difference, 0.001 [0.009]).” (opens the source at this quote in a new tab)
“However, a significant decrease in volume was observed for children with pure lymphatic malformations (mean [SD] difference, –0.005 [0.005]).” (opens the source at this quote in a new tab)

Investigator conclusion on the best indication for systemic sirolimus

“Pure lymphatic malformations seem to be the best indication for sirolimus therapy because evidence of decreasing lymphatic malformation volume per unit of time, oozing, and bleeding and increasing quality of life was found.” (opens the source at this quote in a new tab)
“In combined malformations, sirolimus significantly reduced pain, oozing, and bleeding. Benefits seemed lower for pure venous malformations than for the 2 other subgroups, also based on symptoms.” (opens the source at this quote in a new tab)

Systemic sirolimus: absence of complete regression

“In no case was complete regression observed.” (opens the source at this quote in a new tab)

Health-related quality of life and patient-reported outcomes

Children with no quality-of-life impairment on the dermatology instrument

Assessment	Quoted proportion
Baseline	“27.1%”
Month 12	“54.2%”

Safety results

Safety during the sirolimus intervention period

Outcome	Quoted value
Participants with adverse events	“56”
Adverse events	“231”
Serious adverse events	“5”
Oral-ulcer proportion	“49.2%”

Study limitations

Summary

PERFORMUS included children aged 6 to 18 years and did not study QTORIN. Treatment was open label, although imaging was assessed by a blinded radiologist. The primary analysis did not show an overall effect on malformation-volume change; a reduction was reported for the lymphatic subgroup. Subgroup results should not be substituted for an overall positive primary result. The authors identify inability to control for time as a confounder in the primary analysis because imaging was available at only three time points.