NCT00920647

A Safety and Dose Ranging Study of Idursulfase (Intrathecal) Administration Via an Intrathecal Drug Delivery Device in Pediatric Patients With Hunter Syndrome Who Have Central Nervous System Involvement and Are Receiving Treatment With Elaprase®

Completed Phase 1, PHASE2 Results posted Last updated 28 June 2021

What this trial tests

Phase 1, PHASE2 trial testing Control in Hunter Syndrome in 16 participants. Completed in 29 October 2012.

Timeline

18 November 2009

Primary endpoint
29 October 2012

29 October 2012

Quick facts

Lead sponsor	Shire
Phase	Phase 1, PHASE2
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	16
Start date	18 November 2009
Primary completion	29 October 2012
Estimated completion	29 October 2012
Sites	3 locations across United Kingdom, United States

Drugs / interventions tested

• Control
• Idursulfase IT (1 mg) — full drug profile →
• Idursulfase IT (10 mg) — full drug profile →
• Idursulfase IT (30 mg) — full drug profile →

Conditions studied

• Hunter Syndrome — all drugs for Hunter Syndrome →

Sponsor

Shire — full company profile →

Who can join

Adults 3 to 18, male only, with Hunter Syndrome. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Number of Serious Adverse Event (SAE) Primary · 6 months

Group	Value	95% CI
Control	0
Idursulfase IT (1 mg)	8
Idursulfase IT (10 mg)	3
Idursulfase IT (30 mg)	3

Change From Baseline in CSF Glycosaminoglycans [GAGs] at Week 27 Secondary · Baseline to Week 27

Percent Change from Baseline to Week 27

Group	Value	95% CI
Control	6.68	± 6.301
Idursulfase IT (1 mg)	-79.03	± 5.167
Idursulfase IT (10 mg)	-90.30	± 2.917
Idursulfase IT (30 mg)	-88.87	± 1.035

Level of Idursulfase in the CSF Compartment Resulting From Monthly Idursulfase IT Administrations Secondary · Week 27 (end of study)

Samples collected from patients treated at doses of 1 mg and 30 mg, as well as the control group, were below the lower limit of detection of the bioanalytical method (3.13 ng/mL)

Group	Value	95% CI
Control	NA	± NA
Idursulfase IT (1mg)	NA	± NA
Idursulfase IT (10 mg)	6.74	± 12.02
Idursulfase IT (30 mg)	NA	± NA

Number of Treatment Emergent Adverse Event (AE) Primary · Baseline to week 23

ITT patient population

Group	Value	95% CI
Control	23
Idursulfase IT (1 mg)	147
Idursulfase IT (10 mg)	116
Idursulfase IT (30 mg)	104

Safety Changes in Cerebrospinal Fluid (CSF)- White Blood Cells (WBC) Primary · 6 months

White blood cell count in CSF was monitored throughout the study as a way of assessing any potential inflammation of the meninges induced by idursulfase-IT.

Group	Value	95% CI
Control	0
Idursulfase IT (1 mg)	3
Idursulfase IT (10 mg)	1
Idursulfase IT (30 mg)	2

Safety: Development of Anti-idursulfase Antibodies (CSF) Primary · 6 months

Reflects development of anti-idursulfase antibodies post baseline.

Group	Value	95% CI
Control	0
Idursulfase IT (1 mg)	0
Idursulfase IT (10 mg)	0
Idursulfase IT (30 mg)	0

Safety: Development of Anti-idursulfase Antibodies (Serum) Primary · 6 months

Group	Value	95% CI
Control	1
Idursulfase IT (1 mg)	0
Idursulfase IT (10 mg)	0
Idursulfase IT (30 mg)	0

Clinically Significant ECG Findings at Any Time During the Study. Primary · 6 months

Electrocardiogram (ECG) parameters included: heart rate, sinus rhythm, atrial/ventricular hypertrophy, PR, QRS, QT and QTc intervals.

Group	Value	95% CI
Control	0
Idursulfase IT (1 mg)	0
Idursulfase IT (10 mg)	1
Idursulfase IT (30 mg)	0

Concentration of Idursulfase in Serum After Single Administration (Week 3) in Conjunction With Elaprase Secondary · Weeks 3

Values below lower limit of quantitation (LLOQ) are listed as 0.

Group	Value	95% CI
Idursulfase IT (10 mg)	140022	± 45479
Idursulfase IT (30 mg)	228840	± 37909

Concentration of Idursulfase in Serum After Repeated Doses of Intrathecal Idursulfase-IT Given in Conjunction With Elaprase Secondary · Weeks 23

Group	Value	95% CI
Idursulfase IT (1 mg)	31481
Idursulfase IT (10 mg)	150544	± 43871
Idursulfase IT (30 mg)	174247	± 49795

% Change From Baseline in Urinary GAG Secondary · Baseline to Week 27

Group	Value	95% CI
Control	-7.67	± 20.820
Idursulfase IT (1 mg)	37.83	± 27.971
Idursulfase IT (10 mg)	-22.38	± 4.840
Idursulfase IT (30 mg)	29.70	± 13.700

Adverse events — posted to ClinicalTrials.gov

Time frame: Time of informed consent until 30 days after the patients end of study visit.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Control

Serious: 0/4 (0%)

Deaths: —

Idursulfase IT (1 mg)

Serious: 3/4 (75%)

Deaths: —

Idursulfase IT (10 mg)

Serious: 2/4 (50%)

Deaths: —

Idursulfase IT (30 mg)

Serious: 2/4 (50%)

Deaths: —

Serious adverse events (10 terms)

Reaction	System	Control	Idursulfase IT (1 mg)	Idursulfase IT (10 mg)	Idursulfase IT (30 mg)
Implant site infection	Infections and infestations	—	—	—	—
Dehydration	Metabolism and nutrition disorders	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—
Device dislocation	Injury, poisoning and procedural complications	—	—	—	—
Complication of device insertion	Injury, poisoning and procedural complications	—	—	—	—
Device breakage	Injury, poisoning and procedural complications	—	—	—	—
Device connection issue	Injury, poisoning and procedural complications	—	—	—	—
Device failure	Injury, poisoning and procedural complications	—	—	—	—
Device malfunction	Injury, poisoning and procedural complications	—	—	—	—
Wound dehiscence	Injury, poisoning and procedural complications	—	—	—	—

Other adverse events (159 terms — click to expand)

Reaction	System	Control	Idursulfase IT (1 mg)	Idursulfase IT (10 mg)	Idursulfase IT (30 mg)
Upper respiratory tract	Infections and infestations	—	—	—	—
Procedural Pain	Injury, poisoning and procedural complications	—	—	—	—
Headache	Nervous system disorders	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—
Blood Pressure Diastolic Decreased	Investigations	—	—	—	—
Implant site infection	Infections and infestations	—	—	—	—
Otitis Media	Infections and infestations	—	—	—	—
Clonus	Nervous system disorders	—	—	—	—
Otorrhoea	Ear and labyrinth disorders	—	—	—	—
Blood Pressure Fluctuation	Vascular disorders	—	—	—	—
Flushing	Vascular disorders	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—
Rash	Skin and subcutaneous tissue disorders	—	—	—	—
Pyrexia	General disorders	—	—	—	—
Blood Pressure Systolic Increased	Investigations	—	—	—	—
Blood Pressure Systolic Decreased	Investigations	—	—	—	—
Heart Rate Decreased	Investigations	—	—	—	—
Blood Pressure Decreased	Investigations	—	—	—	—
Protein Total Decreased	Investigations	—	—	—	—
Cardiac Murmur	Investigations	—	—	—	—
CSF Glucose Decreased	Investigations	—	—	—	—
Contusion	Injury, poisoning and procedural complications	—	—	—	—
Procedural Site Reaction	Injury, poisoning and procedural complications	—	—	—	—
Anorectal Infection	Infections and infestations	—	—	—	—
Ear Infection	Infections and infestations	—	—	—	—
Eye Infection	Infections and infestations	—	—	—	—
Gastrointestinal Infection	Infections and infestations	—	—	—	—
Herpes Zoster	Infections and infestations	—	—	—	—
Rhinitis	Infections and infestations	—	—	—	—
Urinary Tract Infection	Infections and infestations	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—
Eosinophilia	Blood and lymphatic system disorders	—	—	—	—
Lymphadenopathy	Blood and lymphatic system disorders	—	—	—	—
Microcystosis	Blood and lymphatic system disorders	—	—	—	—
Seasonal Allergy	Immune system disorders	—	—	—	—
Decreased Appetite	Metabolism and nutrition disorders	—	—	—	—
Dehydration	Metabolism and nutrition disorders	—	—	—	—
Pica	Metabolism and nutrition disorders	—	—	—	—
Abnormal Behaviour	Psychiatric disorders	—	—	—	—

Most-reported serious reactions: Implant site infection, Dehydration, Vomiting, Device dislocation, Complication of device insertion, Device breakage, Device connection issue, Device failure.

Data from ClinicalTrials.gov NCT00920647 adverse events section.

Sponsor's own description

Elaprase (idursulfase), a large molecular protein, is not expected to cross the blood brain barrier at therapeutic levels when administered intravenously. A new formulation of idursulfase, idursulfase-IT, that differs from that of the intravenous (IV) formulation, Elaprase, has been developed to be suitable for delivery into the cerebrospinal fluid (CSF) via intrathecal administration.

This Phase I/II study is designed to obtain necessary safety and exposure data, as well as secondary and exploratory outcome measures, to be interpreted and used in the design of subsequent clinical trials.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies.
   Mitragotri S, Burke PA, Langer R. · · 2014 · cited 1088× · PMID 25103255 · DOI 10.1038/nrd4363
2. Mucopolysaccharidosis Type II: One Hundred Years of Research, Diagnosis, and Treatment.
   D'Avanzo F, Rigon L, Zanetti A, Tomanin R. · · 2020 · cited 113× · PMID 32070051 · DOI 10.3390/ijms21041258
3. Mucopolysaccharidosis type III (Sanfilippo syndrome) and misdiagnosis of idiopathic developmental delay, attention deficit/hyperactivity disorder or autism spectrum disorder.
   Wijburg FA, Węgrzyn G, Burton BK, Tylki-Szymańska A. · · 2013 · cited 98× · PMID 23336697 · DOI 10.1111/apa.12169
4. Development of idursulfase therapy for mucopolysaccharidosis type II (Hunter syndrome): the past, the present and the future.
   Whiteman DA, Kimura A. · · 2017 · cited 60× · PMID 28860717 · DOI 10.2147/dddt.s139601
5. CNS-directed gene therapy for the treatment of neurologic and somatic mucopolysaccharidosis type II (Hunter syndrome).
   Motas S, Haurigot V, Garcia M, Marcó S, et al · · 2016 · cited 53× · PMID 27699273 · DOI 10.1172/jci.insight.86696
6. Differences in MPS I and MPS II Disease Manifestations.
   Hampe CS, Yund BD, Orchard PJ, Lund TC, et al · · 2021 · cited 40× · PMID 34360653 · DOI 10.3390/ijms22157888
7. Presentation and Treatments for Mucopolysaccharidosis Type II (MPS II; Hunter Syndrome).
   Stapleton M, Kubaski F, Mason RW, Yabe H, et al · · 2017 · cited 39× · PMID 29158997 · DOI 10.1080/21678707.2017.1296761
8. Intravenous high-dose enzyme replacement therapy with recombinant palmitoyl-protein thioesterase reduces visceral lysosomal storage and modestly prolongs survival in a preclinical mouse model of infantile neuronal ceroid lipofuscinosis.
   Hu J, Lu JY, Wong AM, Hynan LS, et al · · 2012 · cited 36× · PMID 22704978 · DOI 10.1016/j.ymgme.2012.05.009