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Trial of Efficacy and Safety of Sirolimus in Tuberous Sclerosis and LAM (TESSTAL)

Primary Purpose

Tuberous Sclerosis, Lymphangioleiomyomatosis

Status
Unknown status
Phase
Phase 2
Locations
United Kingdom
Study Type
Interventional
Intervention
sirolimus
Sponsored by
Cardiff University
About
Eligibility
Locations
Outcomes
Full info

About this trial

This is an interventional treatment trial for Tuberous Sclerosis focused on measuring tuberous sclerosis, lymphangioleiomyomatosis, sirolimus, angiomyolioma, rapamycin, mTOR

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • If female, documentation of negative pregnancy test prior to enrolment.
  • Participants, including males, must use an effective form of contraception, whilst taking sirolimus and for twelve weeks after stopping the drug
  • One or more renal angiomyolipomata of at least two centimetres or greater in largest diameter
  • Adequate renal function :glomerular filtration rate > 40 ml/min
  • Clinically definite diagnosis of tuberous sclerosis (modified Gomez criteria) or sporadic LAM (biopsy-proven or compatible high resolution chest CT scan and respiratory function tests.)
  • Signed and dated informed consent

Exclusion Criteria:

  • History of non-compliance or inability to give informed consent
  • Significant haematological or hepatic abnormality (i.e. transaminase levels > 150 i.u./L serum albumin < 30 g/L, haematocrit< 30%, platelets < 100,000/ mm3, adjusted absolute neutrophil count < 1,500/mm3, total WBC < 3,000/ mm3)
  • Greater than 1 g proteinuria daily
  • Multiple bilateral AMLs, where individual lesions cannot be distinguished
  • Renal haemorrhage within preceding year
  • In those who have had a renal haemorrhage, known conservatively managed renal aneurysm(s) greater than 10mm
  • Patients who have had embolisation for AML(s) within the preceding 6 months
  • Patients who are unable to walk 100 metres on the flat
  • Continuous requirement for supplemental oxygen
  • Patients who have had or are being considered for organ transplant
  • Uncontrolled hyperlipidaemia
  • Intercurrent infection at initiation of Sirolimus
  • Surgery within last 2 months
  • Pregnant or lactating women
  • Use of an investigational drug within the last 30 days
  • Change in anti epileptic drug medication within the last 3 months
  • Likely to need vaccination e.g. for travel during the course of the trial (except for influenza vaccine in patients with LAM)
  • Current usage of strong inhibitors of CYP3AE ( such as ketoconazole, voriconazole, itraconazole, tilithromycin or clarithromycin) or strong inducers (such as rifampicin or rifabutin)

Sites / Locations

  • University Hospital of Wales
  • Royal Sussex County Hospital
  • City Hospital

Outcomes

Primary Outcome Measures

longest diameter of renal angiomyolipomas assessed by MRI scan, toxicity graded by National Cancer Institute's Common Terminology Criteria for Adverse Events v3.0
toxicity graded by National Cancer Institute's Common Terminology Criteria for Adverse Events

Secondary Outcome Measures

respiratory function tests (FEV1, FVC, DLCO), cognitive function (memory, executive skills)

Full Information

First Posted
June 21, 2007
Last Updated
April 29, 2008
Sponsor
Cardiff University
Collaborators
University of Nottingham, St Georges Hospital Medical School, Royal Sussex County Hospital, The Tuberous Sclerosis Association, Wyeth is now a wholly owned subsidiary of Pfizer
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1. Study Identification

Unique Protocol Identification Number
NCT00490789
Brief Title
Trial of Efficacy and Safety of Sirolimus in Tuberous Sclerosis and LAM
Acronym
TESSTAL
Official Title
A Trial of the Efficacy and Safety of Sirolimus(Rapamycin)Therapy for Renal Angiomyolipmoas in Patients With Tuberous Sclerosis Complex and Sporadic Lymphangioleiomyomatosis
Study Type
Interventional

2. Study Status

Record Verification Date
April 2008
Overall Recruitment Status
Unknown status
Study Start Date
October 2005 (undefined)
Primary Completion Date
September 2009 (Anticipated)
Study Completion Date
September 2009 (Anticipated)

3. Sponsor/Collaborators

Name of the Sponsor
Cardiff University
Collaborators
University of Nottingham, St Georges Hospital Medical School, Royal Sussex County Hospital, The Tuberous Sclerosis Association, Wyeth is now a wholly owned subsidiary of Pfizer

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to determine the safety and efficacy of the mTOR inhibitor sirolimus as a treatment for renal angiomyolipomas in patients with tyberous sclerosis complex or sporadic lymphangioleiomyomatosis.
Detailed Description
Inherited mutations of the TSC1 or TSC2 gene cause tuberous sclerosis while acquired (somatic) mutations of either gene are associated with sporadic lymphangioleiomyomatosis (LAM). Renal angiomyolipomas are a feature of both disorders. TSC1 and TSC2 regulate signalling through the mammalian target of rapamycin (mTOR) pathway. Inhibition of mTOR may result in a decrease in size of TSC 1/2 assciated lesions. We are treating patients with tuberous sclerosis or sporadic LAM with the mTOR inhibitor rapamycin in a non-randomised, open label pilot study of safety and efficacy. Change in size of renal angiomyolipomas is the primary end point

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Tuberous Sclerosis, Lymphangioleiomyomatosis
Keywords
tuberous sclerosis, lymphangioleiomyomatosis, sirolimus, angiomyolioma, rapamycin, mTOR

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
14 (Anticipated)

8. Arms, Groups, and Interventions

Intervention Type
Drug
Intervention Name(s)
sirolimus
Other Intervention Name(s)
rapamune, rapamycin
Intervention Description
daily oral sirolimus with dosage individualised by trough blood levels
Primary Outcome Measure Information:
Title
longest diameter of renal angiomyolipomas assessed by MRI scan, toxicity graded by National Cancer Institute's Common Terminology Criteria for Adverse Events v3.0
Time Frame
assessments at baseline and 2,6,12 and 24 months
Title
toxicity graded by National Cancer Institute's Common Terminology Criteria for Adverse Events
Time Frame
throughout study
Secondary Outcome Measure Information:
Title
respiratory function tests (FEV1, FVC, DLCO), cognitive function (memory, executive skills)
Time Frame
2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: If female, documentation of negative pregnancy test prior to enrolment. Participants, including males, must use an effective form of contraception, whilst taking sirolimus and for twelve weeks after stopping the drug One or more renal angiomyolipomata of at least two centimetres or greater in largest diameter Adequate renal function :glomerular filtration rate > 40 ml/min Clinically definite diagnosis of tuberous sclerosis (modified Gomez criteria) or sporadic LAM (biopsy-proven or compatible high resolution chest CT scan and respiratory function tests.) Signed and dated informed consent Exclusion Criteria: History of non-compliance or inability to give informed consent Significant haematological or hepatic abnormality (i.e. transaminase levels > 150 i.u./L serum albumin < 30 g/L, haematocrit< 30%, platelets < 100,000/ mm3, adjusted absolute neutrophil count < 1,500/mm3, total WBC < 3,000/ mm3) Greater than 1 g proteinuria daily Multiple bilateral AMLs, where individual lesions cannot be distinguished Renal haemorrhage within preceding year In those who have had a renal haemorrhage, known conservatively managed renal aneurysm(s) greater than 10mm Patients who have had embolisation for AML(s) within the preceding 6 months Patients who are unable to walk 100 metres on the flat Continuous requirement for supplemental oxygen Patients who have had or are being considered for organ transplant Uncontrolled hyperlipidaemia Intercurrent infection at initiation of Sirolimus Surgery within last 2 months Pregnant or lactating women Use of an investigational drug within the last 30 days Change in anti epileptic drug medication within the last 3 months Likely to need vaccination e.g. for travel during the course of the trial (except for influenza vaccine in patients with LAM) Current usage of strong inhibitors of CYP3AE ( such as ketoconazole, voriconazole, itraconazole, tilithromycin or clarithromycin) or strong inducers (such as rifampicin or rifabutin)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Julian R Sampson, DM
Organizational Affiliation
Cardiff Univeristy
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Hospital of Wales
City
Cardiff
State/Province
Wales
ZIP/Postal Code
CF14 4XN
Country
United Kingdom
Facility Name
Royal Sussex County Hospital
City
Brighton
ZIP/Postal Code
BN2 5BE
Country
United Kingdom
Facility Name
City Hospital
City
Nottingham
ZIP/Postal Code
NG5 1PB
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
21525172
Citation
Davies DM, de Vries PJ, Johnson SR, McCartney DL, Cox JA, Serra AL, Watson PC, Howe CJ, Doyle T, Pointon K, Cross JJ, Tattersfield AE, Kingswood JC, Sampson JR. Sirolimus therapy for angiomyolipoma in tuberous sclerosis and sporadic lymphangioleiomyomatosis: a phase 2 trial. Clin Cancer Res. 2011 Jun 15;17(12):4071-81. doi: 10.1158/1078-0432.CCR-11-0445. Epub 2011 Apr 27.
Results Reference
derived

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Trial of Efficacy and Safety of Sirolimus in Tuberous Sclerosis and LAM

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