ProgeriaPhase 2NCT00879034
A Study of Zoledronic Acid, Pravastatin, and Lonafarnib for Patients With Progeria
A Phase 2 study testing Lonafarnib, Zoledronic Acid and Pravastatin in people with Progeria and Hutchinson-Gilford Syndrome, run by Boston Children's Hospital at 1 site in United States.
Trial summary
This is an open label single arm feasibility trial. A combination of two oral agents (pravastatin and lonafarnib) and one intravenous (IV) agent (zoledronic acid) will be administered at doses and schedule currently applied in pediatrics. These agents all target farnesylation pathways at different points. Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Progeria, Hutchinson-Gilford Syndrome
- What is being tested?
- Lonafarnib, Zoledronic Acid and Pravastatin
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 5 participants
- Where
- 1 siteUnited States
- Study dates
- Mar 2009to Apr 2009
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Genetic Diagnosis: All patients must have confirmatory mutational analysis showing mutation in the lamin A gene.
- Patients must display clinical signs of progeria as per the clinical trial team.
- Patients must be willing and able to come to Boston for appropriate studies and examinations at initiation of study and at week 4 of study.
- Patient must have adequate organ and marrow function as defined by study parameters
Who cannot join
- Other than the drugs used in this protocol, other drugs targeted to treat Progeria are excluded. Drugs to treat symptoms of Progeria are permitted.
- Patients must not be taking medications that significantly affect the metabolism of lonafarnib at the time they start lonafarnib.
- Patient must have no uncontrolled infection.
- Subjects who have known or suspected hypersensitivity to any of the excipients included in the formulation should not be treated.
- Patients must not be pregnancy of breast-feeding. Female patients of childbearing potential must have negative serum or urine pregnancy test. Male and female patients of reproductive potential must agree to use a medically accepted form of birth control while on study and up to 10 weeks after treatment. It is permissible for female patients to take oral contraceptives or other hormonal methods while receiving treatment with lonafarnib.
Trial locations and contacts
1 site in 1 country.
United States1 site
Children's Hospital Boston
Boston, Massachusetts, 02115
About this study
Official title: A Phase II Pilot Study of Zoledronic Acid, Pravastatin, and Lonafarnib (SCH66336) for Patients With Hutchinson-Gilford Progeria Syndrome (HGPS) and Progeroid Laminopathies
This is an open label single arm feasibility trial. A combination of two oral agents (pravastatin and lonafarnib) and one intravenous (IV) agent (zoledronic acid) will be administered at doses and schedule currently applied in pediatrics. These agents all target farnesylation pathways at different points. Our goal is to inhibit farnesylation of abnormal lamin, the disease-causing protein in Hutchinson-Gilford Progeria Syndrome and progeroid laminopathies (henceforth "progeria"). The drugs will include the intravenous bisphosphonate zoledronic acid, oral HMG co-reductase inhibitor pravastatin and the oral farnesyltransferase inhibitor (FTI) lonafarnib (SCH 66336). Patients with genetically confirmed progeria will be eligible for this protocol. Treatment will be initiated for 4 weeks duration and may be extended depending on tolerability. This study will assess the feasibility of this treatment regimen in the first 4 weeks. If tolerated for 4 weeks, patients can be treated with this regimen for up to 6 months.
Read the detailed description
Progerias are rare "premature aging" diseases in which children die of severe atherosclerosis leading to strokes and heart attacks. It is a multisystem disease with objective clinical markers for disease progression. These include abnormalities in growth and body composition, bone mineral density, join function, endocrine function, alopecia, and vascular disease. There is currently no therapy proven effective for any of the progressive and deleterious aspects of this disorder.
Progeria is caused by a gene defect in the gene LMNA, coding for the nuclear protein lamin A. Lamin A is normally expressed by most differentiated cells, and requires posttranslational farnesylation to incorporate into the nuclear membrane. This trial proposes to use three agents (zoledronic acid, pravastatin, and lonafarnib) to inhibit farnesylation of abnormal lamin, the disease causing protein in Progeria. The primary objective of this study is to evaluate the feasibility of administering intravenous zoledronic acid, oral pravastatin and oral lonafarnib, to patients wtih Progeria for a minimum of 4 weeks.
- Conditions
- Progeria, Hutchinson-Gilford Syndrome
- Being tested
- Lonafarnib, Zoledronic Acid, Pravastatin
- Keywords
- Hutchinson-Gilford Progeria Syndrome, HGPS, Progeria, FTI, Farnesyltransferase Inhibitor, Lonafarnib, Zoledronic Acid, Pravastatin
- Medical subject headings
- Progeria
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LonafarnibDrug
Also called Sarasar, SCH 66336
Lonafarnib capsules are to be orally administered twice per day approximately every 12 hours. Lonafarnib dosing will begin at 150 mg/m2 by mouth twice daily. Dose levels are 150, 115, 90 and 70 mg/m2. Patients experiencing significant drug related grade 3 or 4 toxicity and not responding to therapy interruption or supportive care measures will be dose reduced by one dose level.
Zoledronic AcidDrug
Also called Zometa, Reclast
Zoledronic acid will be administered intravenously at week one of this treatment trial. Week one administration will consist of one infusion over a 30 minute period, 0.0125 mg/kg body weight.
PravastatinDrug
Also called Pravachol
Pravastatin will begin at 5 mg by mouth once daily for children weighing less than 10 kg, and 10 mg by mouth once daily for children weighing 10 kg or greater.
| Study group | Role | What they receive |
|---|---|---|
| Zoledronic Acid,Pravastatin,and Lonafarnib | Experimental | Lonafarnib;Zoledronic acid;Pravastatin Receives: Drug: Lonafarnib; Drug: Zoledronic Acid; Drug: Pravastatin |
What is being measured
The primary outcome is the main question the study is designed to answer.
The Primary Objective of This Study is to Evaluate the Feasibility of Administering Intravenous Zoledronic Acid, Oral Pravastatin and Oral Lonafarnib, to Patients With Progeria for a Minimum of 4 Weeks
Feasibility was assessed by determining the number of participants with adverse events occurring over the course of the 4 week study.
Measured: 4 weeks
Secondary outcomes (5)
To Describe Any Acute and Chronic Toxicities Associated With Treating Progeria Patients With the Combination of Zoledronic Acid, Pravastatin and Lonafarnib
Number of participants with acute and chronic toxicities associated with treating progeria patients with the combination of zoledronic acid, pravastatin and lonafarnib
Measured: 4 weeks
To Investigate Which Clinical and Laboratory Studies Are Needed to Monitor or Alter Therapy to Prevent Unacceptable Toxicity
The number of participants with abnormal CBC w/diff panel, LFTs, renal functions and lipid panels.
Measured: 4 weeks
To Assess the Pharmacokinetics of Lonafarnib in Patients With Progeria.
Measured: 4 weeks
To Assay for the Inhibition of HDJ-2 Farnesylation in Peripheral Blood Leukocytes (PBL)
Measured: 4 weeks
To Obtain Baseline Clinical and Laboratory Data so That Longer-term Measures of Efficacy Will be Achievable if Treatment Continues Beyond the 4-week Feasibility Study Period.
The number of participants from whom baseline clinical and Laboratory data was obtained.
Measured: 4 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Apr 2009 (estimated)
- Study startMar 2009
- Primary completionApr 2009
- Study completionApr 2009
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for ProgeriaStudies of the same condition, open and under way.
- More trials run by Boston Children's HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 5 participants (actual)
Sponsor and investigators
- Lead sponsor
- Boston Children's Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- Dana-Farber Cancer Institute, Brigham and Women's Hospital, Schering-Plough
- Responsible party
- Principal investigator, Monica E. Kleinman, Boston Children's Hospital
- Investigators
- Mark W Kieran, MD, PhD, Study chair, Dana-Farber Cancer Institute; Boston Children's Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00879034
- Sponsor's protocol ID
- 09-02-0074
- Other IDs
- P06087
- Status last verified
- Jun 2019
- First submitted
- 8 Apr 2009
- Last updated
- 13 Jun 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Gordon LB, Massaro J, D'Agostino RB Sr, Campbell SE, Brazier J, Brown WT, Kleinman ME, Kieran MW; Progeria Clinical Trials Collaborative. Impact of farnesylation inhibitors on survival in Hutchinson-Gilford progeria syndrome. Circulation. 2014 Jul 1;130(1):27-34. doi: 10.1161/CIRCULATIONAHA.113.008285. Epub 2014 May 2.
PubMed 24795390Gordon LB, Kleinman ME, Massaro J, D'Agostino RB Sr, Shappell H, Gerhard-Herman M, Smoot LB, Gordon CM, Cleveland RH, Nazarian A, Snyder BD, Ullrich NJ, Silvera VM, Liang MG, Quinn N, Miller DT, Huh SY, Dowton AA, Littlefield K, Greer MM, Kieran MW. Clinical Trial of the Protein Farnesylation Inhibitors Lonafarnib, Pravastatin, and Zoledronic Acid in Children With Hutchinson-Gilford Progeria Syndrome. Circulation. 2016 Jul 12;134(2):114-25. doi: 10.1161/CIRCULATIONAHA.116.022188.
PubMed 27400896Gordon LB, Norris W, Hamren S, Goodson R, LeClair J, Massaro J, Lyass A, D'Agostino RB Sr, Tuminelli K, Kieran MW, Kleinman ME. Plasma Progerin in Patients With Hutchinson-Gilford Progeria Syndrome: Immunoassay Development and Clinical Evaluation. Circulation. 2023 Jun 6;147(23):1734-1744. doi: 10.1161/CIRCULATIONAHA.122.060002. Epub 2023 Mar 15.
PubMed 36919608Fisher MJ, Avery RA, Allen JC, Ardern-Holmes SL, Bilaniuk LT, Ferner RE, Gutmann DH, Listernick R, Martin S, Ullrich NJ, Liu GT; REiNS International Collaboration. Functional outcome measures for NF1-associated optic pathway glioma clinical trials. Neurology. 2013 Nov 19;81(21 Suppl 1):S15-24. doi: 10.1212/01.wnl.0000435745.95155.b8.
PubMed 24249802
Study at a glance
From the registry record, last updated by the sponsor on 13 Jun 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase II Pilot Study of Zoledronic Acid, Pravastatin, and Lonafarnib (SCH66336) for Patients With Hutchinson-Gilford Progeria Syndrome (HGPS) and Progeroid Laminopathies
- ClinicalTrials.gov ID
- NCT00879034
- Acronym / sponsor ID
- 09-02-0074
- Conditions
- Progeria, Hutchinson-Gilford Syndrome
- Keywords
- Hutchinson-Gilford Progeria Syndrome, HGPS, Progeria, FTI, Farnesyltransferase Inhibitor, Lonafarnib, Zoledronic Acid, Pravastatin
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 5 participants (actual)
- Lead sponsor
- Boston Children's HospitalUniversity, hospital or other
- Collaborators
- Dana-Farber Cancer Institute, Brigham and Women's Hospital, Schering-Plough
- Study start
- Mar 2009
- Primary completion
- Apr 2009 (actual)
- Study completion
- Apr 2009 (actual)
- First posted
- 9 Apr 2009 (estimated)
- Results
- Posted 31 Jul 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is an open label single arm feasibility trial. A combination of two oral agents (pravastatin and lonafarnib) and one intravenous (IV) agent (zoledronic acid) will be administered at doses and schedule currently applied in pediatrics. These agents all target farnesylation pathways at different points. Our goal is to inhibit farnesylation of abnormal lamin, the disease-causing protein in Hutchinson-Gilford Progeria Syndrome and progeroid laminopathies (henceforth "progeria"). The drugs will include the intravenous bisphosphonate zoledronic acid, oral HMG co-reductase inhibitor pravastatin and the oral farnesyltransferase inhibitor (FTI) lonafarnib (SCH 66336). Patients with genetically confirmed progeria will be eligible for this protocol. Treatment will be initiated for 4 weeks duration and may be extended depending on tolerability. This study will assess the feasibility of this treatment regimen in the first 4 weeks. If tolerated for 4 weeks, patients can be treated with this regimen for up to 6 months.
Detailed description
Progerias are rare "premature aging" diseases in which children die of severe atherosclerosis leading to strokes and heart attacks. It is a multisystem disease with objective clinical markers for disease progression. These include abnormalities in growth and body composition, bone mineral density, join function, endocrine function, alopecia, and vascular disease. There is currently no therapy proven effective for any of the progressive and deleterious aspects of this disorder.
Progeria is caused by a gene defect in the gene LMNA, coding for the nuclear protein lamin A. Lamin A is normally expressed by most differentiated cells, and requires posttranslational farnesylation to incorporate into the nuclear membrane. This trial proposes to use three agents (zoledronic acid, pravastatin, and lonafarnib) to inhibit farnesylation of abnormal lamin, the disease causing protein in Progeria. The primary objective of this study is to evaluate the feasibility of administering intravenous zoledronic acid, oral pravastatin and oral lonafarnib, to patients wtih Progeria for a minimum of 4 weeks.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Zoledronic Acid,Pravastatin,and Lonafarnib | Experimental | Drug: Lonafarnib, Drug: Zoledronic Acid, Drug: PravastatinLonafarnib;Zoledronic acid;Pravastatin |
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (4 listed)
- Genetic Diagnosis: All patients must have confirmatory mutational analysis showing mutation in the lamin A gene.
- Patients must display clinical signs of progeria as per the clinical trial team.
- Patients must be willing and able to come to Boston for appropriate studies and examinations at initiation of study and at week 4 of study.
- Patient must have adequate organ and marrow function as defined by study parameters
Key exclusion criteria (5 listed)
- Other than the drugs used in this protocol, other drugs targeted to treat Progeria are excluded. Drugs to treat symptoms of Progeria are permitted.
- Patients must not be taking medications that significantly affect the metabolism of lonafarnib at the time they start lonafarnib.
- Patient must have no uncontrolled infection.
- Subjects who have known or suspected hypersensitivity to any of the excipients included in the formulation should not be treated.
- Patients must not be pregnancy of breast-feeding. Female patients of childbearing potential must have negative serum or urine pregnancy test. Male and female patients of reproductive potential must agree to use a medically accepted form of birth control while on study and up to 10 weeks after treatment. It is permissible for female patients to take oral contraceptives or other hormonal methods while receiving treatment with lonafarnib.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| LonafarnibAlso: Sarasar, SCH 66336Lonafarnib capsules are to be orally administered twice per day approximately every 12 hours. Lonafarnib dosing will begin at 150 mg/m2 by mouth twice daily. Dose levels are 150, 115, 90 and 70 mg/m2. Patients experiencing significant drug related grade 3 or 4 toxicity and not responding to therapy interruption or supportive care measures will be dose reduced by one dose level. | Drug | Zoledronic Acid,Pravastatin,and Lonafarnib |
| Zoledronic AcidAlso: Zometa, ReclastZoledronic acid will be administered intravenously at week one of this treatment trial. Week one administration will consist of one infusion over a 30 minute period, 0.0125 mg/kg body weight. | Drug | Zoledronic Acid,Pravastatin,and Lonafarnib |
| PravastatinAlso: PravacholPravastatin will begin at 5 mg by mouth once daily for children weighing less than 10 kg, and 10 mg by mouth once daily for children weighing 10 kg or greater. | Drug | Zoledronic Acid,Pravastatin,and Lonafarnib |
Primary outcome
The Primary Objective of This Study is to Evaluate the Feasibility of Administering Intravenous Zoledronic Acid, Oral Pravastatin and Oral Lonafarnib, to Patients With Progeria for a Minimum of 4 Weeks
Time frame: 4 weeks
Feasibility was assessed by determining the number of participants with adverse events occurring over the course of the 4 week study.
5 secondary outcomes
To Describe Any Acute and Chronic Toxicities Associated With Treating Progeria Patients With the Combination of Zoledronic Acid, Pravastatin and Lonafarnib
Time frame: 4 weeks
To Investigate Which Clinical and Laboratory Studies Are Needed to Monitor or Alter Therapy to Prevent Unacceptable Toxicity
Time frame: 4 weeks
To Assess the Pharmacokinetics of Lonafarnib in Patients With Progeria.
Time frame: 4 weeks
To Assay for the Inhibition of HDJ-2 Farnesylation in Peripheral Blood Leukocytes (PBL)
Time frame: 4 weeks
To Obtain Baseline Clinical and Laboratory Data so That Longer-term Measures of Efficacy Will be Achievable if Treatment Continues Beyond the 4-week Feasibility Study Period.
Time frame: 4 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Jun 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 24795390Gordon LB, Massaro J, D'Agostino RB Sr, Campbell SE, Brazier J, Brown WT, Kleinman ME, Kieran MW; Progeria Clinical Trials Collaborative. Impact of farnesylation inhibitors on survival in Hutchinson-Gilford progeria syndrome. Circulation. 2014 Jul 1;130(1):27-34. doi: 10.1161/CIRCULATIONAHA.113.008285. Epub 2014 May 2.
- Results publication: PubMed 27400896Gordon LB, Kleinman ME, Massaro J, D'Agostino RB Sr, Shappell H, Gerhard-Herman M, Smoot LB, Gordon CM, Cleveland RH, Nazarian A, Snyder BD, Ullrich NJ, Silvera VM, Liang MG, Quinn N, Miller DT, Huh SY, Dowton AA, Littlefield K, Greer MM, Kieran MW. Clinical Trial of the Protein Farnesylation Inhibitors Lonafarnib, Pravastatin, and Zoledronic Acid in Children With Hutchinson-Gilford Progeria Syndrome. Circulation. 2016 Jul 12;134(2):114-25. doi: 10.1161/CIRCULATIONAHA.116.022188.
- Derived from this study: PubMed 36919608Gordon LB, Norris W, Hamren S, Goodson R, LeClair J, Massaro J, Lyass A, D'Agostino RB Sr, Tuminelli K, Kieran MW, Kleinman ME. Plasma Progerin in Patients With Hutchinson-Gilford Progeria Syndrome: Immunoassay Development and Clinical Evaluation. Circulation. 2023 Jun 6;147(23):1734-1744. doi: 10.1161/CIRCULATIONAHA.122.060002. Epub 2023 Mar 15.
- Derived from this study: PubMed 24249802Fisher MJ, Avery RA, Allen JC, Ardern-Holmes SL, Bilaniuk LT, Ferner RE, Gutmann DH, Listernick R, Martin S, Ullrich NJ, Liu GT; REiNS International Collaboration. Functional outcome measures for NF1-associated optic pathway glioma clinical trials. Neurology. 2013 Nov 19;81(21 Suppl 1):S15-24. doi: 10.1212/01.wnl.0000435745.95155.b8.
- Progeria Research FoundationLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Mark W Kieran, MD, PhD study chair
Dana-Farber Cancer Institute; Boston Children's Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Lonafarnib, Zoledronic Acid and Pravastatin in people with Progeria and Hutchinson-Gilford Syndrome, run by Boston Children's Hospital at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 Jun 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 31 Jul 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The Primary Objective of This Study is to Evaluate the Feasibility of Administering Intravenous Zoledronic Acid, Oral Pravastatin and Oral Lonafarnib, to Patients With Progeria for a Minimum of 4 Weeks (time frame: 4 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00879034, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Jun 2019.