Efficacy of Thalidomide in the Treatment of Hereditary Hemorrhagic Telangiectasia

NCT01485224 | Completed Phase 2 DMC

• 1 other identifier: EudratCT 2011-004096-36
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 1

Brief Summary

Hereditary hemorrhagic telangiectasia (HHT) (OMIM 187300 and 600376), also known as Rendu-Osler-Weber syndrome, is an autosomal dominant disease and has a prevalence between 1:5000 and 1:8000 in different populations. Clinically, the occurrence of mucocutaneous and gastrointestinal telangiectasias and of systemic arteriovenous malformations is commonly observed. Recurrent and severe epistaxis, due to the presence of telangiectasias in nasal mucosa, is the most common presentation of HHT, frequently leading to severe anemia requiring intravenous iron and blood transfusions. Although not life threatening, severe epistaxis has a great impact on quality of life in HHT patients and it represents the most important impediment in daily activities, that poses therapeutic challenge. Recently, angiogenesis has been implicated in the pathogenesis of HHT. Circulating concentrations of both TGF-beta and vascular endothelial growth factor (VEGF) are significantly elevated and therefore, anti-angiogenic substances may be effective in the treatment of vascular malformations in this disease. Thalidomide functions as a potent immunosuppressive and antiangiogenic agent. The aim of this study is to assess the clinical effects of thalidomide therapy on the severity of epistaxis in subjects with HHT who are refractory to standard therapies.

Conditions

Hereditary Hemorrhagic Telangiectasia; Epistaxis

Keywords

Hereditary hemorrhagic telangiectasia; Epistaxis; Thalidomide

Outcome Measures

Primary Outcomes (1)

• Percentage of patients showing a decrease in the frequency, intensity and duration of epistaxis and in the blood transfusion requirement.

  Cessation of nose bleeding will be defined as complete response. Reduction in the severity of any bleeding parameter less than complete response will represent partial response.

  up to 24 weeks

Secondary Outcomes (6)

• Size and number of telangiectasias evaluated by endoscopy of nasal mucosa (recording images of the size and localization of telangiectasias)

  up to 24 weeks

• Minimum dose of the drug that reduces bleeding

  up to 24 weeks

• Time to response

  up to 24 weeks

• Time to relapse after the end of treatment

  up to 24 weeks after the end of treatment

• Number of adverse events

  up to 1 year

Study Arms (1)

Thalidomide

EXPERIMENTAL

Single arm study: Eligible patients will receive thalidomide at a starting dose of 50 mg/day by mouth at bedtime for 4 weeks. In the event of unsatisfactory/no response, thalidomide dosage will be progressively increased by 50 mg/day every 4 weeks until complete or partial response, to a maximum dose of 200 mg/day. Treatment will be continued until one of the following criteria is met: * 8 additional weeks of treatment after the achievement of complete response * 16 additional weeks of treatment after the achievement of partial response * 24 weeks of treatment completed without response * unacceptable toxicity. Then, patients will be followed off of thalidomide for 24 weeks.

Drug: Thalidomide

Interventions

Thalidomide DRUG

Eligible patients will receive thalidomide at a starting dose of 50 mg/day by mouth at bedtime for 4 weeks. In the event of unsatisfactory/no response, thalidomide dosage will be progressively increased by 50 mg/day every 4 weeks until complete or partial response, to a maximum dose of 200 mg/day. Treatment will be continued until one of the following criteria is met: * 8 additional weeks of treatment after the achievement of complete response * 16 additional weeks of treatment after the achievement of partial response * 24 weeks of treatment completed without response * unacceptable toxicity. Then, patients will be followed off of thalidomide for 24 weeks.

Also known as: Thalidomide Celgene

Thalidomide

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of HHT, according to the diagnostic criteria world-wide recognized (Curacao criteria), with severe recurrent epistaxis (grade 2-3 according to the criteria proposed by Pagella et al., i.e. at least one episode of overt bleeding/week requiring at least one blood transfusion during the last three months), and refractory to mini-invasive surgical procedures, i.e. argon plasma coagulation. For these patients, there is no effective treatment option currently available
• Age \> 18 years
• Ability of signing written informed consent
• Women of childbearing potential:
• declared intention not to start a pregnancy throughout the study and for four weeks following the date of the last dose of thalidomide (safe contraception, see Celgene guidelines, "Programma di Prevenzione della Gravidanza")
• negative serum pregnancy test obtained within 48 hours prior to the first dose of Thalidomide
• declared intention to undergo pregnancy tests periodically while on the study medication
• Males with female partner of childbearing potential:
• declared intention not to father throughout the study and for one week following the date of the last dose of thalidomide (safe contraception, see Celgene guidelines, "Programma di Prevenzione della Gravidanza")
• Estimated life expectancy must be greater than 10 months

You may not qualify if:

• Pregnant or lactating women, or potentially fertile (both males and females) who have not agreed to avoid pregnancy during the trial period and for four weeks (females) or one week (males) following the date of the last dose of thalidomide
• Neurological diseases
• Psychiatric illness that would prevent granting of informed consent
• Active cardiovascular disease
• High risk for thromboembolic events (comorbidities, such as diabetes or uncontrolled infections, malignancy, immobility, prior history of thromboembolic events, use of erythropoietic agents or other agents such as hormone replacement therapy, central venous catheter, anti-cardiolipin, or anti-beta2 glycoprotein antibodies)
• Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption since thalidomide capsules contain lactose

Sponsors & Collaborators

• Fondazione IRCCS Policlinico San Matteo di Pavia: lead

Study Sites (1)

Clinica Medica 3, Fondazione IRCCS Policlinico S. Matteo

Pavia, 27100, Italy

Location

Related Publications (2)

• Lebrin F, Srun S, Raymond K, Martin S, van den Brink S, Freitas C, Breant C, Mathivet T, Larrivee B, Thomas JL, Arthur HM, Westermann CJ, Disch F, Mager JJ, Snijder RJ, Eichmann A, Mummery CL. Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia. Nat Med. 2010 Apr;16(4):420-8. doi: 10.1038/nm.2131. Epub 2010 Apr 4.

  PMID: 20364125 BACKGROUND

• Invernizzi R, Quaglia F, Klersy C, Pagella F, Ornati F, Chu F, Matti E, Spinozzi G, Plumitallo S, Grignani P, Olivieri C, Bastia R, Bellistri F, Danesino C, Benazzo M, Balduini CL. Efficacy and safety of thalidomide for the treatment of severe recurrent epistaxis in hereditary haemorrhagic telangiectasia: results of a non-randomised, single-centre, phase 2 study. Lancet Haematol. 2015 Nov;2(11):e465-73. doi: 10.1016/S2352-3026(15)00195-7. Epub 2015 Oct 27.

  PMID: 26686256 DERIVED

MeSH Terms

Conditions

Telangiectasia, Hereditary Hemorrhagic; Epistaxis

Interventions

Thalidomide

Condition Hierarchy (Ancestors)

Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Telangiectasis; Hemorrhagic Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Vascular Malformations; Cardiovascular Abnormalities; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nose Diseases; Respiratory Tract Diseases; Otorhinolaryngologic Diseases; Hemorrhage; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Signs and Symptoms, Respiratory; Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidones; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Carlo Balduini, M.D.

  Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Internal Medicine

Study Record Dates

• First Submitted: November 28, 2011
• First Posted: December 5, 2011
• Study Start: November 1, 2011
• Primary Completion: October 1, 2014
• Study Completion: October 11, 2016
• Last Updated: August 29, 2017

Record last verified: 2017-08

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)