Combination Regimen With Sodium Valproate for Severe Hemophilia: a Single-arm, Phase 1, Pilot Trial.

NCT05920512 | Recruiting Phase 1

• 1 other identifier: S2023-261-02
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this clinical trial is to determine the clinical efficacy and toxic effects of sodium valproate, sirolimus and calcitriol in the treatment of severe haemophilia in participants with severe haemophilia . The main questions it aims to answer are the possibility of adding a combination regimen to primary treatment for severe haemophilia . Patients will receive oral sodium valproate extended-release tablets 0.5g/day, sirolimus tablets 1mg/day and osteopontin capsules 0.25μg/day.

Conditions

Hemophilia

Keywords

Hemophilia; Sodium valproate; Sirolimus; Calcitriol

Outcome Measures

Primary Outcomes (2)

• FVIII/FIX Activity

  FVIII/FIX activity in peripheral blood

  through study completion, an average of 1 month

• FVIII/ FIX inhibitor concentration

  FVIII/ FIX inhibitor concentration in peripheral blood

  through study completion, an average of 1 month

Secondary Outcomes (2)

• frequency of joint bleeding

  through study completion, an average of 1 month

• Activated Partial Thromboplastin Time

  through study completion, an average of 1 month

Study Arms (1)

Patients with severe haemophilia

EXPERIMENTAL

confirmed as hemophilia and FVIII/FIX activity \<1%

Drug: Sodium valproate extended-release tablets

Interventions

Sodium valproate extended-release tablets DRUG

Sodium valproate extended-release tablets 0.5g/day; sirolimus tablets 1mg/day and calcitriol capsules 0.25μg/day.

Also known as: sirolimus tablets, calcitriol capsules

Patients with severe haemophilia

Eligibility Criteria

• Age: 14 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with clinically confirmed severe haemophilia;
• Expected survival of ≥ 24 weeks with an ECOG score of 0-2;
• Not having participated in another clinical trial within four weeks;
• Informed consent signed by the patient or an immediate family member.

You may not qualify if:

• Those with other types of blood disorders diagnosed at the morphological or molecular level of the bone marrow;
• Significantly abnormal cardiopulmonary function;
• Hepatic or renal insufficiency;
• Pregnancy or lactation, or inability to use contraception during the trial and for three months before the test and one year after administration
• Persons who are allergic to the drugs likely to be used or where there is a contraindication to their use;
• Those with severe uncontrollable infectious diseases or uncontrolled hypertension, malignancy, etc.;
• Inability to cooperate with a regular follow-up due to psychological, social, family and other geographical circumstances;
• Any other condition that, in the investigator's opinion, makes participation in this trial inappropriate.

Sponsors & Collaborators

• Xue-chun Lu: lead

Study Sites (1)

PLA General Hospital

Beijing, 100853, China

RECRUITING

Related Publications (18)

• Leissinger C. Another Victory for Patients with Hemophilia. N Engl J Med. 2023 Jan 26;388(4):372-373. doi: 10.1056/NEJMe2216176. No abstract available.

  PMID: 36720139 BACKGROUND

• Den Uijl IE, Mauser Bunschoten EP, Roosendaal G, Schutgens RE, Biesma DH, Grobbee DE, Fischer K. Clinical severity of haemophilia A: does the classification of the 1950s still stand? Haemophilia. 2011 Nov;17(6):849-53. doi: 10.1111/j.1365-2516.2011.02539.x. Epub 2011 May 5.

  PMID: 21545376 BACKGROUND

• DiMichele D. Inhibitor development in haemophilia B: an orphan disease in need of attention. Br J Haematol. 2007 Aug;138(3):305-15. doi: 10.1111/j.1365-2141.2007.06657.x.

  PMID: 17614818 BACKGROUND

• Jankowska KI, McGill J, Pezeshkpoor B, Oldenburg J, Atreya CD, Sauna ZE. Clinical manifestation of hemophilia A in the absence of mutations in the F8 gene that encodes FVIII: role of microRNAs. Transfusion. 2020 Feb;60(2):401-413. doi: 10.1111/trf.15605. Epub 2019 Nov 29.

  PMID: 31785023 BACKGROUND

• Marchesini E, Morfini M, Valentino L. Recent Advances in the Treatment of Hemophilia: A Review. Biologics. 2021 Jun 15;15:221-235. doi: 10.2147/BTT.S252580. eCollection 2021.

  PMID: 34163136 BACKGROUND

• Lu P, Yan M, He L, Li J, Ji Y, Ji J. Crosstalk between Epigenetic Modulations in Valproic Acid Deactivated Hepatic Stellate Cells: An Integrated Protein and miRNA Profiling Study. Int J Biol Sci. 2019 Jan 6;15(1):93-104. doi: 10.7150/ijbs.28642. eCollection 2019.

  PMID: 30662350 BACKGROUND

• Moghimi B, Sack BK, Nayak S, Markusic DM, Mah CS, Herzog RW. Induction of tolerance to factor VIII by transient co-administration with rapamycin. J Thromb Haemost. 2011 Aug;9(8):1524-33. doi: 10.1111/j.1538-7836.2011.04351.x.

  PMID: 21585650 BACKGROUND

• Johannessen SI, Landmark CJ. Antiepileptic drug interactions - principles and clinical implications. Curr Neuropharmacol. 2010 Sep;8(3):254-67. doi: 10.2174/157015910792246254.

  PMID: 21358975 BACKGROUND

• Mintzer S, Mattson RT. Should enzyme-inducing antiepileptic drugs be considered first-line agents? Epilepsia. 2009 Sep;50 Suppl 8:42-50. doi: 10.1111/j.1528-1167.2009.02235.x.

  PMID: 19702733 BACKGROUND

• Verrotti A, Coppola G, Parisi P, Mohn A, Chiarelli F. Bone and calcium metabolism and antiepileptic drugs. Clin Neurol Neurosurg. 2010 Jan;112(1):1-10. doi: 10.1016/j.clineuro.2009.10.011. Epub 2009 Nov 12.

  PMID: 19913352 BACKGROUND

• Stanford S, Pink R, Creagh D, Clark A, Lowe G, Curry N, Pasi J, Perry D, Fong S, Hayes G, Chandrakumaran K, Rangarajan S. Adenovirus-associated antibodies in UK cohort of hemophilia patients: A seroprevalence study of the presence of adenovirus-associated virus vector-serotypes AAV5 and AAV8 neutralizing activity and antibodies in patients with hemophilia A. Res Pract Thromb Haemost. 2019 Jan 25;3(2):261-267. doi: 10.1002/rth2.12177. eCollection 2019 Apr.

  PMID: 31011710 RESULT

• Nathwani AC, Gray JT, McIntosh J, Ng CY, Zhou J, Spence Y, Cochrane M, Gray E, Tuddenham EG, Davidoff AM. Safe and efficient transduction of the liver after peripheral vein infusion of self-complementary AAV vector results in stable therapeutic expression of human FIX in nonhuman primates. Blood. 2007 Feb 15;109(4):1414-21. doi: 10.1182/blood-2006-03-010181. Epub 2006 Nov 7.

  PMID: 17090654 RESULT

• Mingozzi F, Anguela XM, Pavani G, Chen Y, Davidson RJ, Hui DJ, Yazicioglu M, Elkouby L, Hinderer CJ, Faella A, Howard C, Tai A, Podsakoff GM, Zhou S, Basner-Tschakarjan E, Wright JF, High KA. Overcoming preexisting humoral immunity to AAV using capsid decoys. Sci Transl Med. 2013 Jul 17;5(194):194ra92. doi: 10.1126/scitranslmed.3005795.

  PMID: 23863832 RESULT

• Puetz J, Soucie JM, Kempton CL, Monahan PE; Hemophilia Treatment Center Network (HTCN) Investigators. Prevalent inhibitors in haemophilia B subjects enrolled in the Universal Data Collection database. Haemophilia. 2014 Jan;20(1):25-31. doi: 10.1111/hae.12229. Epub 2013 Jul 16.

  PMID: 23855900 RESULT

• Rocca A, Minucci S, Tosti G, Croci D, Contegno F, Ballarini M, Nole F, Munzone E, Salmaggi A, Goldhirsch A, Pelicci PG, Testori A. A phase I-II study of the histone deacetylase inhibitor valproic acid plus chemoimmunotherapy in patients with advanced melanoma. Br J Cancer. 2009 Jan 13;100(1):28-36. doi: 10.1038/sj.bjc.6604817.

  PMID: 19127265 RESULT

• Nilubol N, Merkel R, Yang L, Patel D, Reynolds JC, Sadowski SM, Neychev V, Kebebew E. A phase II trial of valproic acid in patients with advanced, radioiodine-resistant thyroid cancers of follicular cell origin. Clin Endocrinol (Oxf). 2017 Jan;86(1):128-133. doi: 10.1111/cen.13154. Epub 2016 Sep 8.

  PMID: 27392538 RESULT

• Nathwani AC, Tuddenham EG, Rangarajan S, Rosales C, McIntosh J, Linch DC, Chowdary P, Riddell A, Pie AJ, Harrington C, O'Beirne J, Smith K, Pasi J, Glader B, Rustagi P, Ng CY, Kay MA, Zhou J, Spence Y, Morton CL, Allay J, Coleman J, Sleep S, Cunningham JM, Srivastava D, Basner-Tschakarjan E, Mingozzi F, High KA, Gray JT, Reiss UM, Nienhuis AW, Davidoff AM. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med. 2011 Dec 22;365(25):2357-65. doi: 10.1056/NEJMoa1108046. Epub 2011 Dec 10.

  PMID: 22149959 RESULT

• Rangarajan S, Walsh L, Lester W, Perry D, Madan B, Laffan M, Yu H, Vettermann C, Pierce GF, Wong WY, Pasi KJ. AAV5-Factor VIII Gene Transfer in Severe Hemophilia A. N Engl J Med. 2017 Dec 28;377(26):2519-2530. doi: 10.1056/NEJMoa1708483. Epub 2017 Dec 9.

  PMID: 29224506 RESULT

MeSH Terms

Conditions

Hemophilia A

Interventions

Sirolimus; Calcitriol

Condition Hierarchy (Ancestors)

Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals; Dihydroxycholecalciferols; Hydroxycholecalciferols; Cholecalciferol; Cholestenes; Cholestanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Sterols; Vitamin D; Secosteroids; Membrane Lipids; Lipids

Study Officials

• Xuechun Lu, M.D.

  Department of Hematology, the Second Medical Center of PLA General Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Xuechun Lu, M.D.

CONTACT

13241892863; luxuechun@126.com

Jundong ZHANG

CONTACT

15536032300; drzjd123@163.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Director of Hematology Department of the Second Medical Center of PLA General Hospital

Study Record Dates

• First Submitted: June 6, 2023
• First Posted: June 27, 2023
• Study Start: April 1, 2022
• Primary Completion: April 1, 2025
• Study Completion: April 1, 2025
• Last Updated: February 29, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)