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

Hemophilia Clinical Trial

Official title:

PLA General Hospital

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05920512
• Other study ID #: S2023-261-02
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: April 1, 2022
• Est. completion date: April 1, 2025

Study information

• Verified date: February 2024
• Source: Chinese PLA General Hospital
• Contact: Xuechun Lu, M.D.
• Phone: 13241892863
• Email: luxuechun[@]126.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 10
• Est. completion date: April 1, 2025
• Est. primary completion date: April 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 14 Years to 85 Years

Eligibility

Inclusion Criteria:

1. Patients with clinically confirmed severe haemophilia;

2. Expected survival of = 24 weeks with an ECOG score of 0-2;

3. Not having participated in another clinical trial within four weeks;

4. Informed consent signed by the patient or an immediate family member.

Exclusion Criteria:

1. Those with other types of blood disorders diagnosed at the morphological or molecular level of the bone marrow;

2. Significantly abnormal cardiopulmonary function;

3. Hepatic or renal insufficiency;

4. Pregnancy or lactation, or inability to use contraception during the trial and for three months before the test and one year after administration

5. Persons who are allergic to the drugs likely to be used or where there is a contraindication to their use;

6. Those with severe uncontrollable infectious diseases or uncontrolled hypertension, malignancy, etc.;

7. Inability to cooperate with a regular follow-up due to psychological, social, family and other geographical circumstances;

8. Any other condition that, in the investigator's opinion, makes participation in this trial inappropriate.

Related Conditions & MeSH terms

• Hemophilia
• Hemophilia A

Intervention

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

Locations

Country	Name	City	State
China	PLA General Hospital	Beijing

Sponsors (1)

Lead Sponsor	Collaborator
Xue-chun Lu

Country where clinical trial is conducted

China, 

References & Publications (18)

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. — View Citation

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. — View Citation

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. — View Citation

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

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. — View Citation

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. — View Citation

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. — View Citation

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 dec — View Citation

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. — View Citation

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. — View Citation

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 — View Citation

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 — View Citation

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):128-1 — View Citation

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.12 — View Citation

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. — View Citation

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 mela — View Citation

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 — View Citation

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. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	FVIII/FIX Activity	FVIII/FIX activity in peripheral blood	through study completion, an average of 1 month
Primary	FVIII/ FIX inhibitor concentration	FVIII/ FIX inhibitor concentration in peripheral blood	through study completion, an average of 1 month
Secondary	frequency of joint bleeding	Record the number of joint bleeds each month	through study completion, an average of 1 month
Secondary	Activated Partial Thromboplastin Time	activated partial thromboplastin time in peripheral blood	through study completion, an average of 1 month